Mirtazapine action

Mirtazapine (Remeron). Mirtazapine is the newest of the atypical antidepressants. It mainly works by blocking the alpha-2 negative feedback receptor and thus increases norepinephrine and serotonin activity. In addition, mirtazapine blocks serotonin-2 and serotonin-3 receptors to produce a specific serotonin action like nefazodone. Mirtazapine is approved for the treatment of depression. Its use in the anxiety disorders is being studied. 

Mirtazapine has a novel mechanism of action that in theory should promote anxiolytic effects, although evidence from studies of anxiety disorders is awaited. It increases synaptic release of serotonin and noradrenaline via blockade of presynaptic inhibitory a2-adrenoceptors, as well as blocking post-synaptic 5-HT2 and 5-HT3 serotonin receptors and Hi histamine receptors. Mirtazapine has good efficacy for anxiety symptoms associated with depression (Fawcett and Barkin 1998), and in controlled studies was superior to... 

Other available antidepressants have unique mechanisms of action that may have an impact on norepinephrine, serotonin, or dopamine indirectly through other mechanisms. For example, mirtazapine s direct antagonism of presynaptic a2-adrenergic receptors results in an indirect increase in central noradrenergic and serotonergic activity. 

Mirtazapine is an antidepressant with a novel mechanism of action affecting both 5-HT and noradrenergic function. A recent systematic, open-label study found that 9 (34.6%) of 26 subjects (5 females, 21 males mean age, 10.1 +/— 4.8 years, age range 3.8-23.5 years) with autistic disorder and other PDDs were much improved or very much improved on the CGI after a mean duration of treatment of 5 months (Posey et al., 2001). The dosage range for mirtazapine was 7.5 to 45 mg/day with a mean daily dose of 30.29 mg +/— 12.64 mg. Target symptoms of aggression, self-injury, irritability, hyperactivity, anxiety, depression, and insomnia showed improvement. Adverse effects were transient and minimal and included increased appetite, irritability, and sedation. Based upon these preliminary data, a double-blind, placebo-controlled trial appears warranted. 

On the basis of the large placebo-controlled studies, mirtazapine has undoubted antidepressant action and is licensed in both Europe and the United States [Claghorn and Lesem 1995 Sitsen et al. 1995). The evidence for superior efficacy is again limited by the failure to set up studies that were large enough to provide an adequate test of two active antidepressants. Nevertheless, mirtazapine has been shown to be more effective than trazodone in hospitalized patients with major depression (van Moffaert et al. 1995) and in a more recent study, mirtazapine was more effective than fluoxetine given in a dose of 20 mg [S. A. Montgomery 1996). 

We are not aware, however, of any studies, to date, that show that either mianserin or mirtazapine produces sustained adrenoceptor or h-HTj receptor blockade in humans. Indeed, in animals, mianserin has been reported not to block Oj adrenoceptors following long-term administration [Sugrue 1980]. Elsewhere it has been argued that the 5-HT2 antagonism might be important in the action of mianserin because the more selective Oj antagonists tested, to date, do not, by themselves, appear to be clearly effective antide-... 

Although the efficacy of tricyclic antidepressants in the treatment of unipolar depression is beyond reproach, the side-effect profile of these agents makes them less desirable as first-line therapeutic agents. Introduction of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine in the past decade has revolutionized the treatment of depression universally. The side-effect profile of SSRIs, such as nausea, diarrhea and sexual dysfunction, is considerably more benign than that of tricyclic drugs. Multiple controlled trials have proven the efficacy of SSRIs vs. placebo (Nemeroff, 1994). Recently, a number of SNRIs (serotonin and noradrenaline reuptake inhibitors) and so-called atypical antidepressants have been marketed that may have additional advantages over SSRIs, such as more rapid onset of action (venlafaxine. mirtazapine) and low sexual side-effect potential ( bupropion, nefazodone). Additionally, it appears that venlafaxine may be more efficacious in cases of treatment-refractory depression (Clerc et al., 1994 Fatemi et al., 1999). Finally, in a recent report (Thase et al., 2001),... 

