3. Treatment of depression

This affective disorder, which has a very long evolution, is generally underdiagnosed and insufficiently treated, statistical data showing that currently only half of the persons affected by depression have undergone pharmacological or non-pharmacological treatment. Despite the fact that 80–90% of cases of depression can be successfully treated, this disease considerably affects the quality of life of both patient and his family.

It is particularly important to early diagnose depression and rapidly establish the appropriate therapy to reduce the consequences of this pathological condition on the general (physical and mental) status of the patient.

Management of depression is complex, including therapeutic lines with targeted action on associated organic pathology, psychotherapy with the final goal of rebalancing the patient [13]. The treatment of affective disorders is of long duration and individualized, involving an adequate cooperation between doctor, patient, and his family for the choice of the appropriate antidepressant drug from a pharmacological and economical point of view.

Modern treatment of depression combines pharmacotherapy with alternative methods (represented by psychotherapy, hypnosis, cognitive behavioral treatment, interpersonal therapies). Short-term psychotherapeutic approaches, especially cognitive behavioral methods and interpersonal therapies, have been shown to be highly effective in relieving symptoms and diminishing the number of depressive episodes [14, 15]. More obvious results are obtained by combining psychotherapy with pharmacotherapy, which consists of the administration of antidepressants, their efficiency being demonstrated in 80% of depression cases. The pharmacodynamic effects of antidepressants occur after a period of time ranging from 2 to 4 weeks, during which psychotherapy has beneficial effects [16, 17].

It is known that in many cases the patients are rapidly discontinuing medication, conditions in which psychotherapy exhibits beneficial effects by increasing the patient's compliance/adherence, resulting in diminution or even elimination of the sense of isolation, as well as the powerless and hopeless feelings. These results improve communication with the patient, who becomes more conscious that stopping the administration of recommended drugs can lead to a recurrence of the disease. There are a lot of tools like questionnaires or patient-reported outcomes (PROs) that identify some different patterns of behavior of patients with depression with the aim of improving patients' adherence [18].

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 therapy may be associated.

### 3.1. Pharmacotherapy

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), gamma-

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 aug-

This affective disorder, which has a very long evolution, is generally underdiagnosed and insufficiently treated, statistical data showing that currently only half of the persons affected by depression have undergone pharmacological or non-pharmacological treatment. Despite the fact that 80–90% of cases of depression can be successfully treated, this disease consider-

It is particularly important to early diagnose depression and rapidly establish the appropriate therapy to reduce the consequences of this pathological condition on the general (physical and

Management of depression is complex, including therapeutic lines with targeted action on associated organic pathology, psychotherapy with the final goal of rebalancing the patient [13]. The treatment of affective disorders is of long duration and individualized, involving an adequate cooperation between doctor, patient, and his family for the choice of the appropriate

Modern treatment of depression combines pharmacotherapy with alternative methods (represented by psychotherapy, hypnosis, cognitive behavioral treatment, interpersonal therapies). Short-term psychotherapeutic approaches, especially cognitive behavioral methods and interpersonal therapies, have been shown to be highly effective in relieving symptoms and diminishing the number of depressive episodes [14, 15]. More obvious results are obtained by combining psychotherapy with pharmacotherapy, which consists of the administration of antidepressants, their efficiency being demonstrated in 80% of depression cases. The pharmacodynamic effects of antidepressants occur after a period of time

It is known that in many cases the patients are rapidly discontinuing medication, conditions in which psychotherapy exhibits beneficial effects by increasing the patient's compliance/adherence, resulting in diminution or even elimination of the sense of isolation, as well as the powerless and hopeless feelings. These results improve communication with the patient, who becomes more conscious that stopping the administration of recommended drugs can lead to a recurrence of the disease. There are a lot of tools like questionnaires or patient-reported outcomes (PROs) that identify some different patterns of behavior of patients with depression

antidepressant drug from a pharmacological and economical point of view.

ranging from 2 to 4 weeks, during which psychotherapy has beneficial effects [16, 17].

with the aim of improving patients' adherence [18].

aminobutyric acid (GABA), and glutamate [12].

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

mentation in persons with serotonin deficiency.

ably affects the quality of life of both patient and his family.

3. Treatment of depression

mental) status of the patient.

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, moderate, severe, temporary, or lasting).

Table 1 summarizes the adult doses and some side effects of selected antidepressants (seizures and conduction abnormalities are dose-dependent side effects) [19].

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 patient should be supervised and supported by family and entourage.

### 3.1.1. Classical antidepressants (first generation)

• Monoamine oxidase (MAO) inhibitors (MAOIs)

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


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 food interactions [23, 24].

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,


• Tricyclic antidepressants have the following mechanisms of action:

• Inhibition of 5-HT2A receptors (but also affinity for 5-HT6 and 5-HT7 receptors)

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• Inhibition of serotonin transporter

• Stimulation 5-HT1A receptors

• Inhibition of alpha-2 receptors

• Inhibition of muscarine receptors

citalopram, escitalopram)

weeks [17, 28, 29].

a lot of adverse effects, thus limiting their indications.

