ANTIDEPRESSANTS

dr.  Dwi  Indria  Anggraini,  MSc.,  SpKK.

Dept.  of  Pharmacology,  Lampung  University
INTRODUCTION
The Nature of Depression
Affective disorders (disorders of mood).

A heterogeneous disorder:
• presenting 1/> core symptoms; often associated with other
psychiatric conditions (anxiety, eating disorders and drug addiction).
2 distinct types of depressive syndrome:
• unipolar depression (mood changes are always in the same
direction)
• bipolar disorder (depression alternates with mania).
INTRODUCTION
Theories of Depression
The Monoamine Theory

• Caused by a functional deficit of the monoamine transmitters, NA, and 5-HT in the brain

Neuroendocrine Mechanisms

• Hypothalamic cells release CRH à secrete ACTH à cortisol secretion.

• The plasma cortisol concentration and CRH concentrations in the brain and CSF of depressed
patients are increased.
• CRH hyperfunction may be associated with depression.

Trophic Effects and Neuroplasticity

• Lowered levels of brain-derived neurotrophic factor (BDNF) or malfunction of its receptor (TrkB)
• Glycogen synthase kinase 3 (GSK3β) has been implicated in the pathogenesis of depression
• Changes in glutamatergic-NT may also be involved in depression à elevated cortical levels of
glutamate.
pathways (e.g. those controlling pituitary hormone release) in depressed patients have also given equivocal results.

Table 47.1
Pharmacological evidence supporting the monoamine hypothesis of depression

Drug(s) Principal action Effect in depressed patients

Tricyclic antidepressants Block noradrenaline and 5-HT reuptake Mood ↑

Monoamine oxidase (MAO) Increase stores of noradrenaline and 5-HT Mood ↑

inhibitors

Reserpine Inhibits noradrenaline and 5-HT storage Mood ↓

α-Methyltyrosine Inhibits noradrenaline synthesis Mood ↓ (calming of manic patients)

Methyldopa Inhibits noradrenaline synthesis Mood ↓

Electroconvulsive therapy ? Increases central nervous system responses to noradrenaline and Mood ↑
5-HT

Tryptophan (5-hydroxytryptophan) Increases 5-HT synthesis Mood ? ↑ in some studies

Tryptophan depletion Decreases brain 5-HT synthesis Induces relapse in SSRI-treated

patients

5-HT, 5-hydroxytryptamine; SSRI, selective serotonin reuptake inhibitor.

The pharmacological evidence does not enable a clear distinction to be drawn between the noradrenaline and 5-HT theories of depression.
Clinically, it seems that inhibitors of noradrenaline reuptake and of 5-HT reuptake are equally effective as antidepressants, although individual
Fig. 47.1. Simplified diagram showing mechanisms believed to be involved in the pathophysiology of depression.
Types of Antidepressant Drug
Monoamine Monoamine
Inhibitors of Melatonin receptor
receptor oxidase inhibitors
monoamine uptake agonists
antagonists (MAOIs)
•Selective serotonin (5-HT) • Mirtazapine, • Irreversible: non- • Agomelatine is an
reuptake inhibitors (SSRIs) à trazodone, mianserin competitive inhibitors agonist at MT 1 and
fluoxetine, fluvoxamine,
paroxetine, sertraline,
à non-selective and à phenelzine, MT 2 melatonin
citalopram, escitalopram, inhibit a range of tranylcypromine; receptors, and a
vilazodone amine receptors non-selective with weak 5-HT 2C
•Classic TCAs à imipramine, including α-2 respect to the MAO- antagonist.
desipramine, amitriptyline, adrenoceptors and A and -B subtypes.
nortriptyline, clomipramine
5-HT2 receptors; also • Reversible: MAO-A-
•Mixed 5-HT and NA-reuptake have weak effects
inhibitors à venlafaxine, selective inhibitors à
desvenlafaxine , duloxetine. on monoamine moclobemide.
•NA-reuptake inhibitors à uptake.
bupropion, reboxetine,
atomoxetine.
•The herb. St John's wort: main
active ingredient is hyperforin:
it has similar clinical efficacy
to most of the prescribed
antidepressants; a weak
monoamine uptake inhibitor
 Table 47.2

