Following long-term training with citalopram, both mirtazapine and mianserin block its discriminative stimulus properties in rats

RATIONALE: The discriminative stimulus (DS) properties of the selective serotonin (5-HT) uptake inhibitor (SSRI), citalopram, are mediated by 5-HT2C receptors. Interestingly, the "atypical" antidepressants, mianserin and mirtazapine, behave as antagonists at 5-HT2C receptors. OBJECTIVE: Herein, we evaluated the influence of mianserin and mirtazapine upon the DS effects of citalopram. METHODS: In a two-lever drug discrimination procedure, rats initially trained to discriminate citalopram (2.5 mg/kg, i.p.) from saline were retrained with a lower dose of citalopram (0.63 mg/kg, i.p.). Subsequently, generalization and antagonist studies were conducted with mianserin and mirtazapine. RESULTS: Both dose-dependently blocked, but did not generalize to, the DS properties of citalopram without markedly disrupting response rates. Their effective dose50s were 0.1 and 1.4 mg/kg, s.c., respectively. CONCLUSION: These observations are consistent with a role of 5-HT2C receptors in mediation of the interoceptive properties of SSRIs and suggest that the DS effects of citalopram are not related to its "antidepressant" properties per se. Finally, they underline the distinctive nature of mirtazapine and mianserin as compared to antidepressant agents which interact with 5-HT uptake sites.     

Mirtazapine-induced arthralgia

AIM: With this article, we intend to corroborate the assumed association between mirtazapine and arthralgia by presentation of eight case reports, and we describe a possible mechanism of action. METHODS AND RESULTS: The Netherlands Pharmacovigilance Centre Lareb received eight case reports on arthralgia associated with use of mirtazapine. These case reports are presented in short. We also present worldwide data on this association. CONCLUSIONS: The Lareb reports support the association between mirtazapine and arthralgia. A comparison is made between mirtazapine, mianserin and nefazodone, as these antidepressants show similarities in their mode of action and are all associated with arthralgia. We suggest that this adverse drug reaction may be induced by enhanced 5HT1-mediated neurotransmission.     

Enantiomeric antidepressant drugs should be considered on individual merit

Many antidepressants have been introduced as racemic drugs, the enantiomers of which may differ in some of their pharmacodynamic and pharmacokinetic properties. This review argues that each enantiomer of a chiral antidepressant should be evaluated according to its individual characteristics rather than by extrapolation from the racemate, or by assumptions based on the stereoselective characteristics of other enantiomeric drugs. For example, in some cases the enantiomers' pharmacodynamic and therapeutic properties can be complementary, which suggests that the racemate should be used clinically. In other cases where enantiomers show qualitatively similar but quantitatively different properties to the racemate, using a single enantiomer might be more appropriate. In yet further cases, a distomer may induce the metabolism of the eutomer, enantiomers may be metabolised by different enzymes, there may be a different profile of drug-drug interactions, and therapeutic drug monitoring may be simpler. Therefore, this review exemplifies the principle that each enantiomer of a chiral antidepressant should be evaluated according to its individual pharmacological, pharmacokinetic and pharmacogenetic characteristics. These factors are discussed in relation to five chiral antidepressants: trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. It is hoped that an appreciation of the stereoselective differences between enantiomers will facilitate improvements in the benefit:risk ratio of drugs used in the management of depression. Copyright 2001 John Wiley & Sons, Ltd.     

