de Boer T.
The pharmacologic profile of mirtazapine.
J Clin Psychiatry 1996;57 Suppl 4:19-25
"Mirtazapine (Org 3770) is a new antidepressant with prominent alpha 2-adrenergic auto- and heteroreceptor antagonistic properties and no effect on monoamine reuptake. Mirtazapine increases noradrenergic and serotonergic transmission, as measured by on-line microdialysis and by enhancement of noradrenergic locus ceruleus and serotonergic raphe nucleus cell firing. Mirtazapine has a low affinity for 5-HT1A receptors but shows 5-HT1A-agonistic-like effects in a conditioned taste aversion test and by causing lower lip retraction in rats. Mirtazapine therefore causes enhancement of 5-HT1-mediated transmission. Other studies show that both 5-HT2 and 5-HT3 receptors are specifically blocked. The enhancement of both noradrenergic and serotonergic transmission probably underlies the therapeutic activity of mirtazapine. Blockade of 5-HT2 and 5-HT3 receptors possibly prevents side effects associated with nonselective 5-HT activation and may also contribute to the anxiolytic and sleep-improving properties of mirtazapine." [Abstract]

Schittecatte M, Dumont F, Machowski R, Cornil C, Lavergne F, Wilmotte J.
Effects of mirtazapine on sleep polygraphic variables in major depression.
Neuropsychobiology 2002;46(4):197-201
"Mirtazapine, a noradrenergic and specific serotonergic antidepressant(NaSSA), was administered on a flexible schedule in a sample of 17 drug-free patients meeting DSM-IV criteria for a major depressive episode. Sleep polygraphic recordings were performed before and during acute and chronic treatment. Severity of depression and subjective assessment of changes within different aspects of sleep were also evaluated. During the acute administration (first 2 days), mirtazapine significantly increased total sleep time, sleep efficiency, stage II, stage rapid eye movement and slow-wave sleep percentages, and decreased sleep latency and stage awake percentage. These effects persisted after 5 weeks of treatment. Subjectively, mirtazapine induced an improvement of sleep. This open, noncontrolled study suggests that mirtazapine ameliorates the sleep disturbances encountered in depressed patients both objectively and subjectively." [Abstract]

Schule C, Baghai T, Rackwitz C, Laakmann G.
Influence of mirtazapine on urinary free cortisol excretion in depressed patients.
Psychiatry Res. 2003 Oct 15;120(3):257-64.
"Mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on urinary free cortisol (UFC) excretion was investigated in depression. Twenty patients (six men, 14 women) suffering from major depression according to DSM-IV criteria were treated with mirtazapine for 3 weeks. The patients received 15 mg mirtazapine on day 0; 30 mg mirtazapine on day 1; and 45 mg mirtazapine per day from day 2 to the end of the study (day 21). UFC excretion was measured before treatment (day 1), at the beginning (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Urine samples were collected from 08:00 to 08:00 h the following day. On the days of urine sampling, the severity of depressive symptoms was assessed using the 21-item version of the Hamilton Rating Scale for Depression (21-HAMD). There was a significant reduction of UFC excretion during 3-week mirtazapine therapy, which was already obvious after the first day of treatment (day 0). However, there were no significant across-subjects correlations between UFC reduction and decrease in 21-HAMD sum scores. Apparently, the mirtazapine-induced rapid reduction of cortisol secretion in depressed patients is not necessarily correlated with a favorable therapeutic response." [Abstract]

