■ 1 History of Depression and Antidepressants

“To live is to suffer, to survive is to find some meaning in the suffering.” Nietzsche’s words ring true to many. Depression is romanticized at times due to its association with poets and artists, but in reality depression, especially major depressive disorder (MDD), can be debilitating.

There are two types of depression: MDD and bipolar, also known as manic–depressive illness. Severe changes in mood is the primary clinical manifestation of both disorders. MDD presents as feelings of intense sadness and despair with little drive for either socialization or communication; physical changes such as insomnia, anorexia, and sexual dysfunction can also occur. Mania is manifested by excessive elation, irritability, insomnia, hyperactivity, and impaired judgment. It may afflict as much as 1% of the population.

MDD is among the most common psychiatric disorders in humans, affecting up to 10% of men and 20% of women over the course of their lives. Among those affected, 28% experience a moderate degree of functional impairment, while 59% experience severe reductions in their normal functional ability. About 19 million Americans suffer from depression per year. In terms of disease burden, MDD ranks as the fourth most costly illness in the world, with estimated annual costs of depression in the US amounting to approximately $43.7 billion.

While we all agree that depression exists, we do not all agree on the causes of depression. The exact causes of depression are not definitively known. However, in the 1950s, it was observed that in addition to its other pharmacological properties, reserpine (a Rauwolfia alkaloid) induced a depressive state in normal patients and also depleted levels of neurotransmitters such as norepinephrine (NE) and serotonin (5-HT). This observation and others led to the hypothesis that the biological basis of major mood disorders may include abnormal monoamine neurotransmission. Substances such as NE, serotonin, and dopamine (DA) mediate neurotransmission. These substances are released from presynaptic neurons, cross the synaptic gap, and interact with receptors on the postsynaptic cells. The synthesis, transmission, and processing of these neurotransmitters provide a number of points of intervention through which a pharmacological agent may affect transmission. The monoamine hypothesis of depression has held true thus far and manipulation of neurotransmission has been the mainstay of antidepressant therapy for more than half a century. Recently, the serotonin/NE link hypothesis has gained momentum as well, as manifested by the popularity of Cymbalta (1).

Several interventions for MDD are possible, including (1) inhibiting enzymes that synthesize neurotransmitters, (2) preventing neurotransmitter storage in synaptic vesicles, (3) blocking the release of the neurotransmitter into the synaptic gap, (4) inhibiting neurotransmitter degradation, (5) blocking neurotransmitter reuptake (removal), (6) agonism or antagonism of the postsynaptic receptor, and (7) inhibiting signal transduction within the postsynaptic cell. Pharmacological agents have been identified which affect all of these processes; however, the mainstays of antidepressant therapy have been agents that affect neurotransmitter degradation and reuptake.

1.1 Monoamine Oxidase Inhibitors

Discovered in 1951 by Hoffmann-La Roche, antibacterial isoniazid (2) was credited with dramatically reducing the incidence of tuberculosis in the United States. In 1952, iproniazid (Marsilid, 3) was initially prepared, also by Hoffmann-La Roche, as an anti-tuberculosis drug to improve upon isoniazid (2)’s profile. Kline at Rockland State Hospital observed that iproniazid (3) showed a mood-enhancing effect on TB patients.¹–⁴ From then on, iproniazid (3) was widely prescribed “off-label” (i.e., for a use not approved by the FDA) as an antidepressant. However, hepatoxicity (possibly because the presence of the oxidizable group hydrazine) was observed with iproniazid (3) and it was withdrawn from the US market in 1961.

Mood elevation was assumed to result from the accumulation of amines such as NE and serotonin in the central nervous system (CNS). It was later found that both were monoamine oxidase inhibitors (MAOIs). Monoamine deoxidase (MAO) is a flavin-containing enzyme found in the mitochondria of neurons and other cell types. It oxidatively deaminates naturally occurring sympathomimetic monoamines such as NE, dopamine, and serotonin within the pre-synapse. MAOIs and their use in the treatment of depressed patients was a major milestone in modern psychiatry. Due to their unfavorable efficacy-safety profile, they have been replaced—initially by tricyclic antidepressants (their use has been in decline as well) and now largely by selective serotonin reuptake inhibitors (SSRIs).

At present, three MAOIs are still in use: phenelzine (Nardil, 4), tranylcypromine (Parnate, 5), and isocarboxazid (Marplan, 6). All three MAOIs are nonselective MAOIs, inactivating both Type A and Type MAOs. They inhibit MOA irreversibly so they are also known as suicide inhibitors. They are classified as first-generation MAOIs.