Antidepressants activate the lysophosphatidic acid receptor LPA1 to induce insulin-like growth factor-I receptor transactivation,stimulation of ERK1/2 signaling and cell proliferation in CHO-K1 fibroblasts

Different lines of evidence indicate that the lysophosphatidic acid (LPA) receptor LPA₁ is involved in neurogenesis, synaptic plasticity and anxiety-related behavior, but little is known on whether this receptor can be targeted by neuropsychopharmacological agents. The present study investigated the effects of different antidepressants on LPA₁ signaling. We found that in Chinese hamster ovary (CHO)-K1 fibroblasts expressing endogenous LPA₁ tricyclic and tetracyclic antidepressants and fluoxetine induced the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and CREB. This response was antagonized by either LPA₁ blockade with Ki16425 and AM966 or knocking down LPA₁ with siRNA. Antidepressants induced ERK1/2 phosphorylation in human embryonic kidney (HEK)-293 cells overexpressing LPA₁, but not in wild-type cells. In PathHunter™ assay measuring receptor-β-arrestin interaction, amitriptyline, mianserin and fluoxetine failed to induce activation of LPA₂ and LPA₃ stably expressed in CHO-K1 cells. ERK1/2 stimulation by antidepressants and LPA was suppressed by pertussis toxin and inhibition of Src, phosphatidylinositol-3 kinase and insulin-like growth factor-I receptor (IGF-IR) activities. Antidepressants and LPA induced tyrosine phosphorylation of IGF-IR and insulin receptor-substrate-1 through LPA₁ and Src. Prolonged exposure of CHO-K1 fibroblasts to either mianserin, mirtazapine or LPA enhanced cell proliferation as indicated by increased [³H]-thymidine incorporation and Ki-67 immunofluorescence. This effect was inhibited by blockade of LPA₁- and ERK1/2 activity. These data provide evidence that different antidepressants induce LPA₁ activation, leading to receptor tyrosine kinase transactivation, stimulation of ERK1/2 signaling and enhanced cell proliferation.     

The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors

BACKGROUND AND PURPOSE

Antidepressants are known to interact with the opioid system through mechanisms not completely understood. We previously reported that tricyclic antidepressants act as agonists at distinct opioid receptors. Here, we investigated the effect of the atypical antidepressant mianserin at cloned and native opioid receptors.

EXPERIMENTAL APPROACH

Effects of mianserin were examined in CHO cells transfected with human opioid receptors, C6 glioma cells and rat brain membranes by the use of radioligand binding and functional assays including the stimulation of [³⁵S]GTPγS binding and MAPK phosphorylation.

KEY RESULTS

Mianserin displayed 12- and 18-fold higher affinity for κ- than µ- and δ-opioid receptors respectively. In [³⁵S]GTPγS assays, mianserin selectively activated κ-opioid receptors. The agonist activity was antagonized by the selective κ-opioid blocker nor-binaltorphimine (nor-BNI). The mianserin analogue mirtazapine also displayed κ-opioid agonist activity. Mianserin and mirtazapine increased ERK1/2 phosphorylation in CHO cells expressing κ-opioid receptors and C6 cells, and these effects were antagonized by nor-BNI. In rat striatum and nucleus accumbens, mianserin stimulated [35S]GTPγS binding in a nor-BNI-sensitive manner with maximal effects lower than those of the full κ-opioid agonists (–)-U50,488 and dynorphin A. When combined, mianserin antagonized the effects of the full κ-opioid receptor agonists in [³⁵S]GTPγS assays and reduced the stimulation of p38 MAPK and ERK1/2 phosphorylation by dynorphin A.

CONCLUSIONS AND IMPLICATIONS

In different cell systems, mianserin directly activates κ-opioid receptors, displaying partial agonist activity at brain receptors. Thus, this property appears to be a common feature of different classes of antidepressants.     

Effects of mianserin, a new antidepressant, on the in vitro and in vivo uptake of monoamines.