Monoamine uptake inhibitors

Types47.2
Table of antidepressant drugs and their characteristics

Types of antidepressant drugs and their characteristics

Type and Action(s) Unwanted effects Risk of overdose Pharmacokinetics Notes
examples
Type and Action(s) Unwanted effects Risk of overdose Pharmacokinetics Notes
examples
Monoamine uptake inhibitors
Monoamine
(1) SSRIs uptake
All inhibitors
highly selective Nausea, diarrhoea, Low risk in overdose but – –
(1) SSRIs for highly
All 5-HT selective Nausea,
agitation,diarrhoea,
insomnia, mustrisk
Low notinbeoverdose
used in but – –
for 5-HT anorgasmia
agitation, insomnia, combination
must with MAO
not be used in
Inhibit metabolism of other
anorgasmia inhibitors
combination with MAO
drugs, metabolism
Inhibit so risk of of other inhibitors
interactions
drugs, so risk of
Fluoxetine As above interactions
As above As above Long t 1/2 (24– –
Fluoxetine As above As above As above 96$h) t 1/2 (24–
Long –

Fluvoxamine As above As above As above 96$h)

t 1/2 18–24$h Less nausea than with other
Fluvoxamine As above As above As above t 1/2 18–24$h SSRIs
Less nausea than with other
Paroxetine As above As above As above t 1/2 18–24$h SSRIs
Withdrawal reaction
Paroxetine As above As above As above t 1/2 18–24$h Withdrawal reaction
Citalopram As above As above As above t 1/2 24–36$h –
Citalopram As above As above As above t 1/2 24–36$h –
Escitalopram As above As above As above t 1/2 24–36$h Active S isomer of
Escitalopram As above As above As above t 1/2 24–36$h citalopram
Active S isomer of
Fewer side effects
citalopram
Vilazodone As above. Also As above As above t 1/2 25$h Fewer
_ side effects
Antidepressant has 5-HT
drugs - ClinicalKey 7/14/16, 6:11 AM
Vilazodone As above. 1A
Also As above As above t 1/2 25$h _
receptor
has 5-HTpartial
1A
agonist activity
receptor partial
Sertraline As above As above As above
https://www.clinicalkey.com/#!/content/book/3-s2.0-B9780702053627000471 t 1/2 24–36$h – Page 5 of 22
Monoamine uptake inhibitors
Sertraline
agonist activity

As above As above As above t 1/2 24–36$h –

(2) Classical Inhibition of NA Sedation Ventricular dysrhythmias – ‘First-generation’

TCA group a and 5-HT reuptake Anticholinergic effects (dry High risk in combination antidepressants, still very
(hl0000430) mouth, constipation, with CNS depressants widely used, although newer
blurred vision, urinary compounds generally have
retention, etc.) fewer side effects and lower
Postural hypotension risk with overdose
Seizures
Impotence
Interaction with CNS
depressants (especially
alcohol, MAO inhibitors)

Imipramine Non-selective As above As above t 1/2 4–18$h –

Converted to
desipramine

Desipramine NA selective As above As above t 1/2 12–24$h –

Amitriptyline Non-selective As above As above t 1/2 12–24$h; Widely used, also for
converted to neuropathic pain ( Ch. 42 )
nortriptyline

Nortriptyline NA selective As above As above Long t 1/2 (24– Long duration, less sedative
(slight) 96$h)

Clomipramine Non-selective As above As above t 1/2 18–24$h Also used for anxiety
disorders

(3) Other 5-HT/NA uptake inhibitors

 the amine transporter ( Ch. 14 ). Most TCAs inhibit noradrenalin

TCAs uptake. It has been suggested that improvement of emotional sym

u Metabolism of imipramine, which is typical of
that of other TCAs.
u The hydroxylating enzyme CYP2D6 is subject
to genetic polymorphism, which may
account for individual variation in response to
TCAs
relief of biological symptoms results from facilitation of noradren
metabolites of TCAs have considerable pharmacological activity
parent drug in respect of their noradrenaline/5-HT selectivity ( T
Inhibition  of  neuronal  noradrenaline  and  5-­
hydroxytryptamine  (5-­HT)  uptake  by  tricyclic  
Table 47.3
antidepressants  and  their  metabolites  
Inhibition of neuronal noradrenaline and 5-hydroxytryptamine (5-HT) upta
Drug/metabolite NA uptake 5-HT uptake

