2. Pathophysiology of depression

Literature data highlighted that the pathophysiological mechanisms involved in the manifestation of affective disorders are mediated by numerous neurotransmitters, such as norepinephrine, serotonin, dopamine, acetylcholine, gamma-aminobutyric acid, and glutamate. In order to explain the phenomena that occur in the depression, several theories have been issued depending on the neuro-mediators involved in the pathogenic links, responsible for the development of the behavioral disturbances [8].

Monoaminergic theory of depression postulates that depressive manifestations are caused by the lack of one or more of the three essential neuro-mediators (serotonin, dopamine, norepinephrine) from the central nervous system synapses. These areas are situated especially in the cortex of the frontal lobe (dorsolateral, prefrontal, and orbitofrontal), the self-processing headquarters. In these areas, regional atrophy and atrophic alterations were observed, following the stress associated with the hypothalamic-pituitary-adrenal axis [8, 9].

Different types of deficits modulate the characters of depression:

1. Introduction

medical condition [3–5].

high frequency of comorbidities [1, 2].

126 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

Depression [major depressive disorder (MDD)] is a pathological affective disorder characterized by the presence of various emotional, physical, behavioral, and cognitive symptoms, with variable duration of manifestations, with progressive evolution toward worsening, and with a

According to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition, the clinical symptomatology includes a series of manifestations lasting more than 2 weeks: depressed mood, diminishing interest in current activities (home and work), lack of pleasure and energy, permanent fatigue, loss of confidence and self-esteem, feelings of guilt, inability to make decisions, lack of initiative, loss of attention and concentration, sleep disturbances (insomnia or hypersomnia), appetite disturbances, weight gain, modification of psychomotor activity, and recurrent thoughts of death. The symptoms are not caused by a substance or another

To determine the severity of depressive symptoms, a number of depression rating scales are available. Montgomery-Asberg Depression Rating Scale, Hamilton Depression Scale, and Young Mania Rating Scale are clinician-administered scales. In addition, self-administered scales can be useful (Patient Health Questionnaire, Beck Depression Inventory, Zung Self-

The treatment of MDD is based on pharmacotherapy, which includes numerous drugs with

The aim of this chapter is to review the literature, highlight important aspects regarding the main incriminated theories of depression and the side effects of agents used to treat MDD, and

This chapter synthetizes the classic and modern features concerning the MDD pathophysiology and treatment, as well as the information about the newest antidepressants introduced in the therapy (desvenlafaxine, levomilnacipran, vilazodone, and vortioxetine), detailing the mechanism of action, pharmacokinetic aspects, their side effects, and benefits. The first two substances have similar mechanisms of action to existing medications, and the other two compounds are multimodal antidepressants, which combine SSRI activity with additional receptor activity.

Literature data highlighted that the pathophysiological mechanisms involved in the manifestation of affective disorders are mediated by numerous neurotransmitters, such as norepinephrine, serotonin, dopamine, acetylcholine, gamma-aminobutyric acid, and glutamate. In order to explain the phenomena that occur in the depression, several theories have been issued depending on the neuro-mediators involved in the pathogenic links, responsible for the devel-

especially point out the most relevant details of the latest antidepressant drugs.

Rating Depression Scale, and Mood Disorder Questionnaire) [6, 7].

various structures and mechanisms of action.

2. Pathophysiology of depression

opment of the behavioral disturbances [8].


A therapeutic response consists of 50% alleviation of the symptoms following administration of the antidepressant medication. A small percentage of people may develop resistance to antidepressants (through lack of synthesis or transport or excess metabolism of one or more monoamines). These patients are recommended to either potentiation of the treatment or electroconvulsive therapy, as a solution for achieving remission of the depression.

In these conditions, the therapeutic targets of currently used antidepressant drugs are aimed at augmenting the monoaminergic deficiency at the synaptic level.

This response can be achieved by:


There is also evidence for the involvement of other (secondary) systems in the pathogenesis of depression, with the participation of acetylcholine, somatostatin, leptin, substance P, thyrotropin-releasing hormone (TRH), brain-derived neurotrophic factor (BRNF), gammaaminobutyric acid (GABA), and glutamate [12].

Depending on the clinical manifestations experienced by the patient (anxiety, insomnia, psychotic symptoms), antidepressant medication may be combined for limited periods of time with anxiolytic, sedative, or antipsychotic drugs. If affective disorders heavily respond to classical antidepressants, mood-stabilizing agents, electroconvulsive therapy, or bright light

New Antidepressant Medication: Benefits Versus Adverse Effects

http://dx.doi.org/10.5772/intechopen.72003

129

A wide range of antidepressants are available nowadays, belonging to various therapeutic classes, with various mechanisms of action, effective in some affective disorders, but also a host of adverse effects as well as the possibility of interacting with other prescribed medications. In selecting the antidepressant, it is necessary to balance, on the one hand, its effectiveness in the affective disorder, and on the other hand, the adverse effects may occur (mild,

Table 1 summarizes the adult doses and some side effects of selected antidepressants (seizures

Some of the antidepressant medication side effects may be unpleasant, others are dangerous to the patient, and they should be reported to the physician, who will decide to replace the drug or to adjust the dose. It is necessary to mention that, apart from specific adverse reactions, all antidepressants present a risk of suicide, especially at the beginning of treatment; therefore, the

These agents inhibit the metabolism of monoamines (but not their synthesis) and release norepinephrine from postganglionic deposits (mebanazine, tranylcypromine, phenelzine) [20]. They have low selectivity, inhibiting other enzymes including dopamine-B-oxidase, diamine oxidase, amino acid decarboxylase, and choline dehydrogenase, which are responsible for some of the side effects of the group. Some of them act selectively for only one of the two MAO forms, the MAO-A: moclobemide, miaprine, pirlindole, and toloxatone [21]. The MAO-B inhibitors,

• Irreversible, long-acting, noncompetitive inhibitors (phenelzine, tranylcypromine), of both

• Reversible, short-acting, MAO-A selective inhibitors (moclobemide, brofaromine) that are

MAOIs were among the first antidepressant drugs to be clinically introduced, which are used nowadays much less than other antidepressants because of their toxicity and serious drug and

For most of MAOIs, the enzyme blocking takes 2–6 weeks (new enzyme synthesis occurring only after 2 weeks) [25]. During this time, the administration of drugs that augment the monoamines' level (such as tricyclic antidepressants, fluoxetine, naphazoline, xylometazoline,

such as selegiline and rasagiline, are reserved for Parkinson's disease therapy [22]:

and conduction abnormalities are dose-dependent side effects) [19].

patient should be supervised and supported by family and entourage.

therapy may be associated.

moderate, severe, temporary, or lasting).

3.1.1. Classical antidepressants (first generation)

MAO-A and MOA-B subtypes

experienced in Canada

food interactions [23, 24].

• Monoamine oxidase (MAO) inhibitors (MAOIs)

3.1. Pharmacotherapy

It should be underlined that the reduction of any monoaminergic neuro-mediator is accompanied by upregulation events that increase the reactivity to small amounts of monoamine: this could be the mechanism responsible for hyper-serotoninergic reactions (serotoninergic pseudo-syndrome) manifested at the beginning of the treatment, with monoaminergic augmentation in persons with serotonin deficiency.