1 The effects of mianserin and of selected tricyclic antidepressants were compared in a number of monoamine uptake models. 2 The ability of mianserin to block the noradrenergic neurone membrane amine pump of rabbit brain stem slices was comparable to that of imipramine and amitriptyline and less than that of desipramine and nortriptyline. Both mianserin and desipramine were competitive inhibitors of noradrenaline uptake in vitro. The effect of mianserin on noradrenaline uptake in vivo was studied both peripherally and centrally. The ability of 6-hydroxydopamine to lower rat heart noradrenaline levels was found to be very sensitive to inhibition by tricyclic antidepressants. Mianserin was active in this model. However, its ability to block the 6-hydroxydopamine-induced fall in rat heart noradrenaline concentration was appreciably less than that of the tricyclics studied. 3 Mianserin, like tricyclic antidepressants, was essentially devoid of effect on dopamine uptake both in vitro and in vivo. 4 The ability of mianserin to inhibit [3H]-5-hydroxytryptamine uptake by rat hypothalamic synaptosomes was appreciably less than that of the tricyclic antidepressants studied. Mianserin was essentially devoid of effect on rat brain 5-hydroxytryptamine uptake in vivo. 5 It is concluded that in certain situations large doses of mianserin may block noradrenaline uptake in vivo. However, in no way does mianserin rival tricyclic antidepressants in blocking monoamine uptake in vivo. The clinical efficacy of mianserin cannot be attributed to inhibition of monoamine uptake.     

Antidepressants and their effect on sleep

Given the relationship between sleep and depression, there is inevitably going to be an effect of antidepressants on sleep. Current evidence suggests that this effect depends on the class of antidepressant used and the dosage. The extent of variation between the effects of antidepressants and sleep may relate to their mechanism of action. This systematic review examines randomised-controlled trials (RCTs) that have reported the effect that antidepressants appear to have on sleep. RCTs are not restricted to depressed populations, since several studies provide useful information about the effects on sleep in other groups. Nevertheless, the distinction is made between those studies because the participant's health may influence the baseline sleep profiles and the effect of the antidepressant. Insomnia is often seen with monoamine oxidase inhibitors (MAOIs), with all tricyclic antidepressants (TCAs) except amitriptyline, and all selective serotonin reuptake inhibitors (SSRIs) with venlafaxine and moclobemide as well. Sedation has been reported with all TCAs except desipramine, with mirtazapine and nefazodone, the TCA-related maprotiline, trazodone and mianserin, and with all MAOIs. REM sleep suppression has been observed with all TCAs except trimipramine, but especially clomipramine, with all MAOIs and SSRIs and with venlafaxine, trazodone and bupropion. However, the effect on sleep varies between compounds within antidepressant classes, differences relating to the amount of sedative or alerting (insomnia) effects, changes to baseline sleep parameters, differences relating to REM sleep, and the degree of sleep-related side effects.     

Randomized Controlled Trials of Add-On Antidepressants in Schizophrenia

Background:

Despite adequate treatment with antipsychotics, a substantial number of patients with schizophrenia demonstrate only suboptimal clinical outcome. To overcome this challenge, various psychopharmacological combination strategies have been used, including antidepressants added to antipsychotics.

Methods:

To analyze the efficacy of add-on antidepressants for the treatment of negative, positive, cognitive, depressive, and antipsychotic-induced extrapyramidal symptoms in schizophrenia, published randomized controlled trials assessing the efficacy of adjunctive antidepressants in schizophrenia were reviewed using the following parameters: baseline clinical characteristics and number of patients, their on-going antipsychotic treatment, dosage of the add-on antidepressants, duration of the trial, efficacy measures, and outcomes.

Results:

There were 36 randomized controlled trials reported in 41 journal publications (n=1582). The antidepressants used were the selective serotonin reuptake inhibitors, duloxetine, imipramine, mianserin, mirtazapine, nefazodone, reboxetin, trazodone, and bupropion. Mirtazapine and mianserin showed somewhat consistent efficacy for negative symptoms and both seemed to enhance neurocognition. Trazodone and nefazodone appeared to improve the antipsychotics-induced extrapyramidal symptoms. Imipramine and duloxetine tended to improve depressive symptoms. No clear evidence supporting selective serotonin reuptake inhibitors’ efficacy on any clinical domain of schizophrenia was found. Add-on antidepressants did not worsen psychosis.

Conclusions:

Despite a substantial number of randomized controlled trials, the overall efficacy of add-on antidepressants in schizophrenia remains uncertain mainly due to methodological issues. Some differences in efficacy on several schizophrenia domains seem, however, to exist and to vary by the antidepressant subgroups—plausibly due to differences in the mechanisms of action. Antidepressants may not worsen the course of psychosis. Better designed, larger, and longer randomized controlled trials are needed.     