• D2 receptor stimulation

• Inhibition of alpha-1 receptors [27]

3.1.2. Heterocyclic antidepressants (second or third generation)

• With nonselective action on the amine neurotransmitters

• Without anticholinergic effects (venlafaxine, bupropion)

• With anticholinergic effects (maprotilin, nomifensine, amoxapine)

• Inhibition of H1 receptors (for some compounds even H2 receptors)

contraction, nausea and vomiting, and rarely rhabdomyolysis [16]:

• 5-HT2A/5-HT2C receptor antagonists (trazodone, nefazodone, mirtazapine)

• Heterocyclic antidepressants have the following mechanisms of action:

• Blockade of sodium and calcium channels (being responsible for cardiotoxicity) [16]

Various mechanisms of actions are responsible for the pharmacodynamic effects as well as for

Adverse reactions are particularly due to the muscarine receptor blockade and consist of mucosal dryness, blurred vision, diminution of digestive tract motility, constipation, urinary retention, cognitive impairment and memory disturbances, increased body temperature, akathisia (psychological restlessness without physical agitation), tachycardia, hypotension, arrhythmias, and, in case of overdose, cardiotoxicity. Other side effects of tricyclic antidepressants include excessive sweating, paradoxical emotional changes (anxiety or the lack of emotional reactivity), modification in appetite and body weight, sexual dysfunction, muscle

• Selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, sertraline, paroxetine, fluvoxamine,

The onset of the therapeutic effect varies from a few hours to 2–3 days after SSRI administration. The peak blood concentration is reached in 10–21 days. Some of SSRIs persist for a long time in the body, for example, fluoxetine, which is completely eliminated only after 5

• Inhibition of norepinephrine transporter • Slight inhibition of dopamine reuptake

0, absent; +, very low; 2+, low; 3+, moderate; 4+, severe.

Table 1. Antidepressant drugs: adult doses and selected side effects [19].

or other drugs) or ingestion of food containing tyramine, the catecholamine precursor, can generate severe increase in blood pressure and death. In this situation, the intestinal fermented tyramine can be transported in blood and replaces norepinephrine in the vesicles, resulting in amplification the effects of the normal norepinephrine stimulation [26].

The main side effects of nonselective MAOIs are "cheese reaction" (severe hypertensive response to tyramine-containing foods, such as cheese, beer, wine, liver, sardines, well-hung meat, yeast, or soybean derivatives), anticholinergic side effects (dry mouth, blurred vision, urinary retention, etc.), postural hypotension, insomnia, weight gain, sexual side effects, convulsions (in overdose), and hepatotoxicity (rare). Nausea, insomnia, and agitation, but no "cheese reactions," were reported for moclobemide [19, 23].

	- Imipramine, desipramine, clomipramine, trimipramine, amitriptyline
	- Nortriptyline, butriptyline, doxepin, protriptyline [16]
	- Inhibition of serotonin transporter
	- Inhibition of norepinephrine transporter
	- Slight inhibition of dopamine reuptake
	- Stimulation 5-HT1A receptors
	- Inhibition of 5-HT2A receptors (but also affinity for 5-HT6 and 5-HT7 receptors)
	- Inhibition of alpha-1 receptors [27]
	- Heterocyclic antidepressants have the following mechanisms of action:

or other drugs) or ingestion of food containing tyramine, the catecholamine precursor, can generate severe increase in blood pressure and death. In this situation, the intestinal fermented tyramine can be transported in blood and replaces norepinephrine in the vesicles, resulting in

The main side effects of nonselective MAOIs are "cheese reaction" (severe hypertensive response to tyramine-containing foods, such as cheese, beer, wine, liver, sardines, well-hung meat, yeast, or soybean derivatives), anticholinergic side effects (dry mouth, blurred vision, urinary retention, etc.), postural hypotension, insomnia, weight gain, sexual side effects, convulsions (in overdose), and hepatotoxicity (rare). Nausea, insomnia, and agitation, but no "cheese reactions," were

• Tricyclic antidepressants are divided into subgroups with similar general structures:

• Imipramine, desipramine, clomipramine, trimipramine, amitriptyline

amplification the effects of the normal norepinephrine stimulation [26].

• Nortriptyline, butriptyline, doxepin, protriptyline [16]

reported for moclobemide [19, 23].

0, absent; +, very low; 2+, low; 3+, moderate; 4+, severe.

Table 1. Antidepressant drugs: adult doses and selected side effects [19].

