other agents, the MAO inhibitors exert undesirable pharmacodynamic interactions

with all other antidepressants, especially with TCAs and SSRIs, including the high

risk for serotonin syndrome with mirtazapine, reboxetine, venlafaxine, and

tianeptine. Mirtazapine and mianserine are relatively safe alpha-2-adrenoreceptor

antagonists in the elderly. Both are well tolerated by patients with cardiovascular

disease, their use results in weak weight gain and sedation, but they neither have

influence on the CYP 450 coenzyme system nor is their metabolism affected by

majority of other drugs.

Finally, the mixed group of antidepressant drugs include agomelatine and

tianeptine. Both are relatively newly approved substances with less clinical experi-

ence compared to the members of aforementioned groups. Agomelatine is a

melatonergic analogue acting as MT1/MT2 agonist and 5-HT2C antagonist. It is

90% metabolized by CYP4501A2 coenzyme and should be used carefully together

with CYP4501A2 strong inhibitors (e.g., celecoxib) because serum levels of

agomelatine may rise (He et al. 2018). Tianeptine is a mu-opioid receptor agonist

(MOR) that elicits its effects via modulation of glutaminergic pathway (Samuels

et al. 2017). This compound has demonstrated efficacy in patients resistant to SSRI

therapy and avoids some negative side effects (e.g., sexual dysfunction) seen with

SSRIs. Its therapeutic safety in the elderly has been affirmed by some investigators.

The main PK and PD parameters of the frequently used antidepressants are

summarized in Table 15.1. Clinical and pharmacological data, including PK details

of few novel antidepressants were recently reported by Faquih et al. (2019). Due to

the scarcity of population-based data, these new compounds were not included in the

tables.

Age-associated metabolic changes in the PK and PD characteristics of psychotro-

pic medications cause increased prevalence of iatrogenic effects or unwanted ADRs.

Much pronounced biochemical and pathophysiological changes have been observed

in the CNS of older persons regarding neuro-hormones and neurotransmitters:

Table 15.1 Basic reference data of frequently used antidepressant drugs obtained from young

healthy volunteers (data source: Drug Product Monographs)

Ingredient

Usual maintenance dose

Terminal HL

Eliminaon

Main metabolic pathway Its inhibitory effect Need for age-dependent

(mg/day)

(hours)

(organ, %)

(CYP isoenzyme)

on CYP enzyme

dose adjustment

amitriptyline

100-250

25

kidney

2D6, 2C19, 3A4

2C19, 1A2,(2D6)

dose reducon recomm.

imipramine

150-200

9-28

kidney 80%, liver 20%

2D6,

2C19, 1A2, (2D6)

careful dose escalaon

desipramine

100-250

7-60

kidney 80%, liver 20%

2D6, 1A2, 3A4, 2C

(2D6, 2C19)

nortriptyline

100-150

25

kidney

2D6

(2D6, 2C19)

dose reducon recomm.

doxepin

150-200

6-24

kidney

2D6

2D6, 2C19

fluoxene

5-40

96-144

kidney, 60%

2D6

2D6, 2C19, 2C9,(3A4)

0

paroxene

20-30

24

liver 46%

2D6

2D6, (1A2, 2C9,2C19)

0

sertraline

50-150

26

kidney 40%, liver 40%

3A4, 2C19

2C19, (1A2, 2D6,3A4)

0

citalipram

20-40

36

hepac 85%, kidney 15%

2C19, 3A4, 2D6

(1A2)

dose reducon recomm.

escitalopram

10-20

30

kidney

2C19, 3A4, 2D6

2D6

dose reducon recomm.

venlafaxine

150-225

5

kidney, 87%

(2D6)

(2D6)

0

duloxene

40-120

8-17

kidney

1A2, 2D6

2D6

0

mirtazepine

15-45

20-40

kidney 75%, liver15%

2D6, 1A2, 3A4

(2D6)

0

reboxene

8-12

13

kidney 78%

3A4

0

0

agomelane

25-50

1-2

kidney, 80%

1A2, (2C9, 2C19)

(1A2)

0

anepne

25 - 37,5

3

kidney

non-CYP

0

dose reducon recomm.

1A2 strong effect, 2D6 medium effect, (1A2) weak effect, 0 no effect/not required

248

M. Bhaskar et al.