Absence of an effect of mianserin on the actions of clonidine or methyldopa in hypertensive patients

Summary The concurrent administration of tricyclic antidepressants has been shown in man to result in a clinically significant impairment of the antihypertensive effect of clonidine. This interaction is thought to be related to competition for central ₂ receptors where clonidine acts as an agonist and the tricyclics act as antagonists. Although it seems to cause less cardiovascular effects than tricyclic antidepressants, the tetracyclic antidepressant, mianserin also has been reported to be an receptor antagonist and may, therefore, also interfere with the antihypertensive activity of centrally-acting drugs. This study investigates the effects of acute and chronic mianserin administration in patients with essential hypertension established on long term treatment with either clonidine or methyldopa. The first dose of mianserin was not associated with an increase in blood pressure and during a further two weeks of mianserin therapy there were no significant alterations in blood pressure, supine or erect. Similarly, mianserin did not alter heart rate either after acute or after chronic administration. Mianserin itself had a sedative effect but there was no interference with the sedation attributable to clonidine or methyldopa. Mianserin caused no reduction in salivary flow and did not influence the reduced saliva production caused by clonidine. Both clonidine and methyldopa are associated with a reduction in sympathetic outflow but there was no evidence in this study of any further change in plasma noradrenaline or 24 h urinary catecholamine excretion. This study demonstrates that if mianserin is given acutely or chronically, it does not interfere with the effects of the centrally acting antihypertensive drugs, clonidine and methyldopa. Mianserin may therefore be a suitable antidepressant for patients receiving these antihypertensive agents if drug treatment for depression is indicated.     

Effects of antidepressants on receptor-activated and Ca2+-activated contractions of rabbit isolated aorta

Helically-cut strips of rabbit aorta were used to examine the inhibitory effects of some antidepressants on the contractile responses produced by norepinephrine (NE), serotonin (5-HT) or K+. The order of potency of antidepressants in antagonizing 5-HT-induced responses was: mianserin greater than amitriptyline greater than imipramine (IMI) greater than desipramine greater than or equal to nomifensine. With NE as agonist, the order of potency was: amitriptyline greater than mianserin greater than IMI greater than desipramine greater than or equal to nomifensine. Viloxazine (10(-5) M) was ineffective on 5-HT- or NE-induced contractions. For K+-induced contraction (which is mediated by Ca2+ entry into smooth muscle cells) tricyclic antidepressants were about equipotent with mianserin; nomifensine and viloxazine were relatively ineffective. These results indicate that certain antidepressants have multiple effects on arterial smooth muscle. Such effects could underlie not only the side-effects, but also the therapeutic actions of these agents.     

Pharmacodynamic studies on mianserin and its interaction with clonidine

Summary There is evidence that clonidine's hypotensive effect is reduced by the concurrent administration of tricyclic antidepressants. It has been proposed that this results from an interaction at ₂-receptors in the brain stem where clonidine acts as a relatively selective agonist and the tricyclic antidepressants as antagonists. Mianserin is an antidepressant with a tetracyclic structure and, although it has been reported to cause less cardiovascular disturbance, there is evidence that it also has -adrenoceptor blocking effects. This study in 6 normotensive healthy male volunteers was designed to investigate a possible interaction between clonidine and the antidepressant mianserin. Administration of the first dose of 20 mg mianserin was associated with acute cardiovascular effects, notably transient postural hypotension, but no significant disturbance of heart rate or blood pressure was detected after 3 days continuous treatment with mianserin 20 mg tid. Following pre-treatment with mianserin or placebo the responses to a single oral dose of 300 µg clonidine were then assessed. The combination of mianserin and clonidine was not associated with any attenuation of clonidine's hypotensive effect, erect or supine, but there was significant attenuation of clonidine's supine bradycardic effect. There was no evidence that mianserin interfered with the ability of clonidine to diminish salivary flow, cause sedation, and reduce catecholamine output, but it was noted that mianserin itself had a very pronounced sedative effect. Mianserin alone had no significant effect on salivary flow. This short term study demonstrates that mianserin does not significantly interfere with the responses to a single oral dose of clonidine.     