Drug Initial dose

(mg/day)

Usual dosage range (mg/day)

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

Side effects

Amitriptyline 25 100–300 4+ 4+ 3+ 3+ 3+ Bupropion 150 150–300 + 0 0 4+ + Citalopram 20 20–40 0 + 0 2+ 2+ Desipramine 25 100–300 2+ 2+ 2+ 2+ 2+ Desvenlafaxine 50 50 + + 0 2+ + Doxepin 25 100–300 3+ 4+ 2+ 3+ 2+ Duloxetine 30 30-90 + 0 + 0 0 Escitalopram 10 10–20 0 0 0 0 0 Fluoxetine 20 20–60 0 0 0 2+ 0 Fluvoxamine 50 50–300 0 + 0 2+ 0 Imipramine 25 100–300 3+ 3+ 4+ 3+ 3+ Mirtazapine 15 15–45 + 2+ 2+ 0 + Nefazodone 100 300–600 0 3+ 3+ 2+ + Nortriptyline 25 50–150 2+ 2+ + 2+ 2+ Paroxetine 20 20–60 + + 0 2+ 0 Sertraline 50 50–200 0 0 0 2+ 0 Trazodone 50 150–300 0 4+ 3+ 2+ + Venlafaxine 37.5–75 75–225 + + 0 2+ +

Anticholinergic effects

Sedation Orthostatic

hypotension

Seizures Conduction

abnormalities


Various mechanisms of actions are responsible for the pharmacodynamic effects as well as for a lot of adverse effects, thus limiting their indications.

Adverse reactions are particularly due to the muscarine receptor blockade and consist of mucosal dryness, blurred vision, diminution of digestive tract motility, constipation, urinary retention, cognitive impairment and memory disturbances, increased body temperature, akathisia (psychological restlessness without physical agitation), tachycardia, hypotension, arrhythmias, and, in case of overdose, cardiotoxicity. Other side effects of tricyclic antidepressants include excessive sweating, paradoxical emotional changes (anxiety or the lack of emotional reactivity), modification in appetite and body weight, sexual dysfunction, muscle contraction, nausea and vomiting, and rarely rhabdomyolysis [16]:


The onset of the therapeutic effect varies from a few hours to 2–3 days after SSRI administration. The peak blood concentration is reached in 10–21 days. Some of SSRIs persist for a long time in the body, for example, fluoxetine, which is completely eliminated only after 5 weeks [17, 28, 29].

During the treatment, the upregulation of the synapses can initially trigger a pseudoserotoninergic syndrome, with psychomotor agitation, akathisia, insomnia, tremor, muscle fasciculation, fever, and vomiting. This syndrome is sensitive to benzodiazepine therapy, and usually the spontaneous resolution appears within a few days [16, 23].

beginning of 2008, a product containing desvenlafaxine (Ellefore) was withdrawn from the market in the European Union, due to its insufficient documentation and clinical experience; but later in 2012, Pfizer corporation obtained the authorization for the use of Pristiq® in Spain. It also received the market authorization in Canada for the pharmacotherapy of depression in February 2009. A few years later, FDA approved the use of both brand and generic products

In vitro studies revealed that desvenlafaxine determines the inhibition of serotonin and norepinephrine reuptake (10 times more potent for serotonin than for norepinephrine), thus blocking the removal of the main mediators (serotonin, norepinephrine) that affect mood, increasing their concentration at the synaptic level [32, 38]. No notable influence on muscarine, histamine, or alpha-1 adrenergic receptors and on the activity of monoamino oxidase was proven. Moreover, the lack of the influence on the functionality on sodium, potassium, chlo-

Dosage forms 50 mg, light-pink square pyramid extended-

Administration Orally, once daily, with or without food

Bioavailability 80% (being not influenced by the meals)


Elimination 45% is eliminated and unchanged in urine, 72

Absorption Not influenced by food intake

T1/T2 Approximately 11 hours

Time to maximum concentration 7.5 hours

Protein-binding percentage 30%

Volume of distribution 3.4 L

glucuronosyltransferase participation) and secondarily is metabolized by oxidation (through

Table 2. Pharmacological aspects of desvenlafaxine [32, 34, 38–41].

Metabolism Is mainly conjugated (via uridine 5<sup>0</sup>

N-demethylation)

Dosage Initial dosage of 50 mg, approximately at the same

Steady-state plasma concentrations Achieved within 4–5 days after oral administration

succinate)

succinate)

moment of time, each day, maintenance dose of 50 mg;

of a unique dose

CYP2D6 is not involved

hours after oral administration

CYP3A4

release tablet (containing 76 mg of desvenlafaxine

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100 mg, reddish-orange square pyramid extendedrelease tablet (containing 152 mg of desvenlafaxine

the maximum accepted daily dose is 400 mg

containing desvenlafaxine fumarate (Desvenlafaxine fumarate, 2013) [37].

ride, or calcium ion channels was also evidenced [34, 39].

4.1. Pharmacological properties

Pure serotonin syndrome is particularly common for tricyclic antidepressants, more rarely for SSRIs, and most commonly occurs in drug combinations with metabolic inhibitors or with agents that may increase the serotonin level. Serotonin syndrome is manifested by agitation, confusion, excessive sweating, mydriasis, muscle spasms or muscle incoordination, fever, seizures, and coma.

The therapy with SSRIs is long-lasting, with the shortest treatment indicated being 3–6 months. As expected, a degree of dependence occurs; therefore, avoiding sudden discontinuation of treatment with SSRIs is essential. Otherwise insomnia, agitation, confusion, trembling, anxiety, and even hallucinatory phenomena may occur during treatment [30]:


Among the antidepressant groups, SSRIs and SNRIs are preferred because not only of their therapeutic efficacy but also of the relatively small number and decreased severity of adverse effects [28, 30, 31].
