Hudan Taufiq Prodi Farmasi FK Unissula

(1)

Hudan Taufiq

(2)



Survey di AS dan UK: 20 % populasi memiliki sejarah

gangguan depresi dalam hidupnya



Kejadian depresi pada wanita lebih sering dibandingkan

pria (5:2)



Bisa terjadi pada setiap umur, tetapi paling banyak terjadi

pada usia 25-44 tahun



pasien depresi juga beresiko terhadap terjadinya

alcoholism, penyalah-gunaan obat, kejadian bunuh diri,

gangguan kecemasan, dll.



Ada kecenderungan hubungan famili dengan kejadian

depresi



_{8-18% pasien depresi memiliki sedikitnya satu}

keluarga dekat (ayah, ibu, kakak atau adik) yang memiliki

sejarah depresi

(3)



Depression is a common mental disorder

that presents with depressed mood, loss of

interest or pleasure, feelings of guilt or low

self-worth, disturbed sleep or appetite, low

energy, and poor concentration.

(4)



Etiologinya sangat kompleks



banyak faktor

dapat terjadi bersama menyebabkan gangguan

depresi



Pasien depresi menunjukkan adanya perubahan

neurotransmitter otak antara lain : norepinefrin,

serotonin, dopamine



Pada pasien dengan “bakat” depresi : kemampuan

menerima musibah (kematian, kehilangan kerja,

sakit, kehilangan fungsi pada usia produktif) lebih

kecil dibanding orang normal



_depresi

(5)

(6)

(7)



Depresi



sembuh dalam 3 bulan,



jika tidak



bisa sampai 6-12 bulan



Walaupun menggunakan obat



20-35% pasien

mengalami gejala residual dan gangguan fungsi

sosial

(8)



Untuk menegakkan diagnosis depresi, perlu

dilakukan pemeriksaan mengenai kemungkinan

penyebab yang berasal dari masalah medis,

psikiatrik, atau disebabkan karena obat/alcohol



Rasa tertekan/sedih karena kehilangan/kematian

orang yang dicintai pada orang normal akan

sembuh dengan sendirinya



sedangkan jika gejala

tetap bertahan sampai 2 bulan dan diikuti keinginan

bunuh diri, kemunduran psikomotor, kegagalan

fungsional, perasaan tidak berguna dan gejala

psikotik



maka mengarah pada penyakit

(9)



Diagnosa depresi ditegakkan jika :



_{Terdapat sedikitnya 5 gejala yang terjadi dalam waktu}

2 minggu



_{Gejala-gejala tsb menyebabkan rasa tertekan yang}

signifikan atau menyebabkan gangguan fungsi sosial,

okupasional, atau fungsi lainnya



_{Gejala bukan disebabkan karena adanya kondisi}

(10)



Gangguan depresi ditandai oleh satu/lebihmajor

depressive episode



Satu major depressive episode ditandai oleh 5 atau

lebih gejala, antara lain:



_{perasaan tertekan/depresi sepanjang hari, hampir setiap}

hari



_{kehilangan interes atau kesenangan terhadap hampir}

semua aktivitas



_{berkurangnya berat badan secara signifikan, atau}

bertambah BB, dengan penurunan atau kenaikan nafsu

makan hampir setiap hari

(11)



_{insomnia atau hipersomnia hampir setiap hari}



_{kemunduran psikomotor}



_{kelelahan atau kehilangan energi}



_{perasaan tidak berguna atau perasaan bersalah yang}

berlebihan atau tidak semestinya



tidak bisa konsentrasi berpikir, daya ingat menurun



_{secara berulang berpikir tentang ingin mati atau}

(12)



Kumpulan gejala depresi adalah



_{gangguan vegetatif (tidur, nafsu makan, berat badan}

dan dorongan seksual);



_{gambaran kognitif, (perhatian, toleransi terhadap}

frustrasi, memori, distorsi negatif);



_{kontrol impuls (pembunuhan, bunuh diri);}



gambaran perilaku, (motivasi, perasaan senang,

minat, kelelahan)