Schule C, Baghai T, Zwanzger P, Ella R, Eser D, Padberg F, Moller HJ, Rupprecht R.
Attenuation of hypothalamic-pituitary-adrenocortical hyperactivity in depressed patients by mirtazapine.
Psychopharmacology (Berl). 2003 Mar;166(3):271-5. Epub 2003 Jan 28.
"RATIONALE: It has been suggested that hypothalamic-pituitary-adrenocortical (HPA) system dysregulation plays an important role in the pathophysiology of depression and that normalization of HPA axis hyperactivity precedes successful treatment with antidepressants. Mirtazapine acts as an antagonist at presynaptic alpha(2)-receptors and at postsynaptic 5-hydroxytryptamine (5-HT)(2), 5-HT(3) and histamine H(1) receptors. It has been shown acutely to inhibit cortisol secretion in healthy subjects. OBJECTIVE: In this study, we investigated whether mirtazapine may downtune HPA axis hyperactivity in depressed patients and whether this is related to treatment outcome. METHODS: Forty patients suffering from a major depressive episode (DSM-IV criteria) were treated with mirtazapine for 5 weeks. The combined dexamethasone suppression/CRH stimulation test (DEX/CRH test) was performed before and after 1 week of mirtazapine treatment (45 mg daily). RESULTS: Mirtazapine effectively reduced the overshoot of cortisol and ACTH during the DEX/CRH test both in treatment responders and non-responders within 1 week. CONCLUSIONS: Apparently, mirtazapine rapidly attenuates HPA axis hyperactivity in depressed patients via direct pharmacoendocrinological effects. However, this amelioration of HPA system dysregulation is not necessarily related to clinical improvement." [Abstract]

Schule C, Baghai T, Bidlingmaier M, Strasburger C, Laakmann G.
Endocrinological effects of mirtazapine in healthy volunteers.
Prog Neuropsychopharmacol Biol Psychiatry 2002 Dec;26(7-8):1253-61
"In the present investigation, the influence of acute oral administration of 15-mg mirtazapine on the cortisol (COR), adrenocorticotropin (ACTH), growth hormone (GH) and prolactin (PRL) secretion was examined in 12 healthy male subjects, compared to placebo. METHODS: After insertion of an intravenous catheter, both the mean arterial blood pressure (MAP) and the heart rate were recorded and blood samples were drawn 1 h prior to the administration of mirtazapine or placebo (7:00 a.m.), at time of administration (8:00 a.m.) and during 5 h thereafter in periods of 30 min. Concentrations of COR, ACTH, GH and PRL were measured in each blood sample by double antibody radioimmunoassay and chemiluminescence immunoassay methods. The area under the curve (AUC; 0-300 min after mirtazapine or placebo administration) was used as parameter for the COR, ACTH, GH and PRL response. Furthermore, the urinary free cortisol excretion (UFC) was determined beginning at 8:00 a.m. (time of administration of placebo or mirtazapine) up to 8:00 a.m. the day after. RESULTS: Two-sided t-tests for paired samples revealed significantly lower COR AUC, ACTH AUC, UFC and PRL AUC values after 15-mg mirtazapine compared to placebo, whereas no significant differences were found with respect to GH AUC, MAP and heart rate. CONCLUSIONS: Since the acute inhibition of COR secretion in the healthy volunteers was paralleled by a simultaneous decrease of ACTH release, central mechanisms (e.g., inhibition of hypothalamic corticotropin releasing hormone (CRH) output) are suggested to be responsible for the inhibitory effects of mirtazapine on COR secretion. Our results are of particular interest in the light of the hypercortisolism observed in depressed patients and new pharmacological approaches such as CRH1 receptor antagonists." [Abstract]

Schule C, Baghai T, Goy J, Bidlingmaier M, Strasburger C, Laakmann G.
The influence of mirtazapine on anterior pituitary hormone secretion in healthy male subjects.
Psychopharmacology (Berl) 2002 Aug;163(1):95-101
"The area under the curve (AUC) was used as parameter for the COR, ACTH, GH, and PRL response. Furthermore, the urinary free cortisol excretion (UFC) was determined beginning at 8:00 a.m. (time of application of placebo or mirtazapine) up to 8:00 a.m. the day after. RESULTS. Multivariate analyses of variance revealed significantly lower COR AUC, ACTH AUC, and UFC values after 15 mg mirtazapine compared to placebo, whereas no differences were found with respect to GH and PRL stimulation, MAP, and heart rate." [Abstract]