Imipramine +++ ++

Desmethylimipramine (DMI) ++++ +

(also known as desipramine)

Hydroxy-DMI +++ −

Clomipramine (CMI) ++ +++

Desmethyl-CMI +++ +

Amitriptyline (AMI) ++ ++

Nortriptyline (desmethyl-AMI) +++ ++

Hydroxynortriptyline ++ ++

In addition to their effects on amine uptake, most TCAs affect ot

and 5-HT receptors. The antimuscarinic effects of TCAs do not c
 (slight) 96$h)

Monoamine uptake inhibitors

Clomipramine Non-selective As above As above t 1/2 18–24$h Also used for anxiety
disorders

(3) Other 5-HT/NA uptake inhibitors

Venlafaxine Weak non- As SSRIs Safe in overdose Short t 1/2 (∼5$h) Claimed to act more rapidly
selective NA/5-HT Withdrawal effects common Converted to than other antidepressants,
uptake inhibitor and troublesome if doses desvenlafaxine and to work better in
Also non-selective are missed which inhibits NA ‘treatment-resistant’ patients
receptor-blocking uptake Usually classed as non-
effects selective NA/5-HT uptake
blocker, although in vitro
data show selectivity for 5-
HT

Duloxetine Potent non- Fewer side effects than See SSRIs above t 1/2 ∼14$h Also used to treat urinary
selective NA/5-HT venlafaxine incontinence (see Ch. 29 )
uptake inhibitor Sedation, dizziness, and for anxiety disorders
No action on nausea
monoamine Sexual dysfunction
receptors

St John's wort Weak non- Few side effects reported t 1/2 ∼12$h Freely available as crude
(active principle: selective NA/5-HT Risk of drug interactions herbal preparation
hyperforin) uptake inhibitor due to enhanced drug Similar efficacy to other
Also non-selective metabolism (e.g. loss of antidepressants, with fewer
receptor-blocking efficacy of ciclosporin, acute side effects but risk of
effects antidiabetic drugs, etc.) serious drug interactions
 (active principle: selective NA/5-HT Risk of drug interactions herbal preparation

Monoamine uptake inhibitors

hyperforin) uptake inhibitor due to enhanced drug
Also non-selective metabolism (e.g. loss of
Similar efficacy to other
antidepressants, with fewer
receptor-blocking efficacy of ciclosporin, acute side effects but risk of
effects antidiabetic drugs, etc.) serious drug interactions

NA-selective inhibitors

Bupropion Selective inhibitor Headache, dry mouth, Seizures at high doses t 1/2 ∼12$h Used in depression
of NA over 5-HT agitation, insomnia Plasma half-life associated with anxiety
uptake but also ∼20$h Slow-release formulation
inhibits dopamine used to treat nicotine
uptake dependence ( Ch. 49 )
tidepressant drugs - ClinicalKey
Converted to 7/14/16, 6:11 AM
active metabolites
(e.g. radafaxine)

ps://www.clinicalkey.com/#!/content/book/3-s2.0-B9780702053627000471
Maprotiline Selective NA As TCAs; no significant As TCAs Long t 1/2 ∼40$h Page 6 of 22
No significant advantages
uptake inhibitor advantages over TCAs

Reboxetine Selective NA Dizziness Safe in overdose (low risk t 1/2 ∼12$h Less effective than TCAs
uptake inhibitor Insomnia of cardiac dysrhythmia) The related drug
Anticholinergic effects atomoxetine now used
mainly to treat ADHD ( Ch. 48
)

(4) Monoamine receptor antagonists

Mirtazapine Blocks α 2 , 5-HT Dry mouth No serious drug t 1/2 20–40$h Claimed to have faster onset
 uptake inhibitor Insomnia of cardiac dysrhythmia) The related drug

Monoamine receptor antagonists

Anticholinergic effects atomoxetine now used
mainly to treat ADHD ( Ch. 48
)

(4) Monoamine receptor antagonists

Mirtazapine Blocks α 2 , 5-HT Dry mouth No serious drug t 1/2 20–40$h Claimed to have faster onset
Sedation interactions of action than other
2C and 5-HT 3
Weight gain antidepressants
receptors

Trazodone Blocks 5-HT 2A Sedation Safe in overdose t 1/2 6–12$h Nefazodone is similar
and 5-HT 2C Hypotension
Cardiac dysrhythmias
receptors as well
as H 1 receptors
Weak 5-HT uptake
inhibitor
(enhances NA/5-
HT release)