_{gambaran fisik (somatik) misalnya nyeri kepala, nyeri}

(13)



Major depressive disorder, single episode



Major depressive disorder, recurrent



Dysthymic disorder



gejala lebih sedikit, tapi

kronis, dg gejala terjadi hampir pada sepanjang

waktu sedikitnya 2 tahun



Depressive disorder not otherwise specified



Subklasifikasi lain berdasarkan gejala:



_melankolis



_{lebih berat, kadang tanpa pemicu dari}

lingkungan



_atipikal



_{BB naik, hipersomnia}



_psikotik



_{tjd halusinasi, delusi}

(14)



Depresi kronis



termasuk berat, terjadi

sepanjang waktu, responsive terhadap obat



Depresi musiman (seasonal)



timbul pada

saat/musim tertentu (puncak di musim dingin,

sembuh di musim semi atau panas)



Depresi post partum



onset terjadi dalam

jangka waktu 1 bulan setelah melahirkan



bisa

ringan(blue baby syndrome) atau

(15)



Sasaran : perubahan biologis/efek berupa mood

pasien



Karena mood pasien dipengaruhi kadar

serotonin dan nor-epinefrin di otak



_sasarannya

adalah modulasi serotonin dan norepinefrin otak

dengan agen-agen yang sesuai



Tujuan : menurunkan gejala depresi dan

memfasilitasi pasien untuk kembali ke kondisi

normal.



Strategi : menggunakan terapi nir-obat dan atau

obat anti depresan yang dapat memodulasi kadar

serotonin dan nor-epinefrin di otak

(16)



PSIKOTERAPI



interpersonal dancognitive –

behavioral therapy



_{Terapi interpersonal}



_{berfokus pada konteks sosial}

depresi dan hub pasien dengan orang lain



_{Terapi kognitif-behavioral}



_{berfokus pada mengoreksi}

pikiran negatif, perasaan bersalah yang tidak rasional dan

rasa pesimis pasien



intervensi psikoterapi sama efektifnya dengan obat

antidepresan, tidak ada efek samping, murah



(17)



ELECTROCONVULSIVE THERAPY (ECT)



_{aman dan efektif, namun masih kontroversial}



_{Adverse effect : disfungsi kognitif, disfungsi}

kardiovaskuler, dll.



_{ECT diindikasikan pada :}

▪ _{Depresi yang berat diperlukan respons yang cepat,} ▪ _{treatment lain lebih besar resiko drpd manfaatnya,} ▪ respon terhadap obat jelek, dan

(18)

(19)

(20)



Pada penggunaan obat antidepresi, sulit diprediksi

sebelumnya mana yang akan paling efektif



karena itu, pilihan awal dilakukan secara empiris



Bbrp faktor yg mempengaruhi pemilihan obat anti

depresan antara lain:



_{riwayat respons pasien terhadap obat}



_{farmakogenetik (riwayat respons keluarga thd obat)}



_{jenis depresi}



_{kemungkinan interaksi obat}



_{profil adverse event obat}



_{Harga obat}

(21)

(22)

Available Antidepressants

• 1) Tricyclics and Tetracyclics (TCA)

Imipramine Doxepin Desipramine Amoxepine Trimipramine

Maprotiline Clomipramine Amitriptyline Nortriptyline Protriptyline

• 2) Monoamine Oxidase Inhibitors (MAOIs)

Tranylcypramine Phenelzine Moclobemide

• 3) Serotonin Selective Reuptake Inhibitors (SSRIs) Fluoxetine

Fluvoxamine

Sertraline Paroxetine Citalopram

• 4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)

Venlafaxine Duloxetine

• 5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)

Nefazodone Trazodone

• 6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)

Bupropion

• 7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)

Mirtazapine

• 8) Noradrenalin Specific Reuptake Inhibitor (NRI)

Reboxetine

• 9) Serotonin Reuptake Enhancer

(23)



