including acetylcholine, dopamine, serotonin, melatonin, and kynurenine. The defi-

ciency of these neurotransmitters is associated with depression, dementia and cogni-

tion decline, insomnia, and disturbance in circadian rhythms affecting the sleep and

wake-fullness cycles (Moore and O'Keeffe 1999; Nayak et al. 2019). Serotonin is

responsible for the modulation of some developmental events, such as neuron

migration, cell differentiation, cell division, or synaptogenesis. Serotonin is also

involved in the control of appetite, sleep, memory and learning, temperature regula-

tion, mood, behavior (including sexual function), cognition or mental disorders

among others (Nayak et al. 2019). Additionally, there are reports indicating changes

in the blood-brain barrier (BBB) among aged people, especially with neurological

disorders (Alzheimer’s disease, Parkinson’s disease) which influence the traversing

of drugs from plasma through BBB and reaching CNS. The BBB changes are bound

to cause unwanted responses to psychotropic drugs (Mehta et al. 2015). As men-

tioned earlier, inappropriate drug use and high incidence of ADRs are the major

reasons for high hospital admissions or discontinuation of treatment among elderly.

Geriatrics with dementia or cognitive impairment are at a much greater risk to drug-

related ADRs. The main PK and clinical features along with typical ADRs

associated with antidepressant drugs in elderly versus young adults are summarized

in Table 15.2.

15.12 Clinically Significant Interactions Between Antidepressant

Drugs: Mechanisms of Interactions and Prescribing

Strategies

Drug-drug interactions (DDIs) are caused via ADME alterations, consequently

producing changes in the bioavailability and PK profiles of co-administered drugs.

Some DDIs may produce therapeutic benefits; however, most often DDIs cause

unwanted side effects. Some DDIs can cause clinically adverse reactions resulting

from PK changes. The PK interactions include all alterations during the ADME

phase of one drug induced by another co-administered drug. Mostly, DDIs occur due

to drug-induced inhibition or induction of CYP450 isoenzymes. The interactions

may be additive or potentiative as well as agonistic or antagonistic in manner and

may occur at the cellular or molecular level, or at the receptor site, and mechanisti-

cally can be classified as PK & PD interactions. There is some general information

available about the CYP450 effects of antidepressants: there are known potent

inhibitors of different CYP450 3A4 and CYP450 2D6 isoenzymes. For example,

fluoxetine and paroxetine are potent inhibitors of CYP450 2C19 and can also act as

inhibitors of fluvoxamine and TCA (amitriptyline and imipramine). As a rule, TCAs

are victims of metabolism via hydroxylation; therefore, every CYP450 2D6 inhibitor

can increase the serum levels of tricyclic antidepressant drugs. Combined adminis-

tration of TCAs and SSRIs often results in strong PK interactions, which require

careful titration of TCAs with SSRIs, and avoiding the combination may offer the

best solution, too (English et al. 2012). DDIs are an important reason for hospital

15

The Importance of Drug Dose Adjustment in Elderly Patients with Special. . .

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