Pharmacological Properties

Tricyclic Antidepressants and Other Norepinephrine-Reuptake Inhibitors Knowledge of the pharmacological properties of antidepressant drugs remains incomplete, and coherent interpretation is limited by a lack of a compelling psychobiological theory of mood disorders. The actions of tricyclic antidepressants include a range of complex, secondary adaptations to their initial and sustained actions as inhibitors of NE neuronal transport (uptake 1, via NET; see Chapter 2) and variable blockade of 5-HT transport (via serotonin transporter [SERT]). Tricyclic antidepressants with secondary-amine side chains or the W-demethylated (nor) metabolites of agents with tertiary-amine moieties (e.g., amoxapine, desipramine, maprotiline, norclomipramine, nordoxepin, and nortriptyline) are relatively selective inhibitors of NE transport. Most tertiary-amine tricyclic antidepressants also inhibit the reuptake of 5-HT. Trimipramine is exceptional among the tricyclic antidepressants in that it lacks prominent inhibitory effects at monoamine transport.

The tricyclic and other NE-active antidepressants do not block dopamine (DA) transport (via DAT); they thereby differ from central nervous system (CNS) stimulants, including cocaine, methylphenidate, and amphetamines (see Chapter 10). Nevertheless, they may indirectly facilitate effects of DA by inhibiting the nonspecific transport of DA into noradrenergic terminals in the cerebral cortex. Tricyclic antidepressants also can desensitize D2 autoreceptors through uncertain mechanisms and with uncertain behavioral contributions.

Tricyclic antidepressants variably interact with receptors (e.g., a adrenergic receptor, muscarinic receptor, H1 histamine receptor). Interactions with the adrenergic receptors apparently are critical for responses to increased availability of extracellular NE in or near synapses. Most tricyclic antide-pressants have at least moderate and selective affinity for a1 adrenergic receptors, much less for a2, and virtually none for b receptors. The a2 receptors include presynaptic autoreceptors that limit the neurophysiological activity of noradrenergic neurons ascending from the locus ceruleus in brainstem to supply mid- and forebrain projections. The same noradrenergic neurons provide descending projections to the spinal cord preganglionic cholinergic efferents to the peripheral autonomic ganglia (see Chapters 6 and 10). Autoreceptor mechanisms also reduce the synthesis of NE, presumably by attenuation of the cyclic AMP-PKA activation of tyrosine hydroxylase, via a2 adrenergic receptor inhibition of adenylyl cyclase. Activation of these autoreceptors also inhibits transmitter release.

The a2 receptor-mediated, presynaptic, negative-feedback mechanisms are rapidly activated after administration of tricyclic antidepressants. By limiting synaptic availability of NE, such mechanisms normally tend to maintain functional homeostasis. However, with repeated drug exposure, a2-receptor responses eventually are diminished, possibly from desensitization secondary to increased exposure to the endogenous agonist (NE) or from prolonged occupation of the NE transporter itself via an allosteric effect. Over a period of days to weeks, this adaptation allows the presynaptic production and release of NE to return to, or even exceed, baseline levels. However, long-term treatment eventually can reduce the expression of tyrosine hydroxylase as well as the NE transporter.

The density of functional postsynaptic b adrenergic receptors gradually down-regulates over several weeks of repeated treatment with tricyclics, some selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase (MAO) inhibitors. Combinations of a 5-HT transport inhibitor with a tricyclic antidepressant may have a more rapid b adrenergic receptor-desensitizing effect. Since b-blockers tend to induce or worsen depression in vulnerable persons, it is unlikely that diminished b-receptor signaling contributes directly to the mood-elevating effects of antidepressant treatment. Nevertheless, loss of inhibitory b adrenergic influences on serotonergic neurons may enhance release of 5-HT and thus contribute indirectly to antidepressant effects (see Chapter 10).

With tricyclic antidepressant therapy, postsynaptic a1 adrenergic receptors may be inhibited initially, probably contributing to early hypotensive effects of many tricyclics. Over weeks of treatment, a1 receptors remain available and may even become more sensitive to NE as clinical mood-elevating effects gradually emerge. Therefore, as antidepressant treatment gradually becomes clinically effective, inactivation of transmitter reuptake continues to be blocked, presynaptic production and release of NE returns to or may exceed baseline levels, and a postsynaptic a1 adrener-gic mechanism is operative.