Contoh : amitriptilin, klomipramin, imipramin,

nortriptilin



ATS terbukti efektif dalam mengatasi semua tipe

depresi, terutama gangguan depresi jenis

melankolis yang berat



Semua ATS mempotensiasi aktivitas NE dan 5-HT

dengan cara memblok re-uptakenya



ATS juga mempengaruhi system reseptor lain,

maka selama terapi dengan ATS sering dilaporkan

adanya efek samping pada sistim kolinergik,

neurologik dan kardiovaskuler



efek samping

umum : antikolinergik dan hipotensi orthostatik

(24)

(25)

Reuptake of NE

Monoamine oxidase, located on outer membrane of mitochondria; deaminates catecholamines free in nerve terminal that are not protected by vesicles

Selective inhibitor,

reboxetine _{Cocaine blocks the NET}

Antidepressant

MAO Inhibitors

(26)

(27)

Re-uptake of 5-HT/serotonin

Fluoxetine/Prozac blocks the SERT

Treatment of depression. anxiety disorders,

(28)

(29)

29

1. Depression: that is unresponsive to more commonly

used antidepressants )SSRIs or SNRIs)

2. Panic disorder

3. Control bed-wetting in children (older than 6 years) by

causing contraction of the internal sphincter of the bladder (Imipramine)1

4. Treatment of migraine headache and chronic pain

syndromes for which the cause of the pain is unclear (Amitriptyline)

(30)

30

1. Antimuscarinic SEs: dry mouth ,constipation, urinary

retention, blurred vision, and confusion

2. Life-threatening arrhythmias: The TCAs are class 1A

antiarrhythmic agents

3. Sedation (H₁ antagonism)

4.

weight gain

5.

Sexual dysfunction

6. At therapeutic doses, the TCA drugs lower the seizure

threshold and at toxic doses can cause life-threatening seizures (especially Maprotiline)

7. Amoxapine has dopamine receptor antagonist

properties and can induce EPS, gynecomastia, lactation, and neuroleptic malignant syndrome

(31)

31



Acute poisoning with tricyclic antidepressants or

MAO inhibitors is potentially life-threatening



Compared with TCAs and MAOIs, the other

(32)

32



A 1500 mg dose of imipramine or amitriptyline is

enough to be lethal in many patients



Symptoms: ventricular tachycardia, fibrillation and

seizures are sometimes seen



Management: cardiac monitoring, airway support,

and gastric lavage. Sodium bicarbonate is often

administered to uncouple the TCA from cardiac

sodium channels

(33)

33



If a patient is severely depressed, potentially

suicidal, impulsive, or has a history of substance

abuse, prescribing a relatively safe antidepressant

agent with close clinical follow-up is appropriate

(34)



contoh : fluoksetin, fluvoksamin, paroksetin dan

sertralin



SSRI memiliki spektrum luas (sama seperti ATS)



Efikasinya setara dengan ATS



pasien yg gagal

dengan ATS mungkin akan berespon baik terhadap

SSRI atau sebaliknya



Memunculkan dugaan : ada perbedaan populasi

pasien depresi berdasar patofisiologinya

(NE-mediated vs5-HT-(NE-mediated)



Efek samping sedative, antikolinergik,

kardiovaskuler



tidak ada

(35)

(36)

36

SSRIs

• Stimulation of 5-HT₃ receptors is suspected to contribute to common ADRs, including GIT (NV) and sexual effects (delayed or impaired orgasm) • Stimulation of 5-HT_2C receptors may contribute to

the agitation or restlessness sometimes induced by serotonin reuptake inhibitors

(37)

37

SSRIs-

Clinical uses

1. Major Depression: the primary indication

Obsessive-compulsive disorder (OCD)

(fluvoxamine, clomipramine) 2. Panic disorder

3. Generalized anxiety disorder

4. Posttraumatic stress disorder (Sertraline and paroxetine)

5. Social anxiety disorder (SAD): fluvoxamine, venlafaxine

6. Premenstrual dysphoric disorder (fluxetine & sertraline)

7. Bulimia nervosa (only fluoxetine) 8. Premature ejaculation

(38)

38

SSRIs-

ADEs

1) GIT: nausea, GIT upset, diarrhea.