Serra M, Pisul MG, Dazzi L, Purdy RH, Biggio G.
Prevention of the stress-induced increase in the concentration of neuroactive steroids in rat brain by long-term administration of mirtazapine but not of fluoxetine.
J Psychopharmacol 2002 Jun;16(2):133-8
"In contrast, chronic treatment with mirtazapine prevented or significantly reduced the stress-induced increases in neurosteroid concentrations in the cerebral cortex and plasma, respectively. These results show that mirtazapine, similar to fluoxetine, initially increases the cortical concentration of neuroactive steroids; however, chronic administration of this drug modulates the plasma and brain availability of these hormones in a manner distinct from that of fluoxetine." [Abstract]

Laakmann G, Schule C, Baghai T, Waldvogel E.
Effects of mirtazapine on growth hormone, prolactin, and cortisol secretion in healthy male subjects.
Psychoneuroendocrinology 1999 Oct;24(7):769-84
"In the present study the effects of acute PO-administration of 15 mg mirtazapine on the growth hormone (GH), prolactin (PRL), and cortisol (COR) secretion were examined in eight physically and mentally healthy male subjects, compared to placebo. Mirtazapine is a new antidepressant agent which does not inhibit the reuptake of norepinephrine or serotonin but is an antagonist of presynaptic and, presumably, postsynaptic alpha 2-receptors as well as an antagonist of postsynaptic 5-HT2 and 5-HT3-receptors. After insertion of an i.v. catheter, blood samples were drawn 1 h prior to the administration of mirtazapine or placebo, at time of application, and during the time of 4 h after application in periods of 30 min. Plasma concentrations of GH, PRL, and COR were determined in each blood sample by double antibody RIA methods. The area under the curve (AUC) value was used as parameter for the GH, PRL, and COR response. With respect to GH and PRL secretion, mirtazapine did not show any effects in comparison with placebo. However, in all subjects, the COR concentrations were remarkably lower after mirtazapine compared to placebo, the difference being obvious in the mean value graphs 60 min after the application up to the end of the measurement period. The t-test for paired samples revealed a highly significant difference (P < 0.01) in COR-AUC-values between the mirtazapine group (mean COR-AUC: 1558.07 micrograms/100 ml x 240 min) and the placebo group (mean COR-AUC: 2698.86 micrograms/100 ml x 240 min). Further studies have to elucidate the question whether the demonstrated inhibition of COR secretion after application of 15 mg mirtazapine is caused by central or peripheral effects of this substance." [Abstract]

Schule C, Baghai T, Laakmann G.
Mirtazapine decreases stimulatory effects of reboxetine on cortisol, adrenocorticotropin and prolactin secretion in healthy male subjects.
Neuroendocrinology. 2004 Jan;79(1):54-62. [Abstract]

Schreiber S, Bleich A, Pick CG.
Venlafaxine and mirtazapine: different mechanisms of antidepressant action, common opioid-mediated antinociceptive effects--a possible opioid involvement in severe depression?
J Mol Neurosci 2002 Feb-Apr;18(1-2):143-9
"When mice were tested with a hotplate analgesia meter, both venlafaxine and mirtazapine induced a dose-dependent, naloxone-reversible antinociceptive effect following ip administration. Summing up the various interactions of venlafaxine and mirtazapine with opioid, noradrenergic and serotonergic agonists and antagonists, we found that the antinociceptive effect of venlafaxine is influenced by opioid receptor subtypes (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) combined with the alpha2-adrenergic receptor, whereas the antinociceptive effect of mirtazapine mainly involves mu- and kappa3-opioid mechanisms." [Abstract]