Additional neuropharmacological changes that may contribute to the clinical effects of tricyclic antidepressants include indirect facilitation of 5-HT (and perhaps DA) neurotransmission through excitatory a1 "heteroreceptors" on other monoaminergic neurons, or desensitized, inhibitory a2 autoreceptors, as well as D2 autoreceptors. Activated release of 5-HT and DA may, in turn, lead to secondary down-regulation of 5-HT1 autoreceptors, postsynaptic 5-HT2 receptors, and perhaps D2 autoreceptors and postsynaptic D2 receptors.

Other adaptive changes observed in response to long-term treatment with tricyclic antidepressants include altered sensitivity of muscarinic acetylcholine receptors and decreases in gamma-aminobutyric acid (GABAb) receptors and possibly N-methyl-D-aspartate (NMDA) glutamate receptors. In addition, the cyclic AMP-PKA pathway is more activated in some cells, with effects on CREB and brain-derived neurotrophic factor (BDNF). Additional changes may reflect indirect effects of antidepressant treatment or recovery from depressive illness; these include normalization of glucocorticoid release and glucocorticoid receptor sensitivity and shifts in the production of prostaglandins and cytokines and in lymphocyte functions.

The neuropharmacology of tricyclic antidepressants is not explained simply by blockade of the transport-mediated removal of NE, even though this effect undoubtedly is a crucial event that initiates a series of important secondary adaptations. Interactions of antidepressants with monoaminer-gic synaptic transmission are illustrated in Figure 17-1.

Selective Serotonin Reuptake Inhibitors (SSRIs) The late and indirect actions of these anti-depressant and antianxiety agents remain less well understood than are those of tricyclic antide-pressants, but there are striking parallels between responses in the noradrenergic and serotonergic systems. Like tricyclic antidepressants, which block NE reuptake, the SSRIs block neuronal transport of 5-HT both immediately and chronically, leading to complex secondary responses. Increased synaptic availability of 5-HT results in stimulation of a large number of postsynaptic 5-HT receptor types (see Chapter 11), which may contribute to adverse effects characteristic of this class of drugs, including GI effects (nausea and vomiting) and sexual effects (delayed or impaired orgasm). Stimulation of 5-HT2C receptors may contribute to the agitation or restlessness sometimes induced by SSRIs.

In both serotoninergic and noradrenergic neurons, negative feedback mechanisms rapidly emerge to restore homeostasis. In the 5-HT system, 5-HT1-subtype autoreceptors (types 1A and 7 at raphe cell bodies and dendrites, type 1D at terminals) suppress serotoninergic neurons in the raphe nuclei of the brainstem, inhibiting both tryptophan hydroxylase (probably through reduced phosphorylation-activation) and neuronal release of 5-HT. Repeated treatment leads to gradual down-regulation and desensitization of autoreceptor mechanisms over several weeks (particularly of 5-HT1D receptors at nerve terminals), with a return or increase of presynaptic activity, production, and release of 5-HT. Additional secondary changes include gradual down-regulation of postsynaptic 5-HT2A receptors, which may contribute to antidepressant effects directly and by influencing the function of noradrenergic and other neurons via serotonergic heteroreceptors. Many other postsynaptic 5-HT receptors presumably remain available to mediate increased sero-tonergic transmission and contribute to the mood-elevating and anxiolytic effects of this class of drugs.

Complex late adaptations occur upon repeated treatment with SSRIs, including indirect enhancement of NE output by reduction of tonic inhibitory effects of 5-HT2A heteroreceptors. Finally, similar nuclear and cellular adaptations occur as with the tricyclic antidepressants, including increased intraneuronal cyclic AMP, activation/phosphorylation of transcription factors (e.g., CREB), and increased production of BDNF.

Other Drugs Affecting Monoamine Neurotransmitters

The MAO inhibitor tranylcypromine is amphetamine-like in structure but interacts only weakly at DA transporters.Thephenylpiperazine nefazodone, and to a lesser extent, the structurally related trazodone have weak inhibitory actions on 5-HT transport; nefazodone also may have a minor effect on NE transport. This agent also has a prominent direct antagonistic effect at 5-HT2A receptors that may contribute to antidepressant and anxiolytic activity. Both drugs also may inhibit presynaptic 5-HTj subtype autoreceptors to enhance neuronal release of 5-HT, though they probably also exert at least partial-agonist effects on postsynaptic 5-HTj receptors. Trazodone also blocks cerebral a1 and H1 receptors, possibly contributing to its tendency to induce priapism and sedation, respectively.

