Monoamine Reuptake Inhibitors

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Monoamine reuptake inhibition is the most common mechanism by which antidepres-sant drugs work. Drugs with this pharmacological action include the old TCAs, the selective 5-HT reuptake inhibitors (SSRIs), and several newer drugs such as venlafax-ine, duloxetine, and reboxetine. The older drugs in this group (such as imipramine, desipramine, and amitriptyline) tend to be relatively nonselective and frequently have many active metabolites. The newer drugs tend to be highly selective for reuptake blockade with less receptor blocking properties and because of this have fewer side effects (e.g., venlafaxine). Table 8.5 shows the relative affinity of selected antidepressants for binding to the 5-HT and NE transporters.

NE Reuptake Inhibitors (NRIs). Desipramine is one of the classical NRIs, and there are extensive data available regarding its clinical efficacy profile. It is well established as effective in the acute treatment of major depressive episodes in 45 to 63 percent of outpatients and 48 to 63 percent in inpatients (Depression Guideline Panel,

TABLE 8.4. Antidepressant Treatments

NE reuptake inhibitors

5-HT/NE reuptake

5-HT reuptake inhibitors

inhibitors

Desipramine (Norpramin

Imipramine (Tofranil and

Fluoxetine (Prozac)

and others)

others)

Sertraline (Zoloft)

Nortriptyline (Pamelor)

Doxepin (Sinequan)

Paroxetine (Paxil)

Protriptyline (Vivactil)

Amitriptyline (Elavil and

Fluvoxamine (Luvox)

Maprotiline (Ludiomil)

others)

Citalopram (Celexa)

Atomoxetine (Strattera)

Trimipramine (Surmontil)

S-Citalopram (Lexapro)

Reboxetine

Venlafaxine (Effexor)

Duloxetine (Cymbalta)

Milnacepram

Drugs with mixed actions

NE/DA reuptake inhibitors

Receptor antagonists

Chlorimipramine

Bupropion (Wellbutrin)

Nefazodone (Serzone)

(Anafranil)

Trazodone (Deseryl)

Mirtazapine (Remeron)

Amoxapine (Asendin)

Risperidone (Risperdal)

Olanzepine (Zyprexa)

Quetiapine (Seroquel)

Irreversible MAO

Monoamine releasing

5-HT1A partial agonists

inhibitors

agents

Isocarboxazid (Marplan)

d -Amphetamine (Dexedrine)

Buspirone (Buspar)

Phenelzine (Nardil)

Methylphenidate (Ritalin)

Gepirone

Tranylcypromine (Parnate)

Pemoline (Cylert)

Somatic treatments

Novel pharmacological

Psychotherapy treatments

targets

Electroconvulsive therapy

Neurokinin-1 receptor

Cognitive behavioral therapy

Full spectrum light therapy

antagonists

Interpersonal therapy

Vagal nerve stimulation

CRF antagonists

Transcranial magnetic

Glucocorticoid antagonists

stimulation

Glutamate receptor

Exercise

antagonists

MAO, monoamine oxidase; NE, norepinephrine; DA, dopamine; 5-HT, serotonin; CRF, corticotrophin releasing factor.

MAO, monoamine oxidase; NE, norepinephrine; DA, dopamine; 5-HT, serotonin; CRF, corticotrophin releasing factor.

1993). Like other tricyclic antidepressants, it has a host of pharmacological properties that contribute to its side effect burden. These include anticholinergic, antihistaminer-gic, and antiadrenergic effects (Depression Guideline Panel, 1993).