Optimizing antidepressant treatment: efficacy and tolerability

It has been suggested that dual-action antidepressants acting on both serotonin and noradrenaline pathways in the brain may offer superior therapeutic benefit over classical antidepressants, particularly in severe depression. Directly acting dual-action antidepressant drugs include venlafaxine and milnacipran. In addition, mirtazapine and nefazodone, may indirectly potentiate serotonergic and noradrenergic transmission, although evidence that they do indeed do so in vivo is limited. Meta-analysis of clinical trials suggests that venlafaxine has a more rapid onset of action than selective serotonin reuptake inhibitors (SSRIs), and the same may also be true for milnacipran and mirtazapine. Efficacy, both in terms of extent of antidepressant effect and in the proportion of patients responding, is probably superior to that of SSRIs, at least for venlafaxine and milnacipran. In terms of tolerability, all dual-action drugs clearly appear to be better tolerated than tricyclic antidepressants. Mirtazapine and nefazodone have specific side-effect profiles as a result of their antagonist action at biogenic amine and other receptors. Milnacipran, and to a lesser extent venlafaxine, are slightly better tolerated than SSRIs.     

Imipramine- and mianserin-induced acute cell injury in primary cultured rat hepatocytes: implication of different cytochrome P450 enzymes

The antidepressants, imipramine and mianserin, have been reported to cause liver damage. We investigated a role of cytochrome P450 (CYP)-mediated formation of a reactive metabolite in antidepressant-induced acute cell injury using hepatocytes isolated from male and female Wistar rats, and male Dark Agouti rats, which have different relative abundance of CYP enzymes. Culture of the hepatocytes with imipramine and mianserin caused a marked decrease in glutathione followed by protein thiol, which preceded lactate dehydrogenase leakage. The decreases in glutathione and protein thiol contents by imipramine were significantly slower in hepatocytes from male Dark Agouti rats than those from male Wistar rats, whereas no significant sex difference in Wistar rats was observed. The decrease in thiol by mianserin was significantly slower in hepatocytes from female Wistar than those from male Wistar rats, whereas no significant differences were found between Wistar and Dark Agouti males. Results consistent with alteration of the thiols were obtained for lactate dehydrogenase leakage induced by imipramine and mianserin. These findings indicated that CYP-mediated metabolic activation was involved in acute cell injury induced by the antidepressants; namely a CYP2D enzyme(s), which is deficient in Dark Agouti rats, and a male specific CYP enzyme(s) were suggested to be responsible for the cytotoxicity of imipramine and mianserin, respectively. Received: 6 January 1999 / Accepted: 22 February 1999     

Pharmacological principles of antidepressant efficacy

Both noradrenaline (NA) and serotonin (5-HT) appear to be involved in depression. Evidence suggests that dual-acting antidepressants, i.e. those that affect both monoamine systems, such as tricyclic antidepressants and the noradrenergic and specific serotonergic antidepressant mirtazapine, may have greater efficacy and a faster onset of action than drugs that act on a single monoamine system only, such as the selective serotonin reuptake inhibitors (SSRIs). Cell firing is reduced by SSRIs in the short-term, but is increased by mirtazapine, probably due to its actions on both NA (via alpha(2) antagonism) and 5-HT (via alpha(1)-stimulation by NA). This may help to explain clinical evidence suggesting that mirtazapine has a faster onset of action than the more selective antidepressants.     