Nowakowska E, Chodera A, Kus K.
Behavioral and memory improving effects of mirtazapine in rats.
Pol J Pharmacol 1999 Nov-Dec;51(6):463-9
"These experiments examined the effects of the antidepressant mirtazapine in several behavioral and memory tests. The tests were carried out on male Wistar rats weighing about 200 g. The drugs were injected 30 min before the tests. The aim of the locomotor activity test was to select a dose which had no influence on the motility of the animals and, at the same time, was active at least in one behavioral test. The chosen dose was 2.5 mg/kg. In the two-compartment exploratory test, 2.5 mg/kg of mirtazapine had a distinct anxiolytic effect after the first treatment, after 7 days the effect was weaker but still significant and it disappeared after 14 days. In the forced swimming test, the immobility time was shortened only after 14 days of administering the drug. In the maze test, mirtazapine shortened the food finding time (it improved memory) and counteracted memory loss induced by scopolamine. In the conditioned avoidance responses test (CARs), mirtazapine improved memory only after its earlier impairment by scopolamine. The authors cohclude, contrary to some published data, that after proper dose (adequate for other tests but not for the locomotor activity test), mirtazapine has a distinct memory improving activity or a memory restoring effect after scopolamine treatment." [Abstract]

Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A, Dekeyne A, Nicolas JP, Lejeune F.
Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram.
Eur J Neurosci 2000 Mar;12(3):1079-95
"Mirtazapine displayed marked affinity for cloned, human alpha2A-adrenergic (AR) receptors at which it blocked noradrenaline (NA)-induced stimulation of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]-GTPgammaS) binding. Similarly, mirtazapine showed high affinity for cloned, human serotonin (5-HT)2C receptors at which it abolished 5-HT-induced phosphoinositide generation. Alpha2-AR antagonist properties were revealed in vivo by blockade of UK-14,304-induced antinociception, while antagonist actions at 5-HT2C receptors were demonstrated by blockade of Ro 60 0175-induced penile erections and discriminative stimulus properties. Mirtazapine showed negligible affinity for 5-HT reuptake sites, in contrast to the selective 5-HT reuptake inhibitor, citalopram. In freely moving rats, in the dorsal hippocampus, frontal cortex (FCX), nucleus accumbens and striatum, citalopram increased dialysate levels of 5-HT, but not dopamine (DA) and NA. On the contrary, mirtazapine markedly elevated dialysate levels of NA and, in FCX, DA, whereas 5-HT was not affected. Citalopram inhibited the firing rate of serotonergic neurons in dorsal raphe nucleus, but not of dopaminergic neurons in the ventral tegmental area, nor adrenergic neurons in the locus coeruleus. Mirtazapine, in contrast, enhanced the firing rate of dopaminergic and adrenergic, but not serotonergic, neurons. Following 2 weeks administration, the facilitatory influence of mirtazapine upon dialysate levels of DA and NA versus 5-HT in FCX was maintained, and the influence of citalopram upon FCX levels of 5-HT versus DA and NA was also unchanged. Moreover, citalopram still inhibited, and mirtazapine still failed to influence, dorsal raphe serotonergic neurons. In conclusion, in contrast to citalopram, mirtazapine reinforces frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission. These actions reflect antagonist properties at alpha2A-AR and 5-HT2C receptors." [Abstract]

Dazzi L, Ladu S, Spiga F, Vacca G, Rivano A, Pira L, Biggio G.
Chronic treatment with imipramine or mirtazapine antagonizes stress- and FG7142-induced increase in cortical norepinephrine output in freely moving rats.
Synapse 2002 Jan;43(1):70-7
"Exposure to footshock in control rats induced a marked increase in extracellular norepinephrine concentrations in the prefrontal cortex (+120%). Long-term administration with imipramine or mirtazapine (10 mg/kg, i.p., twice or once a day, respectively, for 14 days) reduced (+50%) the effect of stress on basal norepinephrine output. Acute administration of FG7142 (30 mg/kg, i.p.), an anxiogenic benzodiazepine receptor inverse agonist, induced a marked increase in norepinephrine output (+90%) in control rats. In rats chronically treated with imipramine or mirtazapine this effect was completely antagonized. On the contrary, acute administration of these antidepressant drugs failed to reduce stress- and FG7142-induced increase in norepinephrine output. The plastic changes in the sensitivity of norepinephrine neurons to footshock stress and drug-induced anxiogenic stimuli may reveal a new important neuronal mechanism involved in the long-term modulation of emotional state. This action might be relevant for the anxiolytic and antidepressant effect of antidepressant drugs." [Abstract]