Bupropion is a very weak DA reuptake blockade inhibitor; its behavioral profile in laboratory animals and humans is that of a central nervous system (CNS) stimulant and indirect DA agonist (Bolden-Watson and Richelson, 1993). It has no significant effects at blocking reuptake of 5-HT or NE, although its primary metabolite (hydroxybupro-pion) is a potent NE reuptake inhibitor (Ferris and Cooper, 1993). Hydroxybupropion

TABLE 8.5. Affinity of Selected Antidepressants for Binding to NE and 5-HT Transporters

Drug

NE (nM/L)

5-HT (nM/L)

NE/5-HT

Reboxetinea

11.0

440.0

0.03

Atomoxetinea

5.0

77.0

0.06

Desipramineb

13.7

75.5

0.18

Amitriptylineb

13.8

9.4

1.47

Nefazodoneb

586.5

339.5

1.73

Imipramineb

15.5

5.0

3.10

Duloxetinec

5.6

0.7

8.00

Venlafaxineb

1668.0

13.5

123.56

Fluoxetined

599.0

1.1

544.55

Paroxetined

45.0

0.1

450.00

Fluvoxamined

1427.0

2.3

620.43

Sertralined

714.0

0.3

2380.00

Citalopramd

6190.0

1.6

3868.75

Escitalopramd

7841.0

1.1

7128.18

Bupropiona

>10,000

>10,000

bRoth B, (2003); NIH Psychoactive Drug Screening Program,

http://pdsp.cwra.edu/stest.asp. c Bymaster et al. (2001). dOwens et al. (2001).

bRoth B, (2003); NIH Psychoactive Drug Screening Program,

http://pdsp.cwra.edu/stest.asp. c Bymaster et al. (2001). dOwens et al. (2001).

is produced rapidly in humans, with peak plasma levels of up to 3 times those of bupropion and a half-life of 24 hr. Therefore, orally administered bupropion is likely to lead to significant NE reuptake inhibition and relatively less DA reuptake inhibition. Bupropion increases locomotor activity and causes stereotyped behaviors in laboratory animals. In humans, it can cause restlessness, insomnia, anorexia, and psychosis. Bupropion is structurally related to phenylethylamines and unrelated to the TCAs, SSRIs, or MAOIs. It has no significant potency at binding to any known neurotransmitter receptors. Clinical studies have demonstrated that bupropion is effective in the treatment of major depressive episodes (Depression Guideline Panel, 1993). While early studies suggested that bupropion might be less likely to cause hypomania or mania in bipolar patients, subsequent studies suggested that it can cause mania and psychosis in bipolar patients, especially those with high pretreatment levels of the DA metabolite, homovanillic acid (HVA) (Golden et al., 1988). In a recent open-label study, bupropion was not effective for treatment of PTSD (Canive et al., 1998). However, contrary to commonly held clinical impressions, bupropion was reported to have therapeutic effects in a patient with social phobia (Emmanuel et al., 1991). Additionally, a recent review contrasting the relative efficacy of bupropion and sertraline in treatment of anxiety symptoms in patients with major depression showed that a baseline Hamilton Anxiety Scale (Ham-A) score did not predict response to either drug (Rush et al., 2001), and both drugs equally reduced Ham-A total score (Trivedi et al., 2001).

Reboxetine was approved for use as an antidepressant in much of western Europe, South America, and Mexico in 1998. Reboxetine is the only truly selective NRI being marketed as an antidepressant, although U.S. Food and Drug Administration (FDA) approval has recently been granted to atomoxetine, a selective NRI (Bymaster et al., 2002) approved for the treatment of attention deficit disorder. Reboxetine potently inhibits the reuptake of NE without having significant effects on the reuptake of 5-HT or DA. It does not inhibit MAO, nor does it bind to 5-HT1a or 5-HT2a, DA1 or DA2, a-or p-adrenergic, muscarinic cholinergic, gamma-aminobutyric acid (GABA), benzodi-azepine, or histamine H1 receptors. Reboxetine has primarily been studied in European trials involving about 665 nonelderly and 56 elderly (age >65 years) depressed patients (Burrows et al., 1998). It is administered twice per day at doses ranging from 4 to 12 mg/day. The European data show that reboxetine is more effective than placebo and comparable to imipramine, desipramine, and fluoxetine for the treatment of major depression. Reboxetine has also been found to be equally effective as imipramine in severely ill depressed patients and melancholic depressed patients. One study found that while reboxetine restored normal function as measured on a social adjustment scale, fluoxetine did not (Dubini et al., 1997). The finding of improved social adjustment was interpreted to support the specific involvement of the NE system in "sustaining drive" (Dubini et al., 1997). A recent study showed reboxetine to be highly effective in treatment of panic disorder (Versiani et al., 2002).