2) Sexual dysfunction: loss of libido, delayed orgasm, or diminished arousal.

3) CNS: Sleep disturbances. For this reason,

fluoxetine is usually administered in the morning after breakfast

4) Weight gain particularly paroxetine

5) SSRIs have also been associated with

extrapyramidal side effects, especially those with Parkinson’s disease

6) There is an association of paroxetine with cardiac

(39)

39

SSRIs-

D/D interactions

A. Pharmacokinetic interactions:

• The SSRIs are potent inhibitors of the CYP450 • The potential for drug-drug interactions differs

significantly across the SSRIs

• Paroxetine and fluoxetine are potent CYP2D6 inhibitors responsible for the elimination of TCA drugs, neuroleptic drugs, and some antiarrhythmic and β-adrenergic antagonist drugs

(40)

40

SSRIs-

D/D interactions

A. Pharmacokinetic interactions:

• Fluvoxamine, a CYP3A4 inhibitor, may elevate the levels of concurrently administered substrates for this enzyme such as diltiazem and induce bradycardia or hypotension

• Citalopram and escitalopram have the least effect on the cytochrome P450 system & have the most favorable profile regarding D–D interactions

(41)

41

SSRIs-

D/D interactions

B. Pharmacodynamic interactions:

• The most serious interaction with the SSRIs are with MAOIs that produce a serotonin syndrome

• Fluoxetine* has to be discontinued 4 to 6 weeks before an MAOI can be administered to mitigate the risk of serotonin syndrome

* Fluoxetine is metabolized to an active product, norfluoxetine. The elimination half-life of norfluoxetine is about three times longer than fluoxetine and contributes to the longest half-life of all the SSRIs

(42)

 Contoh : venlafaksin, trazodon, bupropion



Contoh: fenelzin, moklobemid (di Ind),

tranilsipromin



MAO inhibitors memiliki spektrum aktivitas yang

berbeda dengan ATS



_{lebih bnyk digunakan}

untuk depresi atypical (dgn tanda-tanda: mood

reactivity, irritability, hypersomnia, hyperphagia, dll)



Keterbatasan penggunaan MAOI : banyak interaksi

dengan obat dan makanan (keju, daging, MSG,

kecap, coklat, apokat, dll (yang kaya akan tiramin)

(43)

(44)

44

SNRIs-

Clinical uses

1. Depression: in patients in whom SSRIs are ineffective

2. chronic joint and muscle pain: duloxetine 3. Fibromyalgia: milnacipran

4. Urinary stress incontinence (duloxetine in Europe)

• Off-label uses include autism, binge eating disorders, hot

flashes (desvenlafaxine), pain syndromes, premenstrual dysphoric disorders, and post-traumatic stress disorders (venlafaxine)

(45)

45

I. SNRIs- ADRs

• SNRIs have many of the serotonergic adverse effects associated with SSRIs

• In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation

• All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation

• The SNRIs have relatively fewer CYP450 interactions than the SSRIs

(46)

46

MAO inhibitors

• Agents:

selegline,

phenelzine,

and

tranylcypromine

• MAO exists in the human body in two

molecular forms, known as type A and type B

• Norepinephrine

and

serotonin

are

preferentially metabolized by MAO-A. MAO-B

is more likely to be involved in the catabolism

of human brain dopamine

(47)

47

MAO inhibitors

• The MAO inhibitors inactivate the enzyme,

permitting neurotransmitter molecules to

escape degradation and, therefore, to both

accumulate within the presynaptic neuron

and leak into the synaptic space

• Selective MAO-A inhibitors are more

effective in treating major depression than

type B inhibitors

(48)

(49)

49

MAO inhibitors

• MAOIs are classified by their specificity for MAO-A or -B and whether their effects are reversible or irreversible

• Phenelzine and tranylcypromine are examples of irreversible, nonselective MAOIs

• Moclobemide is a reversible and selective inhibitor of MAO-A

• Selegiline is an irreversible MAO-B–specific agent at low doses, but at higher doses it becomes a nonselective MAOI similar to other agents

(50)