Finally, the atypical antidepressants mirtazapine and mianserin are structural analogs of 5-HT with potent antagonistic effects at several postsynaptic 5-HT receptor types (including 5-HTm, 5-HT2c and 5-HT3 receptors) and can produce gradual down-regulation of 5-HT2A receptors. Mirtazapine limits the effectiveness of inhibitory a2 adrenergic heteroreceptors on serotonergic neurons as well as inhibitory a2 autoreceptors and 5-HT2A heteroreceptors on noradren-ergic neurons. These effects may enhance release of amines and contribute to the antidepressant effects of these drugs. Mirtazapine also is a potent histamine Hj-receptor antagonist and is relatively sedating. Mianserin is not used in the U.S. owing largely to its bone marrow suppression.

Protein kinases activated

Protein phosphorylation

Diverse effector mechanisms (see text)

Presynaptic serotonin neuron

Postsynaptic receptive neuron

FIGURE 17-1 Sites of action of antidepressants. A. In varicosities ("terminals") of norepinephrine (NE) neurons projecting from brainstem to forebrain, L-tyrosine is oxidized to dihydroxyphenylalanine (L-DOPA) by tyrosine hydroxylase (TH), then decarboxylated to dopamine (DA) by aromatic l-amino acid decarboxylase (AAD) and stored in vesicles, where side-chain oxidation by dopamine b-hydroxylase (DbH) converts DA to NE. Following exocytotic release by depolarization in the presence of Ca2+ (inhibited by lithium), NE interacts with postsynaptic a and b adrenergic receptor (R) subtypes as well as presynaptic a2 autoreceptors. Regulation of NE release by a2 receptors is principally through attenuation of Ca2+ currents and activation of K+ currents. Inactivation of trans-synaptic communication occurs primarily by active transport ("reuptake") into presynaptic terminals (inhibited by most tricyclic antidepressants [TCAs] and stimulants), with secondary deamination (by mitochondrial monoamine oxidase [MAO], blocked by MAO inhibitors). Blockade of inactivation of NE by TCAs initially leads to a2 receptor-mediated inhibition of firing rates, metabolic activity, and transmitter release from NE neurons; gradually, however, a2 autoreceptor response diminishes and presynaptic activity

Monoamine Oxidase Inhibitors

The MAOs comprise two structurally related flavin-containing enzymes, designated MAO-A and MAO-B, that share ~70% homology but are encoded by distinct genes. They are localized in mito-chondrial membranes and widely distributed throughout the body in nerve terminals, the liver, intestinal mucosa, platelets, and other organs. Within the CNS, MAO-A is expressed predominantly in noradrenergic neurons, while MAO-B is expressed in serotonergic and histaminergic neurons. MAO activity is closely linked functionally with an aldehyde reductase and an aldehyde dehydrogenase, depending on the substrate and tissue.

MAO regulates the metabolic degradation of catecholamines, 5-HT, and other endogenous amines in the CNS and peripheral tissues. Hepatic MAO has a crucial defensive role in inactivating circulating monoamines and compounds (e.g., the indirect-acting sympathomimetic tyramine) that are ingested or originate in the gut and get absorbed into the portal circulation. Inhibition of this enzyme system by MAO inhibitors causes a reduction in metabolism and a subsequent increase in the concentrations of biogenic amines. MAO-A preferentially deaminates Epi, NE, and 5-HT and is selectively inhibited by clorgyline, while MAO-B metabolizes phenethylamine and is inhibited by selegiline. DA and tyramine are metabolized by both MAO isozymes and both types are inhibited by phenelzine, tranylcypromine, and isocarboxazid.

Selective MAO-A inhibitors are more effective in treating major depression than type B inhibitors. The MAO-B inhibitor selegiline is approved for treatment of early Parkinson's disease and acts by potentiating remaining DA in degenerating nigrostriatal neurons and possibly by reducing neuronal damage due to reactive products of the oxidative metabolism of DA or other potential neurotoxins (see Chapter 20). Selegiline also has antidepressant effects, particularly at doses >10 mg that also inhibit MAO-A or yield amphetamine-like metabolites. Several short-acting selective inhibitors of MAO-A (e.g., brofaromine and moclobemide) and toloxatone have at least moderate antidepressant effects and are less likely to potentiate the pressor actions of tyra-mine and other indirect-acting sympathomimetic amines than are the nonselective, irreversible MAO inhibitors.