Comparison of six new antidepressants on isolated rat atria

The effects of six new antidepressants were studied and compared as to their electromechanical properties on isolated rat atria. All of the compounds reduced rate and amplitude of contractions, depressed atrial excitability and prolonged the sinus node recovery time. They also inhibited the amplitude of the slow contractions elicited by isoprenaline in K-depolarized atria. In decreasing order, the relative order of potency found was: mianserin approximately equal to maprotiline approximately equal to lofepramine greater than nomifensine approximately equal to trazodone greater than viloxazine. On atrial transmembrane action potentials mianserin, maprotiline and viloxazine decreased amplitude and maximum rate of depolarization and shortened the duration and depolarized the resting membrane potential. All these effects are similar to those previously reported with imipramine and amoxapine. Thus, differences between the cardiodepressant effects of the newer and older antidepressants are only quantitative but not qualitative. Possible explanations of the lower incidence of cardiovascular complications with the newer compounds are discussed.     

Discriminative stimulus properties of the “atypical” antidepressant, mirtazapine, in rats: a pharmacological characterization

Rationale  Though interoceptive properties of antidepressants have been described, discriminative stimulus (DS) properties of mirtazapine, which does not affect monoamine reuptake, remain uncharacterized. Objectives  The objectives of the study are to train rats to recognize a mirtazapine DS, then perform substitution studies with other antidepressants and drugs acting at sites occupied by mirtazapine. Materials and methods  Using a two-lever, fixed-ratio 10 schedule, rats were trained to discriminate mirtazapine (2.5 mg/kg, i.p.) from saline. Results  Sessions, 63 ± 8, were necessary to reach the criterion for 14 rats that all subsequently recognized (100%) mirtazapine at the training dose. Mirtazapine blocks serotonin (5-HT)_2C receptors, and the 5-HT_2C antagonists, SB242,084, SB243,213 and S32006, revealed dose-dependent and full (≥80%) substitution at doses of 2.5, 2.5, and 0.63 mg/kg, respectively. By contrast, the 5-HT_2A antagonists, MDL100,907 and SR46349-B, the 5-HT_2B antagonist, SB204,741, and the 5-HT₃ antagonist, ondansetron, showed no significant substitution. Though mirtazapine indirectly recruits 5-HT_1A receptors, the 5-HT_1A agonists, buspirone and 8-OH-DPAT, did not substitute. Mirtazapine blocks α₂-adrenoceptors, but several α₂-adrenoceptor antagonists (yohimbine, RX821,002 and atipamezole) failed to substitute. Despite blockade by mirtazapine of histamine H₁ receptors, no substitution was seen with the selective H₁ antagonist, pyrilamine. Finally, the selective noradrenaline reuptake inhibitor, reboxetine (0.16), fully substituted for mirtazapine, whereas the 5-HT/noradrenaline reuptake inhibitors, duloxetine and S33005, several 5-HT reuptake inhibitors (citalopram, fluvoxamine, and paroxetine) and the dopamine reuptake inhibitors, bupropion and GBR12,935, did not substitute. Conclusion  Mirtazapine elicits a DS in rats for which selective antagonists at 5-HT_2C receptors display dose-dependent substitution, whereas drugs acting at other sites recognized by mirtazapine are ineffective.     

In vitro immunoregulatory effects of antidepressants in healthy volunteers

Major depression is accompanied by an activation of the inflammatory response system (IRS) and antidepressants may have immunoregulatory activities. This study was carried out to compare the effect of imipramine, mianserin and lithium on the in vitro production of Th1-like cytokines, such as IL-2, IFN-gamma, lymphotoxin and Th2-like cytokines such as IL-4, IL-10 as well as IL-12 and TGF-beta. Peripheral blood mononuclear cells (PBMC) of 16 healthy volunteers were stimulated with polyclonal activators (phytohemagglutinin with lipopolysaccharide PHA + LPS) with or without incubation with imipramine, mianserin (1 microM) or lithium (1 mM). Imipramine and mianserin exhibited similar activities enhancing unstimulated IFN-gamma and IL-10 production. In PHA + LPS-stimulated PBMC both antidepressants inhibited IFN-gamma, IL-2 and lymphotoxin production (Th1-like cytokines) as well as IL-12 and IL-4 production. Under the same in vitro conditions, both antidepressants stimulated production of negative immunoregulatory cytokines such as IL-10 and TGF-beta. Lithium differed significantly from imipramine and mianserin, as it enhanced IL-2, IFN-gamma, IL-10 and TGF-beta production and inhibited only IL-4. All three examined antidepressants reduced IFN-gamma/IL-10 ratio. None of the antidepressants at the used concentrations induced apoptosis in PBMC so those changes in cytokine production were not the result of selective killing of certain cell subpopulations. Imipramine and mianserin at high concentrations negatively influenced reactive oxygen species (ROS) production in neutrophils, however, at concentrations in the therapeutical range none of the antidepressants used influenced "oxidative burst" in neutrophils. The results indicate that antidepressants exert immunoregulatory effects on human leukocyte functions, especially on cytokine production.     