One of the side effects of MAOIs is hypertension, also secondary to catecholamine excess, usually in association with the consumption of other catechols or catechol precursors such as tyramine (the so-called cheese effect). In an effort to develop safer MAOIs—at least away from the hypertensive liability, two subtypes of the MAO receptor have been identified, MAO-A and MAO-B. An irreversible selective MAO-B inhibitor, selegiline (Eldepryl, 7), has been used to treat movement disorders caused by Parkinson’s disease. Selegiline (7) is known as the second-generation MAOI. (Interestingly, selegiline (7) is metabolized to L-methamphetamine and L-amphetamine in humans.⁵,⁶)

In addition to older, irreversible nonselective (first-generation) MAOIs 4–6 and the second generation irreversible selective drug selegiline (7), there are third-generation MAOIs that are newer, reversible selective MAOIs. These include moclobemide (Manerix, 8), toloxatone (Humoryl, 9), and brofaromine (Consonar, 10), which are also known as reversible inhibitors of MOA-A (RIMAs).

Both moclobemide (8) and brofaromine (10) are effective treatments for depression; they seem to be as effective as phenelzine (4) and tranylcypromine (5). Selegiline (7) has significant antidepressive efficacy, but only at high doses where there is likely to be a loss of selective inhibition of MAO-B.⁷ Moclobemide (8) has a more favorable overall tolerability profile than tranylcypromine (5), with a lower incidence of adverse effects. In particular, the lack of behavioral toxicity, minimal potentiation for the tyramine pressor response, and safety in overdose are clear-cut advantages of RIMAs over older MAOIs.

Currently, the MAOIs only play a subordinate role as second-line treatments. They have been largely replaced by tricyclic antidepressants (TCAs), SSRIs, and serotonin and norepinephrine reuptake inhibitors (SNRIs).

1.2 Tricyclic Antidepressants

Imipramine (Tofranil, 12) was prepared by Geigy as an analog of an antipsychotic chlorpromazine (Thorazine, 11).⁸ In 1958, imipramine’s (Tofranil, 12) pronounced mood elevation in tuberculosis patients was disclosed, thus heralding the arrival of TCAs.

Imipramine (12) works by inhibiting NE reuptake at the adrenergic endings, and serotonin to a lesser extent. In general, the MOA of TCAs is inhibition of reuptake of the biogenic amines. When a neurotransmitter is released from a cell, it has only a short period of time to relay its signal before it is either metabolized by MAO or reabsorbed into the cell. All of the TCAs potentiate the actions of NE, serotonin, and to a lesser extent, dopamine. However, the potency and selectivity for inhibiting the uptake of these amines vary greatly among the agents.

In addition to imipramine (Tofranil, 12), TCAs 13–15 are known as the first-generation TCAs to work by a similar mechanism. The so-called second-generation TCAs (also known as atypical antidepressants) include amoxapine (Asendin, 16) and clomipramine (Anafranil, 17).

Structurally different from the TCAs, amoxapine (Asendin, 16) is primarily a norepinephrine reuptake inhibitor, clinically as effective as imipramine (12) although it may be slightly more effective in relieving accompanying anxiety and agitation. Unfortunately, like most TCAs, overdose of amoxapine (16) can result in fatality.

Structurally a TCA, clomipramine (17) exerts inhibitory effects on serotonin (5-HT) reuptake. Its metabolite demethyl-clomipramine also inhibits NE reuptake. Therefore, is classified as an SNRI, the same class as Cymbalta (1). In addition to being prescribed as a TCA, clomipramine (17) has been prescribed to treat obsessive-compulsive disorder (OCD) for many years with about 45–75% of patients responding favorably. Because clomipramine (17) has an additional chlorine atom in comparison to imipramine (12), its half-life is twice as long. The value of t_1/2 for clomipramine (17) is 20–40 h whereas t_1/2 for imipramine (12) is 10–25 h, a testimony to the metabolism-resistant property of a chlorine atom in place of a proton.

Because all TCAs are lipophilic, they are well absorbed after oral administration. They distribute widely in tissues of the body. The most prominent metabolism is demethylation of the ubiquitous dimethylamine to give the corresponding secondary amines that are also active. TCAs have long half-lives, frequently more than 24 h, which allows once-daily dosing. This feature is a major factor in achieving compliance and thus therapeutic success.