50

MAO inhibitors

• Despite their efficacy in treating depression,

because of their risk for drug and

drug-food interactions, the MAO inhibitors are

considered to be last-line agents in many

treatment venues

(51)

51

MAO Inhibitors-

Clinical use

• Depression:

–

Reserved for treatment of depressions that

resist therapeutic trials of the newer, safer

antidepressants

–

Selegiline is the first antidepressant available

in a transdermal delivery system

(52)

52

MAO Inhibitors-

ADRs

• Orthostatic hypotension, weight gain, edema, and sexual dysfunction are common during MAOI therapy

• Sexual SEs: highest rates are associated with the irreversible nonselective MAOIs (phenelzine and tranylcypromine)

• Phenelzine tends to be more sedating than either selegiline or tranylcypromine

• Hepatotoxicity is likely to occur with isocarboxazid or phenelzine

(53)

53

MAO Inhibitors-

D-D interactions

1) Pharmacodynamic interaction

• These combinations of an MAOI with a serotonergic agent (SSRIs, SNRIs, and most TCAs) may result in a life-threatening serotonin syndrome

• Most case reports of serotonin syndrome (and most fatalities) have occurred with a combination of an MAOI and an SSRI

• It is caused by overstimulation of 5-HT receptors in the central gray nuclei and the medulla

(54)

54

MAO Inhibitors-

D-D interactions

1) Pharmacodynamic interaction

• Serotonin syndrome consists of a constellation of psychiatric, neurological, and CV symptoms

• Symptoms range from mild to lethal and include a triad of cognitive (delirium, coma), autonomic (hypertension, tachycardia, diaphoreses) and somatic (myoclonus, hyperreflexia, tremor) effects

(55)

55

MAO Inhibitors-

D-D interactions

• Most serotonergic antidepressants should be discontinued at least 2 weeks before starting a MAOI

• Fluoxetine, because of its long half-life, should be discontinued for 4–5 weeks before an MAOI is initiated

(56)

56

MAO Inhibitors-

D-D interactions

• Serious interaction with MAOIs occurs when an MAOI is combined with tyramine in the diet (e.g. smoked, aged, or pickled meat or fish, aged cheeses, etc)

• MAOIs prevent the breakdown of tyramine in the gut resulting in high serum levels that enhance peripheral noradrenergic effects, including raising BP dramatically (Hypertensive crisis)

• Can be minimized with a low-tyramine diet that begins several days before starting the MAOI & continues for 3-4 weeks after stopping the MAOI

(57)

57

(58)

58

MAO Inhibitors-

D-D interactions

• Serious hypertension can occur with concomitant administration of OTC cough and cold medications containing sympathomimetic amines (pseudoephedrine and phenylpropanolamine)-

(59)

59

5-HT

₂

antagonists

• Agents: Nefazodone, Trazodone, mirtazapine and mianserin (not marketed in the U.S.)

• Inhibition of 5-HT_2A receptors in both animal and human studies is associated with substantial antianxiety, antipsychotic, and antidepressant effects

• Nefazodone is a weak inhibitor of both SERT and NET, whereas trazodone is also a weak but selective inhibitor of SERT

(60)

60

5-HT

₂

antagonists

• Trazodone’s primary metabolite, m-cpp, is a potent 5-HT_2A antagonist, and much of trazodone's benefits as an antidepressant might be attributed to this effect

• Trazodone also has weak-to-moderate presynaptic α-adrenergic–blocking properties and is a modest antagonist of the H1 receptor

(61)

61

5-HT2 antagonists

• Mirtazapine has a complex pharmacology:

1) It is an antagonist of 5-HT₂ and 5-HT₃ receptors

2) By blocking presynaptic α₂-adrenoceptors and enhances the release of both norepinephrine and 5-HT

• Mirtazapine is a potent H1 antagonist, which is associated with the drug's sedative effects

(62)

62

5-HT2 antagonists-

Clinical uses

• Depression:

Mirtazapine can be advantagous

in patients with depression having sleep

difficulties

• Low doses of trazodone (50-100 mg) have

been used widely both alone and concurrently

with SSRIs or SNRIs to treat insomnia

(63)