SSRIs. The five drugs in this class are fluoxetine, sertraline, paroxetine, fluvox-amine, and citalopram (and escitalopram). All are relatively new and were developed because they are potent and selective 5-HT reuptake inhibitors (Leonard, 1992). They share similar side effects and therapeutic spectrum of action, being effective in the treatment of MDE, OCD and panic disorder.

Early clinical experience suggests that while these drugs are more similar than they are different, variations are found in their side effect profiles that are unexplained by current knowledge. These include sedation/asthenia vs. activation and the propensity to cause nausea. In general fluvoxamine and paroxetine are more frequently associated with nausea and a sedation-like feeling referred to as "asthenia," whereas fluoxetine and sertraline are more "activating." Interesting differences that may have clinical relevance include the potency of sertraline in blocking DA reuptake (Bolden-Watson & Richelson, 1993) and in binding to sigma receptors (Tulloch & Johnson, 1992), and of paroxetine for inhibition of NE reuptake (Owens et al., 2000). These data suggest that sertraline may be problematic in psychotic depression and that in high doses paroxetine may be a dual 5-HT/NE reuptake inhibitor, although this is probably only seen at doses higher than the maximum recommended daily dose of 40 mg. Paroxetine is also an inhibitor of the enzyme nitric oxide synthetase (Finkel et al., 2002), possibly contributing to a slightly higher rate of sexual dysfunction compared with other SSRIs (Montejo et al., 2001).

Citalopram is intermediate in most side effects compared to other SSRIs, probably accounting for its popularity in Europe and the United States. Escitalopram, the /-stereoisomer of citalopram, improves on the selectivity of the racemic drug by increasing potency for the 5-HT transporter (Owens et al., 2001). Studies comparing it with citalopram suggest that it has equal efficacy and a similar side effect profile (Gorman et al., 2002).

Clinical Differences between SSRIs and NRIs in Depression Studies. Nelson (1999) recently published a comprehensive review of prior studies comparing an NRI to an SSRI in patients with major depression. Sixteen studies were reviewed (Nelson, 1999). The NE selective agents included desipramine, nortriptyline, reboxetine, lofepramine, and maprotiline, and SSRIs included fluoxetine, paroxetine, sertraline, fluvoxamine, zimelidine, and citalopram. A total of 1563 patients were included in these studies. Response rates were similar, 65 and 60 percent, for the SSRIs and NRIs. When baseline symptoms that predict response were examined, there were no consistent findings across studies, although some studies have found baseline anxiety to predict preferential response to SSRIs versus NRIs (Tyrer et al., 1980; Aberg-Wistedt, 1982). The topic of whether NRIs are as effective for anxiety symptoms/disorders as SSRIs continues to be an important focus of debate. In part, this debate is fueled by the lack of efficacy of NRIs for OCD (Goodman et al., 1990; Leonard et al., 1991; Lelliott and Montiero, 1986) and PTSD (Reist et al., 1989; Dow and Kline, 1997; Canive et al., 1998), as well as a generally held perception that SSRIs are more effective in depressed patients with moderate to severe anxiety symptoms (Blackwell, 1987). Arguing against a significant class difference in efficacy in patients with comorbid major depression and anxiety symptoms are the studies showing NRIs to be effective in panic disorder (Kalus et al., 1991; Lydiard et al., 1993; Villarreal, 1995; Rudolph and Feiger, 1999; Versiani et al., 2002) as well as a recent study showing that a baseline Ham-A score did not predict response to either sertraline or bupropion during treatment of depression (Rush et al., 2001).

