Antidepressants

For the treatment of mood disorders commonly drugs including tricyclic antidepres-sants (TCAs), tetracyclic antidepresantidepres-sants, monoamine oxidase (MAO) inhibitors, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors are used. The first antidepressant was imipramine (IMI), which was one of several iminodibenzyl compounds developed as antihistamine by Geigy Pharmaceuticals in the 1940s and structu-rally similar to the first true antipsychotic chlorpromazine (CPZ) synthesized in 1950. The antidepressant properties of IMI were discovered in 1957 by Roland Kuhn more or less by chance (Kuhn, 1957). Already in 1951, the antituberculosis medication isoniazide was found to enhance the well-being of moribund patients then dancing in the hallway (Robitzek et al., 1952). Numerous variants of TCAs with small variations in the structure were introduced in the following years. In the early 1970s the SSRI fluoxetine was developed, becoming one of the first blockbusters (Wong et al., 1975).

A.1.2.1.1 Non-selective antidepressants

A.1.2.1.1.1 Tricyclic antidepressants

Tricyclic antidepressants block the reuptake of the neurotransmitters norepinephrine (NE) and serotonin (5-HT) and, thus, increase their concentrations in the synaptic cleft (Fig. A.1). They are named after their chemical structure (three aromatic rings) and are used for the treatment of major depressive disorder, dysthymia, bipolar disorder and a number of other medical disorders. Despite their consistent structural appearance the pharmacological effects of TCAs are widely varying and were, therefore, in the past categorized by Kielholz (1971) in groups of psychomotoric inhibiting, psychomotoric neutral and psychomotoric stimulatory antidepressants. This categorization is, however, strongly simplified and is not used anymore.

Y

opipramol, OPI dibenzepin, DBP amoxapine, AMO

Fig. A.1. Structures of tricyclic antidepressants.

Besides the blockade of the monoamine reuptake, TCAs also modulate other receptors and produce many side effects like antimuscarinic effects such as dry mouth, con-stipation, blurry vision and cognitive disorders. Also, sedation as well as the modulation of food intake and weight gain may occur by histamine H1R blockade, while reflex tachycardia and hypotension are α1-adrenergic receptors (α1AR) related, the latter increasing the risk of tumbling of older patients.

In contrast, trimipramine (TMP) is only a weak reuptake inhibitor of monoamines and is, therefore, often considered as atypically. Its main effects are exerted by a potent antagonism at serotonin 5-HT2 receptors (5-HT2Rs), α1AR, muscarinic acetylcholine receptors (mAChRs) and histamine H1 receptor (H1R), less potent at 5-HT1R, D2R and α2AR. The thera-peutic effects like potent antidepressant activity, sedation and anxiolysis are accompanied by potent anticholinergic and antiadrenergic side effects. Due to its antagonism at D2R, also

antipsychotic activity was observed with low incidence of extrapyramidal-motoric symptoms (EPS) (Eikmeier et al., 1991). OPI shows a high affinity to σ1 receptor (Müller et al., 2004), but also acts as antagonist at 5-HT2R, D2R, mAChR and H1R with a low to moderate affinity. In contrast to other TCAs, OPI does not inhibit the reuptake of 5-HT and NE.

Bioavailability ranges between 50–80% and elimination half-life is varying substan-tially. The TCAs are effectively metabolized by cytochrome P450 2D6 hepatic enzymes, which implicates possible interactions with cytochrome P450-inhibiting substances leading to in-creased or even toxic plasma concentrations of TCAs. Due to a low lethal dose, the risk of abusive application of an overdose for the realization of suicidal thoughts is relatively high.

However, TCAs are still used because of their effectiveness, especially in treatment-resistant variants. Despite the development of more selective drugs like selective serotonin reuptake inhibitors (SSRIs) with less frequent and intense side effects TCAs are – although prescribed less commonly – an important and effective medication, specifically in severe cases of major depression.

A.1.2.1.1.2 Tetracyclic antidepressants

Like the TCAs also tetracyclic antidepressants are non-selective monoamine reuptake inhibitors (Fig. A.2). They contain four heterocyclic rings of atoms, but apart from that share most of the properties with TCAs. Chemically, also mianserin (MSN) and MIR belong to this group but display also antagonistic α2-adrenoceptor (α2AR) properties which increase noradrenergic and serotonergic tonus. (Chapter A.1.2.1.2.2).

N X

N

NH

mianserin, MSN, X = CH

mirtazapine, MIR, X = N maprotiline, MPT

Fig. A.2. Structures of tetracyclic antidepressants.

A.1.2.1.2 Selective antidepressants

A.1.2.1.2.1 Selective serotonin reuptake inhibitors

Current standard in treatment of depressive disorders are SSRIs like fluoxetine, citalopram or paroxetine (PRX) (Fig. A.3). Their selective inhibition of 5-HT reuptake compen-sates the imbalance of serotonergic neurotransmission. Postsynaptic 5-HT1AR and 5-HT2AR and presynaptic autoreceptors may also be modulated by the increased neurotransmitter concentration in the synaptic cleft. Adverse effects such as nausea, diarrhea and changes in appetite are observed less frequently than with the more unselective TCAs or MAO inhibitors as affinity to αAR, muscarinic and histamine receptors (HxR) are much lower, although effects as drowsiness, anxiety, insomnia, dry mouth, nervousness, decreased appetite, weight gain and several types of sexual dysfunction may still occur. Due to the serotonergic modulation a prevalent side effect is nausea or rather vomiting. A low affinity to H1R prevents sedative effects. Thus, an intermittent benzodiazepine medication is indi-cated until onset of the antidepressive effects. The serotonin syndrome is an idiosyncratic adverse drug reaction occurring during therapeutic drug use of antidepressants. It is a potentially life-threatening consequence of exceeding serotonergic activity in central nervous system (CNS) and periphery and causes cognitive, autonomic and somatic effects. In children and adolescents administration of most SSRIs is contraindicated because of juvenile suicide (attempts).

HN

O O

F

O

paroxetine, PRX

Fig. A.3. Structure of the selective serotonin reuptake inhibitor PRX.

A.1.2.1.2.2 Noradrenergic and specific serotonergic antidepressants

Although they chemically belong to tetracyclic antidepressants, MSN does not inhibit the reuptake of neurotransmitters and MIR does only marginally. Both substances rather act by antagonizing various receptors such as 5-HT2AR, 5-HT2CR and 5-HT3R and H1R. By blockade of presynaptic α2AR at serotonergic and noradrenergic synapses the concentration of both neurotransmitters is increased so that they are designated as noradrenergic and specific serotonergic antidepressants (NaSSAs).