Although MAO inhibition occurs rapidly and is usually maximal within days, clinical benefits usually are delayed for several weeks, perhaps reflecting down-regulation of serotonergic and adrenergic receptors. Favorable clinical responses occur when human platelet MAO-B is inhibited by at least 85%, suggesting the need to use aggressive dosages to achieve the maximal therapeutic potential of MAO inhibitors. Finally, despite long-lasting inhibition of MAO by the irreversible inhibitors of MAO, optimal therapeutic benefit appears to require daily dosing.

ABSORPTION AND BIOAVAILABILITY Most antidepressants are fairly well absorbed after oral administration; nefazodone is an exception, with a bioavailability of -20%. The MAO inhibitors are absorbed readily when given by mouth. High doses of the strongly anticholinergic tricyclic antidepressants (Table 17-1) can slow GI activity and gastric emptying time, resulting in slower or erratic drug absorption and complicating management of acute overdosages. Serum concentrations of most tricyclic antidepressants peak within several hours. Injectable formulations of tricyclic antidepressants are not commercially available in the U.S.

DISTRIBUTION AND SERUM LEVEL MONITORING Once absorbed, tricyclic antidepressants are widely distributed. They are relatively lipophilic and strongly bind to plasma proteins and constituents of tissues, leading to apparent volumes of distribution as high as 10-50 L/kg. The tendency of tricyclic antidepressants and their ring-hydroxy metabolites to accumulate in cardiac tissue adds to their cardiotoxicity. Serum concentrations of antidepressants that correlate meaningfully with clinical effects are only established for a few tricyclic antidepressants (particularly amitriptyline,

FIGURE 17-1 (Continued) returns. Postsynaptically, b adrenergic receptors activate the GS-adenylyl cyclase (AC)-cyclic AMP (cAMP) pathway. Adrenergic a1 (and other) receptors activate the phospholipase C-Gq-IP3 pathway with secondary modulation of intracellular Ca2+ and protein kinases. Postsynaptic b receptors also desensitize; a1 receptors do not. B. Selective serotonin reuptake inhibitors (SSRIs) have analogous actions to TCAs at 5-HT-containing neurons, and TCAs can interact with serotonergic neurons and receptors. 5-HT is synthesized from l-tryptophan by a relatively rate-limiting tryptophan hydroxylase (TPH); the resulting 5-hydroxytryptophan is deaminated by AAD to 5-hydrox-ytryptamine (5-HT, serotonin). Following release, 5-HT interacts with a large number of postsynaptic 5-HT receptors that exert their effects through a variety of PLC and AC-mediated mechanisms. Inhibitory autoreceptors include types 5-HTXa and perhaps 5-HT7 receptor subtypes at cell bodies and dendrites, as well as 5-HT1D receptors at the nerve terminals; these receptors probably become desensitized following prolonged treatment with a SSRI antidepressant that blocks 5-HT transporters. The adrenergic and serotonergic systems also influence each other, in part through complementary heteroceptor mechanisms (inhibitory a2 receptors on 5-HT neurons, and inhibitory 5-HT1D and 5-HT2A receptors on noradrenergic neurons).

desipramine, imipramine, and nortriptyline), typically at concentrations of -100-250 ng/mL (Table 17-2). Toxic effects of tricyclic antidepressants can be expected at serum concentrations >500 ng/mL; levels >1 ,ug/mL can be fatal. Individual variance in tricyclic antidepressant levels in response to a given dose is as high as ten- to thirtyfold, due largely to genetic control of hepatic CYPs, but the utility of therapeutic drug monitoring in the routine clinical use of antidepressants is limited.

METABOLISM, HALF-LIVES, AND DURATION OF ACTION Tricyclic antidepressants are oxidized by hepatic CYPs, followed by conjugation with glucuronic acid. Hydroxy metabolites frequently retain some pharmacological activity. Conjugation of ring-hydroxylated metabolites with glucuronic acid extinguishes any remaining biological activity. The W-demethylated metabolites of several tricyclic antidepressants are pharmacologically active and may accumulate in concentrations approaching or exceeding those of the parent drug and contribute variably to overall

Table 17-2

Disposition of Antidepressants

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