Dazzi L, Vacca G, Ladu S, Pisu MG, Serra M, Biggio G.
Long-term treatment with antidepressant drugs reduces the sensitivity of cortical cholinergic neurons to the activating actions of stress and the anxiogenic drug FG 7142.
Neuropharmacology 2001 Aug;41(2):229-37
"Certain antidepressant drugs exert an anxiolytic action in both humans and rodents. The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the response of cortical cholinergic neurons to foot-shock stress or to the anxiogenic drug FG 7142 were investigated in freely moving rats. Chronic treatment with imipramine or mirtazapine reduced the increase in cortical acetylcholine output induced by foot-shock stress by approximately 50%. The same treatment also reduced the sensitivity of cortical cholinergic neurons to the stimulatory effect of acute administration of FG 7142. In contrast, the administration of a single dose of either antidepressant 40 min before foot shock or FG 7142 injection failed to increase the threshold of excitability of cortical cholinergic neurons. These results demonstrate that long-term treatment with either imipramine or mirtazapine reduces the sensitivity of cortical cholinergic neurons to stress or to an anxiogenic drug with an efficacy similar to that of acute administration of benzodiazepines. The neurochemical mechanism responsible for regulation of cholinergic neuron sensitivity might contribute to the modulation of cognitive function associated with emotional and affective disorders." [Abstract]

Dazzi L, Serra M, Spiga F, Pisu MG, Jentsch JD, Biggio G.
Prevention of the stress-induced increase in frontal cortical dopamine efflux of freely moving rats by long-term treatment with antidepressant drugs.
Eur Neuropsychopharmacol 2001 Oct;11(5):343-9
"Use of antidepressant drugs in the treatment of anxiety disorders has recently increased due to the anxiolytic effect of some of these agents. Because dopaminergic transmission in the prefrontal cortex is sensitive to anxiogenic or stressful stimuli, the effects of two antidepressant drugs with different mechanisms of action, imipramine and mirtazapine, on the response of rat cortical dopaminergic neurons to stress were investigated. A 2-week (but not single dose) administration of imipramine (10 mg/kg, i.p., twice daily) or mirtazapine (10 mg/kg, i.p., once daily) reduced and completely antagonized, respectively, the increase in dopamine release in the prefrontal cortex elicited by footshock stress. Long-term administration of imipramine or mirtazapine had no marked effect on the stress-induced increases in the brain or plasma concentrations of neuroactive steroids or corticosterone. An attenuation of the response of mesocortical dopaminergic neurons to stress induced by long-term treatment with antidepressants might contribute to the anxiolytic effects of such drugs." [Abstract]

Dekeyne A, Iob L, Millan MJ.
Following long-term training with citalopram, both mirtazapine and mianserin block its discriminative stimulus properties in rats.
Psychopharmacology (Berl) 2001 Jan;153(3):389-92
"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." [Abstract]

Meert TF, Melis W, Aerts N, Clincke G.
Antagonism of meta-chlorophenylpiperazine-induced inhibition of exploratory activity in an emergence procedure, the open field test, in rats.
Behav Pharmacol 1997 Aug;8(4):353-63
"The antagonists were injected s.c. or given orally at various time intervals before mCPP, or they were injected i.v. 10 min after mCPP. The lowest active doses for the attentuation of the mCPP-induced behavioural inhibition after s.c., oral and i.v. administration, respectively, were 0.04, 40 and 10 mg/kg for pizotifen; 0.16, 0.16 and 0.16 mg/kg for mianserin; 0.63, 0.16 and 0.16 mg/kg for methysergide, and 0.16, 2.5 and 2.5 mg/kg for ritanserin. The lowest active doses of mirtazapine after s.c. and i.v. treatment were 0.01 and 0.16 mg/kg. These data indicate that mixed 5-HT1/5-HT2 receptor antagonists such as pizotifen and methysergide, and mixed 5-HT and catecholamine antagonists such as mianserin and mirtazapine are more potent antagonists of mCPP-induced behavioural inhibition in rats than the more selective 5-HT2A/5-HT2C antagonist ritanserin." [Abstract]