Dual NE/5-HT Reuptake Inhibitors. Approved by the FDA for the treatment of major depression in 1994, venlafaxine is the oldest of the newer antidepressants and stands out from most of the others in having minimal effects on blocking neuro-transmitter receptors. It is as potent at blocking 5-HT reuptake as imipramine, but is weaker at blocking NE reuptake, making it slightly more selective for 5-HT than NE, especially at lower doses. It does not inhibit MAO and does not significantly bind to 5-HT, NE, DA, muscarinic cholinergic, a1-, a2-adrenergic, or histamine H1 receptors (Muth et al., 1991).

Venlafaxine has fared well in placebo-controlled studies and has shown efficacy in inpatients and outpatients with major depression and in patients with major depression with melancholia (Feighner, 1993; Rudolph and Feiger, 1999). In contrast to SSRIs, there is evidence for a dose-response relationship, with higher doses being more likely to lead to successful antidepressant responses than lower doses. This has been hypothesized to be due to the likelihood that at lower doses (less than 150 mg/day) venlafaxine is predominantly an SSRI and at higher doses the NE reuptake inhibition begins to contribute to its action (Nirenberg et al., 1994; Benkert et al., 1996).

Several studies suggest that venlafaxine may lead to higher rates of response and a more "robust" profile of response (when more stringent response criteria are used)

when compared to fluoxetine, imipramine, or paroxetine (Thase et al., 2001). This is especially true in severely ill or melancholic depressed patients (Clerk et al., 1994).

Venlafaxine may have as broad (or broader) an efficacy profile as SSRIs. Small open-label studies have suggested efficacy in obsessive-compulsive disorder (OCD) (Zajecka et al., 1990; Rauch et al., 1996; Taryura-Tobias & Neziroglu, 1996; Grossman & Hollander, 1996), panic disorder (Geracioti, 1995; Papp et al., 1998), attention deficit hyperactivity disorder (Wilens et al., 1995; Pleak & Gormly 1995), and social phobia (Kelsey, 1995).

Duloxetine was approved by the FDA for the treatment of major depression in 2003. Like venlafaxine, it selectively and potently blocks reuptake of both 5-HT and NE. Unlike venlafaxine, the binding affinity of duloxetine for 5-HT and NE transporters suggests that it is likely to cause significant reuptake inhibition of both monoamines at the usual clinical doses, therefore requiring less titration to achieve "dual action." It does not inhibit MAO and does not significantly bind to most 5-HT, NE, DA, muscarinic cholinergic, a1-, a2--adrenergic, or histamine H1 receptors (Bymaster et al., 2001). It has weak 5-HT2A and 5-HT6 receptor binding affinities and weakly inhibits DA reuptake (Bymaster et al., 2001), although it is unlikely that these effects are clinically significant at the usual doses.

Duloxetine had a better than average rate of success in the Phase II and III clinical efficacy trials required for FDA approval (Detke et al., 2002; Goldstein et al., 2002). In Phase II and III trials it showed superiority over both placebo and comparator drugs (fluoxetine and paroxetine), reinforcing the message that dual 5-HT/NE antidepressants may have a more robust efficacy profile than selective 5-HT or NE reuptake inhibitors (Thase et al., 2001).

Duloxetine is dosed once daily with a usual initial daily dose of 60 mg. It shows a benign side effect profile, similar to SSRIs, with most patients tolerating the drug extremely well. When side effects occur, the most common include insomnia and asthenia (Goldstein et al., 2002; Detke et al., 2002). There were no significant cardiovascular or genitourinary side effects, no weight gain, and sexual side effects as measured by the Arizona Sexual Experiences Scale did not differ from placebo (Goldstein et al., 2002).

Duloxetine has been shown to be effective in reducing physical symptoms (back pain, shoulder pain, headache) in depressed patients as well as the core depressive symptoms (Detke et al., 2002), possibly due to its dual action on 5-HT and NE systems (Stahl, 2002). These findings have stimulated a renewed interest in reevaluating the diagnostic criteria for major depression given the relative underrepresentation of physical symptoms in the DSM-IV criteria (Fava, 1996).

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