63

I.5-HT

₂

antagonists-

ADRs

1) Sedation (trazodone & mirtazapine): probably because of their potent H₁-blocking activity. Sedation necessitates dosing at bedtime

2) Dose-related GIT SEs

3) Priapism: uncommon but serious side effect requiring surgical intervention in one-third of the cases reported

4) weight gain (mirtazapine)

5) Nefazodone has been associated with hepatotoxicity, including rare fatalities and cases of hepatic failure requiring transplantation

(64)

64

II. Bupropion

• It acts as a weak dopamine and norepinephrine reuptake inhibitor to alleviate the symptoms of depression

• Bupropion has virtually no direct effects on the serotonin system

• Unlike the SSRIs, bupropion does not cause sexual side effects

• It does not block muscarinic, histaminergic, or adrenergic receptors

(65)

65

Bupropion-

Clinical uses

1)

Depression

2)

Bupropion is approved as a treatment for

smoking cessation

• The mechanism by which bupropion is helpful in this application is unknown, but the drug may mimic nicotine's effects on dopamine and norepinephrine and may antagonize nicotinic receptors

(66)

66

Bupropion & Mirtazapine-

SEs

• Bupropion

is occasionally associated with

CNS stimulations (agitation, insomnia, and

anorexia)

(67)

67

Bupropion-

D/D interactions

• Bupropion

is

metabolized

primarily

by

CYP2B6, and its metabolism may be altered

by drugs such as cyclophosphamide

(68)

Block of Amine Pump for:

Drug

Sedation Anti-muscarinic Serotonin Norepinephrine Dopamine

Amitriptyline +++ +++ +++ ++ 0 Amoxapine ++ ++ + ++ + Bupropion 0 0 +, 0 +, 0 ? Citalopram 0 0 +++ 0 0 Clomipramine +++ ++ +++ +++ 0 Desipramine + + 0 +++ 0 Doxepin (Sinequan) +++ +++ ++ + 0 Fluoxetine (Prozac) + + +++ 0, + 0, + Fluvoxamine (Luvox) 0 0 +++ 0 0 Imipramine (Tofranil) ++ ++ +++ ++ 0 Maprotiline ++ ++ 0 +++ 0 Mirtazapine2 ₊₊₊ ₀ ₀ ₀ ₀ Nefazodone ++ +++ +, 0 0 0 Nortriptyline ++ ++ +++ ++ 0 Paroxetine (Seroxat) + 0 +++ 0 0 Protriptyline 0 ++ ? +++ ? Sertraline (Zoloft) + 0 +++ 0 0 Trazodone (Mesyrel) +++ 0 ++ 0 0 Venlafaxine (Efexor) 0 0 +++ ++ 0, +

(69)

Drug

Amitriptyline +++ +++ +++ ++ 0 Amoxapine ++ ++ + ++ + Bupropion 0 0 +, 0 +, 0 ? Citalopram 0 0 +++ 0 0 Clomipramine +++ ++ +++ +++ 0 Desipramine + + 0 +++ 0 Doxepin (Sinequan) +++ +++ ++ + 0 Fluoxetine + + +++ 0, + 0, + Fluvoxamine 0 0 +++ 0 0 Imipramine (Tofranil) ++ ++ +++ ++ 0 Maprotiline ++ ++ 0 +++ 0 Mirtazapine2 ₊₊₊ ₀ ₀ ₀ ₀ Nefazodone ++ +++ +, 0 0 0 Nortriptyline ++ ++ +++ ++ 0 Paroxetine + 0 +++ 0 0 Protriptyline 0 ++ ? +++ ? Sertraline + 0 +++ 0 0 Trazodone (Mesyrel) +++ 0 ++ 0 0 Venlafaxine 0 0 +++ ++ 0, +

(70)