Mianserin Blocks α 1 , α 2 , 5- Milder antimuscarinic and – t 1/2 10–35$h Blood count advised in early
HT 2A and H 1 cardiovascular effects than stages of use
TCAs
receptors
Agranulocytosis, aplastic
anaemia

MAO inhibitors Inhibit MAO-A

 Earlier compounds

MAO inhibitors
have long duration
of action due to
covalent binding to
enzyme

Phenelzine Non-selective ‘Cheese reaction’ to Many interactions (TCAs, t 1/2 1–2$h –

tyramine-containing foods opioids, sympathomimetic Long duration of
(see text) drugs) – risk of severe action due to
Anticholinergic side effects hypertension due to irreversible
Hypotension ‘cheese reaction’ binding
Insomnia
Weight gain
Liver damage (rare)

Tranylcypromine Non-selective As phenelzine As phenelzine t 1/2 1–2$h –

Long duration of
action due to
irreversible
binding

Isocarboxazid Non-selective As phenelzine As phenelzine Long t 1/2 ∼36$h –

Moclobemide MAO-A selective Nausea, insomnia, Interactions less severe t 1/2 1–2$h Safer alternative to earlier
Short acting agitation than with other MAO MAO inhibitors
inhibitors; no ‘cheese
reactions’ reported
 of released transmitter.

2. MAO in the gut wall is important in the inactivation of endogenous and ingested amines such as tyramine that w
MAO Inhibitors
unwanted effects.

Table 47.4
Substrates and inhibitors for type A and type B monoamine oxidase

Type A Type B

Preferred substrates Noradrenaline Phenylethylamine

5-Hydroxytryptamine Benzylamine

Non-specific substrates Dopamine Dopamine

Tyramine Tyramine

Specific inhibitors Clorgyline Selegiline

Moclobemide

Non-specific inhibitors Pargyline Pargyline

Tranylcypromine Tranylcypromine
Isocarboxazid Isocarboxazid

Chemical aspects
 1/2

Moclobemide MAO-A selective Nausea, insomnia, Interactions less severe t 1/2 1–2$h Safer alternative to earlier

Melatonin agonist Short acting agitation than with other MAO

inhibitors; no ‘cheese
MAO inhibitors

reactions’ reported

Melatonin agonist

Agomelatine
epressant MT 1 and MT 2
drugs - ClinicalKey Headache, dizziness, Limited data available at t 1/2 1–2$h Should not be combined
7/14/16, with
6:11 A
receptor agonist. drowsiness, fatigue, sleep present ethanol

Weak 5-HT 2C disturbance, anxiety, Usually taken once daily

antagonist nausea, GI disturbances, before bed
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sweating

5-HT, 5-hydroxytryptamine; ADHD, attention deficit/hyperactivity disorder; CNS, central nervous system; MAO, monoamine oxidase; NA, noradrenaline; SSRI, selective
serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

a Other TCAs include dosulepin, doxepin, lofepramine, trimipramine.

Testing of Antidepressant Drugs

Animal Models
Progress in unravelling the neurochemical mechanisms is, as in so many areas of psychopharmacology, limited by the lack of good animal models
of the clinical condition. There is no known animal condition corresponding to the inherited form of depression in humans, but various procedures
have been described that produce in animals behavioural states (withdrawal from social interaction, loss of appetite, reduced motor activity, etc.)
typical of human depression (see Neumann et$al., 2011 ; O'Leary & Cryan, 2013 ). The use of genetically modified mice (e.g. 5-HT transporter
Selectivity of inhibition
of NA and 5-HT
uptake by various
antidepressants.
Control of 5-hydroxytryptamine (5-HT) release.
References
u Rang HP, Ritter JM, Flower RJ, Henderson G. Antidepressant Drugs. In:
Rang & Dale's Pharmacology. Eighth Edition. 2016, Elsevier Ltd. pp.570-
88.

u Fova M, Papakostas GI. Antidepressants. In: Massachusetts General

Hospital Psychopharmacology and Neurotherapeutics. 2016, Elsevier
Inc. pp.27-43.

u Aronson JK. Antidepressants. In: Meyler’s Side Effects of Psychiatric

Drugs. 2009, Elsevier B.V.