Clomipramine and mianserin in chronic idiopathic pain syndrome

The reduction of pain by two antidepressants, clomipramine and mianserin, was, in this study on 253 patients with chronic idiopathic pain syndrome, found to be not better than a placebo when all patients were compared independently of the classification of pain. The improvement rate was around 40% after 6 weeks of treatment when using a 50% or better reduction in pain level. However, in patients who fulfilled a checklist definition of minor to major depression (30% of the total patient material) clomipramine was superior to mianserin and placebo with an improvement rate of 75% after 6 weeks. Using pain curves over time as outcome measure in the various clinical pain categories it was found that both mianserin and clomipramine seemed superior to placebo in patients with tension headache, but in patients with low back pain syndrome placebo was superior to the two antidepressants. No difference among the three treatments was found in patients with burning mouth syndrome or in patients with abdominal pain. These differences underline the importance of studying specific pain syndromes rather than composite groups of patients with idiopathic pain. The clinical significance of these pain curves needs further placebo controlled investigations.     

Mirtazapine: a review of its use in major depression

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) which has predominantly been evaluated in the treatment of major depression. The drug had equivalent efficacy to tricyclic antidepressants and it was at least as effective as trazodone in the majority of available short term trials in patients with moderate or severe depression, including those with baseline anxiety symptoms or sleep disturbance and the elderly. A continuation study also showed that sustained remission rates were higher with mirtazapine than with amitriptyline and that the drugs had similar efficacy for the prevention of relapse. There is some evidence for a faster onset of action with mirtazapine than with the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). Mirtazapine was more effective than the SSRI fluoxetine at weeks 3 and 4 of therapy and it was also more effective than paroxetine and citalopram at weeks 1 and 2, respectively, in short term assessments (6 or 8 weeks). Preliminary data suggest that the drug may be effective as an augmentation or combination therapy in patients with refractory depression. Anticholinergic events and other events including tremor and dyspepsia are less common with mirtazapine than with tricyclic antidepressants. There was a greater tendency for SSRI-related adverse events with fluoxetine than with mirtazapine, but, overall, mirtazapine had a similar tolerability profile to the SSRIs. Increased appetite and bodyweight gain appear to be the only events that are reported more often with mirtazapine than with comparator antidepressants. In vitro and in vivo data have suggested that mirtazapine is unlikely to affect the metabolism of drugs metabolised by cytochrome P450 (CYP)2D6, although few formal drug interaction data are available. CONCLUSIONS: Mirtazapine is effective and well tolerated for the treatment of patients with moderate to severe major depression. Further research is required to define the comparative efficacy of mirtazapine in specific patient groups, including the elderly and those with severe depression. Clarification of its efficacy as an augmentation therapy and in patients with refractory depression and its role in improving the efficacy and reducing the extrapyramidal effects of antipsychotic drugs would also help to establish its clinical value. The low potential for interaction with drugs that are metabolised by CYP2D6, including antipsychotics, tricyclic antidepressants and some SSRIs, may also make mirtazapine an important option for the treatment of major depression in patients who require polytherapy. Mirtazapine also appears to be useful in patients with depression who present with anxiety symptoms and sleep disturbance.