Even though these TCA agents are efficacious in their management of depression, they have significant side effects and toxicities (e.g., flushing, sweating, orthostatic hypotension, constipation). Some side effects are due to their α-adrenergic blocking activity. All the TCAs are especially toxic in overdose, producing cardiac effects and seizures.

1.3 Selective Serotonin Reuptake Inhibitors

The search for less toxic monoamine reuptake inhibitors led to the development of the safer antidepressants known as SSRIs.⁹–¹³ Initially, AB Astra discovered and marketed zimelidine (Zelmid, 18), the prototype of the SSRIs. Unfortunately, a rare but serious side effect, Guillain-Barré syndrome, surfaced after zimeldine (18) was approved in 1982 and administered in a large patient base. AB Astra pulled it off the market one year later.

Using diphenhydramine (Benadryl, 19) as the starting point, Elli Lilly discovered fluoxetine hydrochloride (Prozac, 20).¹⁴ It was approved by the FDA in 1988 and rapidly revolutionized the treatment of depression thanks largely to its superior safety profile. Prozac transformed debilitating depression into a manageable disease for many patients. In fact, unlike the previous relatively toxic TCAs, which were prescribed primarily by psychiatrists, the much safer Prozac was frequently prescribed by non-psychiatrists and general practitioners, taking the field of psychiatry more into the open. In 2000, Prozac was the most widely prescribed antidepressant drug in the United States with worldwide sales of $2.58 billion.

After Prozac’s (20) tremendous success, many additional SSRIs soon followed. Pfizer’s sertraline hydrochloride (Zoloft, 21) and GSK’s paroxetine hydrochloride (Paxil, 22) were launched in the Unites States in 1992. Compared to Prozac (20), Zoloft (21) has a shorter duration of action and fewer CNS-activating side effects such as nervousness and anxiety. Paxil (22)’s relatively benign side-effect profile favors its use in elderly patients.

Lundbeck’s racemic citalopram (Celexa, 23) was approved by the FDA in 1998 and its single (S)-enantiomer, escitalopram (Lexapro, 24), became available in the United States in 2002. Solvy’s (now part of Abbvie) fluvoxamine (Luvox, 25) was approved by the FDA in 1994. Merck KGaA/Forest’s vilazodone (Viibryn, 26), approved by the FDA in 2011, is a combined SSRI (5-HT) and partial agonist at serotonin 1A (5-HT_1A) receptors.¹⁵ Vilazodone (26) exhibits a ~300-fold selectivity for the serotonin over the NE reuptake and is inactive (or shows negligible activity) against the other 5-HT receptors, including 5-HT_1D, 5-HT_2A, and 5-HT_2C.

Pharmacologically, SSRIs block neuronal transport of serotonin leading to increased synaptic serotonin, which in turn stimulates a large number of postsynaptic serotonin receptor types including 5-HT1B, 5-HT1D, 5-HT3 and 5-HT2C (there are 14 subtypes of serotonin receptors). Stimulation of different receptors leads to analgesia, gastrointestinal side effects and sexual dysfunction (5-HT3), and agitation and restlessness (5-HT2C). There is also a negative-feedback mechanism (by action of 5-HT1A and 1D) that suppresses serotonin neurons and decreases neuronal release of serotonin.¹⁶

SSRIs 20–26 differ from the older TCAs in that they selectively inhibit the reuptake of serotonin into the presynaptic nerve terminals and therefore enhance synaptic concentrations of serotonin and facilitate serotonergic transmission. This increased neurotransmission and the elevated synaptic levels of serotonin alleviate the symptoms and possibly the etiology of depression. Relative to the TCAs they have a favorable side-effect profile and are much safer in overdose. However, they are generally not more efficacious than the TCAs, they exhibit a marked delay in onset of action (it generally takes 2–3 weeks for the efficacy to manifest), and they have their own set of side effects resulting from the nonselective stimulation of serotonergic receptor sites.

SSRIs are now the first-line treatment for depression but their efficacy in major depression is no greater than TCAs. Some studies have shown that TCAs such as clomipramine (17) may have greater efficacy than that SSRIs such as paroxetine (22) and citalopram (23). Although they are not more efficacious than some TCAs, SSRIs possess much better safety profiles with fewer adverse effects and thus show higher compliance rates.

1.4 Serotonin and Norepinephrine Reuptake Inhibitors

Due to genetic disparities, each individual responds differently to different types of antidepressants. Many second- and third-generation antidepressants have been discovered, providing a wide variety of choice in managing depression.