Drug

Amitriptyline +++ +++ +++ ++ 0 Amoxapine ++ ++ + ++ + Bupropion 0 0 +, 0 +, 0 ? Citalopram 0 0 +++ 0 0 Clomipramine +++ ++ +++ +++ 0 Desipramine + + 0 +++ 0 Doxepin (Sinequan) +++ +++ ++ + 0 Fluoxetine + + +++ 0, + 0, + Fluvoxamine 0 0 +++ 0 0 Imipramine (Tofranil) ++ ++ +++ ++ 0 Maprotiline ++ ++ 0 +++ 0 Mirtazapine2 ₊₊₊ ₀ ₀ ₀ ₀ Nefazodone ++ +++ +, 0 0 0 Nortriptyline ++ ++ +++ ++ 0 Paroxetine + 0 +++ 0 0 Protriptyline 0 ++ ? +++ ? Sertraline + 0 +++ 0 0 Trazodone (Mesyrel) +++ 0 ++ 0 0 Venlafaxine (Efexor) 0 0 +++ ++ 0, +

(71)

Drug

Amitriptyline +++ +++ +++ ++ 0 Amoxapine ++ ++ + ++ + Bupropion 0 0 +, 0 +, 0 ? Citalopram 0 0 +++ 0 0 Clomipramine +++ ++ +++ +++ 0 Desipramine + + 0 +++ 0 Doxepin (Sinequan) +++ +++ ++ + 0 Fluoxetine (Prozac) + + +++ 0, + 0, + Fluvoxamine (Luvox) 0 0 +++ 0 0 Imipramine (Tofranil) ++ ++ +++ ++ 0 Maprotiline ++ ++ 0 +++ 0 Mirtazapine2 ₊₊₊ ₀ ₀ ₀ ₀ Nefazodone ++ +++ +, 0 0 0 Nortriptyline ++ ++ +++ ++ 0 Paroxetine (Seroxat) + 0 +++ 0 0 Protriptyline 0 ++ ? +++ ? Sertraline (Zoloft) + 0 +++ 0 0 Trazodone (Mesyrel) +++ 0 ++ 0 0 Venlafaxine (Efexor) 0 0 +++ ++ 0, +

(72)

(73)

(74)

(75)



SSRI lebih sering digunakan sebagai pilihan pertama

karena efek sampingnya yang lebih rendah daripada TCA



Penggunaan TCA (desipramin dan nortriptilin) juga bisa

dilakukan karena range kadar plasma, efikasi dan profile

ADRnya sudah diketahui, tetapi harus diberikan dengan

hati-hati



Trazodon, nefazodon, dan bupropion juga dapat dipilih

karena efek samping anti kolinergik dan efek

kardiovaskulernya relatif rendah



Dosis inisial pada pasien geriatri sebaiknya setengah dari

dosis inisial untuk dewasa, dan kemudian bisa

ditingkatkan pelan-pelan

(76)



Data yang mendukung penggunaan SSRI

maupun TCA pada anak-anak masih sangat

sedikit, tetapi SSRI nampaknya lebih bisa

ditoleransi dan lebih aman



Perlu dilakukan pemeriksaan ECG sebelum

(77)



Secara umum, lebih baik digunakan terapi non-obat



Tetapi jika diperlukan obat, harus dipertimbangkan

risiko dan manfaat



Beberapa studi melaporkan bahwa : untreated

depression during pregnancy appears to carry

substantial perinatal risks, which include suicidal

ideation; increased risk for miscarriages,

hypertension, preeclampsia, and lower birth weight;

and, importantly, an increased risk for postpartum

depression



_{perlu diatasi}

(78)

 SSRIs merupakan obat antidepresan yang paling banyak dipakai

wanita _{ada bukti bahwa ia bekerja lebih efektif pada wanita}

 Laporan menunjukkan tidak ada gangguan pada janin jika digunakan

pada kehamilan

 Beberapa SSRI yang banyak dipakai pada kehamilan: fluoxetine

(Prozac), sertraline (Zoloft), and paroxetine (Paxil).

 Fluoxetine : paling banyak diteliti pemakaiannya pada kehamilan 

tidak ada efek negatif terhadap janin maupun perkembangan selanjutnya

 Sertralin, paroxetin dan citalopram juga telah diteliti  aman bagi

kehamilan

 Dari golongan TCA : Nortriptilin atau desipramin bisa dipilih karena

sudah banyak data tentang obat ini dan kadar terapetik plasmanya sudah diketahui dgn baik.