Treatment of GAD can be undertaken using a number of pharmacological agents. Benzodiazepines have been found to be superior to placebo in several studies and all benzodiazepines appear to be equally effective. However, side effects include sedation, psvchomotor impairment, amnesia and tolerance (Chapter 1). Recent clinical data indicate that SSRIs and SNRIs are effective in the treatment of acute GAD symptoms. Venlafaxine, paroxetine and imipramine have been shown to be effective antianxiety medications in placebo-controlled studies. Case studies also indicate the usefulness of clomipramine, nefazodone, mirtazapine, fluoxetine and fluvoxamine in GAD. Buspirone, a 5-HTla receptor partial agonist, has been shown to be effective in several placebo-controlled, double-blind trials (Roy-Byme and Cowley, 2002). Buspirone has a later onset of action than both benzodiazepines and SSRIs but with the advantage of being non-addictive and non-sedating. 

Mirtazapine has been on the market in the United States since August 1996, and it is available in several other countries. The putative mechanism of action mediating antidepressant activity is the blockade of several serotonin receptors (i.e., 5-HT 2a and 5-HT2c) and a2-adrenergic receptors (172). The latter effect increases NE... 

Other Serotonergic Antidepressants In recent years, new antidepressants with serotonergic actions have also been shown to benefit patients with chronic PTSD, many of whom had been treatment refractory. These drugs include venlafaxine (278), mirtazapine (279), and nefazodone (280). 

Amoxapine is sometimes associated with a parkinsonian syndrome due to its Deblocking action. Mirtazapine has... 

In addition to its efficacy as a first-line antidepressant, mirtazapine may have enhanced efficacy due to its dual mechanism of action (Fig. 7—3), especially in combination with other antidepressants that block serotonin and/or norepinephrine reuptake. This will be discussed below in the section on antidepressant combinations. Mirtazapine may also have utility in panic disorder, generalized anxiety disorder, and other anxiety disorders, but has not been intensively studied for these indications. 

FIGURE 7—12. When mirtazapine blocks histamine 1 receptors, it can cause anxiolytic actions, but also sedation and weight gain as side effects. 

Newer antidepressants. Although the SSRIs are the only antidepressants formally approved for the treatment of panic disorder, recent evidence suggests that several other antidepressants are promising treatments for panic disorder as well. These include nefazodone, venlafaxine XR, mirtazapine, and reboxetine. Bupropion, however, does not seem to have apparent antipanic actions. Since the documentation of efficacy of these newer antidepressants in panic disorder is still emerging, they tend to be used as second-line therapy after SSRIs foil to improve panic or in patients who cannot tolerate them. 

FIGURE 9-6. Various treatments can be given in combination for panic disorder (i.e., panic combos). The basis of all many combination treatments is a serotonin selective reuptake inhibitor (SSRI). Other antidepressants such as venlafaxine, nefazodone, mirtazapine, tricyclic antidepressants, and monoamine oxidase inhibitors can all have antipanic actions, although they are second-line treatments, as are the benzodiazepines. On the other hand, benzodiazepines are often added to SSRIs, particularly at the initiation of an SSRI and intermittently when there is breakthrough panic. Cognitive and behavioral psychotherapies can also be added to any of these drug treatments. 

To review the mechanism of action of dual reuptake inhibitors such as venlafaxine as well as other dual action antidepressants such as mirtazapine, and serotonin 2A antagonists such as nefazodone. 

Three antidepressants—nefazodone, venlafaxine, and mirtazapine—are all related to earlier agents in either structure or mechanism of action. Nefazodone is closely related to trazodone but is less sedating. It produces fewer adverse sexual effects than the SSRIs but is a potent inhibitor of CYP3 A4. (Fluvoxamine causes the same inhibition of CYP3 A4.)... 

None of the newer antidepressants have been shown to be more effective overall than the tricyclics with which they have been compared. Solid evidence to support a claim of more rapid onset of action has been difficult to obtain. Amoxapine and maprotiline seem to have as many sedative and autonomic actions as most tricyclics more recently introduced antidepressants such as bupropion and venlafaxine have fewer, although nefazodone and mirtazapine are very sedating. Amoxapine and maprotiline are at least as dangerous as the tricyclics when taken in overdoses the other newer agents seem to be safer. 

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