The monoamine hypothesis advanced in 1965 postulated that depression is a consequence of decrease of amines such as serotonin (5-HT) and NE. Indeed TCAs inhibit the reuptake of both 5-HT and NE. Relatively selective NE reuptake inhibitors have clear antidepressant efficacy. Increasing NE neurotransmission via blockade of α2-adrenoceptors improves depressive symptoms. Finally, electroconvulsive therapy (ECT) has been shown to increase the release of NE. All this evidence indicates that stopping the removal of NE will have a beneficial effect on the mood. This is why SNRIs are also known as “boosted” SSRIs by some or “better tolerated tricyclic antidepressants” by others. SNRIs have a spectrum of ratios of 5-HT and NE, which are responsible for their diverse pharmacological effects.¹⁷

In 1993, venlafaxine (Effexor, 27) was the first SNRI to be introduced. Effexor was Wyeth’s largest selling drug with over $3 billion in sales in 2004. Today, Effexor (27) has become a therapeutic reference for major depression. Desvenlafaxine (Pristiq, 28), the only major active renal metabolite of venlafaxine (27) was approved by the FDA in 2007 as the first non–hormone-based treatment for menopause. While Effexor (27) has an NE/5-HT affinity ratio of 30, and Pristiq (28) has an NE/5-HT affinity ratio of 13.8, 70% of venlafaxine (27) is metabolized to Pristiq (28), so the effects of the drugs are largely similar.¹⁷ Milnacipran (Ixel, 29) was approved in the United States in 2009 for the treatment of fibromyalgia but not for MDD. Although it has an NE/5-HT affinity ratio of 1.16, which is vastly different from that of venlafaxine (27), the two drugs are clinically equivalent in terms of efficacy, with milnacipran (Ixel, 29) having certain advantages when sexual dysfunction, overdose, and polymedication are concerned.¹⁸

In addition to the MAOIs, TCAs, SSRIs, and SNRIs mentioned above, other antidepressants with different MOA exist as well. For instance, Wyeth’s bupropion (Wellbutrin, 30) is a norepinephrine and dopamine reuptake inhibitors (NDRIs). It was approved in 1985 as both an atypical antidepressant and a smoking cessation aid. Trazodone (Depyrel, 31) is a serotonin receptor antagonist and reuptake inhibitor (SARI). The drug is approved and marketed in several countries for the treatment of MDD in adult patients.¹⁹ On the other hand, vilazodone (Viibryd, 32) is a serotonin partial agonist and reuptake inhibitor (SPARI).²⁰ Lundebeck’s vortioxetine (Brintellix, 33) was approved by the FDA for the treatment of MDD in 2013. It is a novel multimodal compound for the treatment of MDD with combined effects on 5-HT3A and 5-HT1A receptors and on the serotonin transporter (SERT).²¹

In addition to all the dual reuptake inhibitors, serotonin–norepinephrine–dopamine reuptake inhibitors, also known as triple reuptake inhibitors, have been intensively studied during the last decade.²² Although no triple reuptake inhibitors have been licensed in the US just yet, this class of antidepressants could provide better and faster onset medicine to treat MDD.

The focus of this chapter is Lilly’s duloxetine hydrochloride (Cymbalta, 1), an SNRI. It reached the market in 1994 and was a blockbuster drug, racking up to $6.3 billion in sales in 2013. It became available as a generic in December 2013.

■ 2 Pharmacology

2.1 Mechanism of Action

Cymbalta (1) is a dual monoamine modulator. It binds selectively with high affinity to both NE and serotonin (5-HT) transporters and lacks affinity for monoamine receptors within the central nervous system.²³–²⁸

In vitro, Cymbalta (1) inhibits both norepinephrine and serotonin uptake carriers with Ki values of 7.5nM and 0.8 nM, respectively.²³ This translates to an NE/5-HT ratio of 9.4. It does not appear to directly modulate dopaminergic function. Similar to TCAs, Cymbalta (1) has no affinity for dopamine transporter (DAT, Ki 240 nM) and no significant binding affinity for dopamine, serotonin, adrenergic, histaminic, or opioid receptors. It does not affect the activity of γ-aminobutyric acid (GABA) transporter and MAO activity either. So it is a relatively clean (meaning selective) drug. In vitro inhibition profiles of radioligand binding to human monoamine transporters by Cymbalta (1), venlafaxine (27), and milnacipran (29), also all SNRIs, are listed in Table 7.1 for comparison purposes.²⁴

Table 7.1. Transporter binding profiles of antidepressants 1, 27, and 29²³

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