 Jika penggunaan TCA akan dihentikan, harus dikurangi dosisnya

secara perlahan untuk mencegah gejala putus obat. Jika mungkin

(79)



Jika respon tidak tercapai dalam waktu 6 – 8 minggu

terapi, maka ganti dengan antidepresan lain dg golongan

sama, jika belum berhasil, diganti ke antidepresan

golongan yang lain



Evidence: > 50% pasien yang gagal terhadap sertralin,

memberikan respon baik terhadap fluoksetin(J Clin

Psychiatry. 1997 Jan;58(1):16-21.)



Evidence: diperoleh manfaat positif untuk mengganti

(switch) obat dari SSRI ke TCA atau sebaliknya pada

pasien yang mengalami depresi kronik dan resisten

terhadap antidepresan, misalnya switching antara sertralin

dengan imipramin(Arch Gen Psychiatry. 2002

(80)



Untuk respon yang parsial, American Psychiatric

Association menyarankan penambahan antidepressant

dengan klas terapi lain, seperti : lithium, thyroid

supplementation, atypical antipsychotics, dan dopamine

agonists.



Symbyax : contoh kombinasi olanzapine-fluoxetine

(Zyprexa-Prozac) telah disetujui di US untuk mengatasi

depresi bipolar



Strategi kombinasi meliputi penggunaan 2 atau lebih anti

depresan dari golongan yang berbeda dengan sasaran

satu atau lebih neurotransmiter dengan tujuan mencapai

hasil yang lebih menguntungkan

(81)



Sebuah penelitian menunjukkan bahwa pasien yang

mendapat terapi dengan nefazadone (Serzone) plus

suatu bentuk short-term psychotherapy yang

disebut Cognitive Behavioral Analysis System of

Psychotherapy (CBASP) memberikan hasil terapi

yang lebih baik secara signifikan (85 % response, 42

% remission) dibandingkan dengan pasien yang

mendapat terapi dengan Serzone saja (55 %

response, 22 % remission) atau CBASP saja (52 %

response, 24 % remission).N Engl J Med. 2000

(82)

 Sebuah studi meta-analysis terhadap percobaan pada 31

placebo controlled antidepressant menjumpai bahwa

penggunaan antidepresan secara berkelanjutan mengurangi resiko kambuh sebesar 70 %. (Lancet. 2003 Feb

22;361(9358):653-61.)

 The American Psychiatric Association menyarankan untuk

terapi lanjutan selama 4-5 bulan setelah hilangnya gejala.

 Untuk pasien yang punya riwayat depresi kambuhan, the

British Association for Psychopharmacology's 2000 Evidence Based Guidelines for Treating Depressive Disorders with

Antidepressants menyarankan untuk tetap meneruskan terapi antidepresan sedikitnya 6 bulan sampai lima tahun, atau tidak terbatas (seumur hidup).

(83)



Fase akut : 6 – 8 minggu pada dosis terapi penuh dengan

tujuan mengurangi dan menghilangkan gejala



Fase lanjutan(continuation): terapi selama 4-9 bulan

berikutnya pada dosis terapi penuh dengan tujuan

mencegah kekambuhan dan kembalinya gejala depresi



Fase pemeliharaan :

 untuk pasien dg riwayat 3 atau lebih episode depresi 

pelihara terapi pada dosis penuh selama 1-2 tahun berikutnya

 _{Untuk pasien dengan riwayat 2 atau lebih episode dalam 5}

(84)



Hilangnya gejala depresi, perbaikan fungsi sosial

dan okupasional



Adverse reaction, spt: sedasi, efek antikolinergik,

disfungsi seksual



Pasien di atas 40 th sebaiknya diperiksa ECG

sebelum memulai terapi TCA, dan ECG dapat

dilakukan secara periodik selama terapi



Pantau masih/tidaknya ide untuk bunuh diri