Haddjeri N, Blier P, de Montigny C.
Acute and long-term actions of the antidepressant drug mirtazapine on central 5-HT neurotransmission.
J Affect Disord 1998 Dec;51(3):255-66
"Mirtazapine (ORG 3770, Remeron) is a new alpha 2-adrenoceptor antagonist which has been shown to be an effective antidepressant drug. The aims of the studies were to assess, using an in vivo electrophysiological paradigm in the rat, the effects of acute and long-term treatment with mirtazapine on pre- and postsynaptic alpha 2-adrenoceptors and to determine whether this drug could modulate serotonin (5-HT) neurotransmission. Acute administration of mirtazapine produced a transient increase of the firing activity of dorsal raphe 5-HT neurons. This effect was mediated via norepinephrine (NE) neurons because it was abolished in NE-lesioned rats. In fact, this increased firing rate of 5-HT neurons was due to their activation by the enhanced release of NE resulting from the blockade of alpha 2-adrenergic autoreceptors of locus coeruleus neurons. Furthermore, acute mirtazapine injection transiently enhanced the firing activity of locus coeruleus NE neurons and attenuated the suppressant effect of the alpha 2-adrenoceptor agonist clonidine on these NE neurons. Sustained administration of mirtazapine for 21 days (5 mg/kg/day, s.c., using minipumps) lead to a marked increase in the firing rate of 5-HT neurons (75%) but a more modest increase in the firing rate of NE neurons (30%), as well as to a desensitization of alpha 2-adrenergic heteroreceptors on 5-HT terminals in the hippocampus. The desensitization of these heteroreceptors, resulting from an increased synaptic availability of NE induced by mirtazapine would free 5-HT terminals from the inhibitory influence of NE on 5-HT release. These modifications of 5-HT neurons lead to an increased tonic activation of postsynaptic 5-HT1A receptors. The latter conclusion was based on the capacity of the selective 5-HT1A receptor antagonist WAY 100635 to enhance the firing activity of dorsal hippocampus CA3 pyramidal neurons in mirtazapine-treated rats but not in controls. This enhanced 5-HT neurotransmission may underlie to the antidepressant effect of mirtazapine." [Abstract]

Bruijn JA, Moleman P, van den Broek WW, Mulder PG.
Trait anxiety and the effect of a single high dose of diazepam in unipolar depression.
J Psychiatr Res 2001 Nov-Dec;35(6):331-7
"We found no relation between trait anxiety level and treatment response to either imipramine or mirtazapine. The most important finding of this study is the significant differential response to the diazepam test: depressive patients with high trait anxiety showed, predominantly, a disappearance of depressive symptoms without sedation and depressive patients with low trait anxiety showed, predominantly, sedation without disappearance of depressive symptoms. The opposite response to the diazepam test in patients with a different history of trait anxiety in spite of similar depressive symptomatology suggests differences in underlying pathophysiologic mechanisms." [Abstract]

Holzbach R, Jahn H, Pajonk FG, Mahne C.
Suicide attempts with mirtazapine overdose without complications.
Biol Psychiatry 1998 Nov 1;44(9):925-6
"BACKGROUND: One important aim of pharmacotherapy in depressed patients is the prevention of suicide attempts. Therefore, the medication given should be efficient and safe in overdose. RESULTS: We saw two patients after they had overdosed with mirtazapine because of suicidal intention. Both patients had taken 30 and 50 times a normal daily dose and achieved a full recovery without any complications or harm. CONCLUSIONS: Mirtazapine seems to be a safe compound in overdose. Therefore, it is an important therapeutic agent in depressed and suicidal patients." [Abstract]

Velazquez C, Carlson A, Stokes KA, Leikin JB.
Relative safety of mirtazapine overdose.
Vet Hum Toxicol 2001 Dec;43(6):342-4
"It appears that ingestions of mirtazapine approximately 10-fold of therapeutic exhibit minimal acute toxicity. From this and other cases in the literature exhibiting a 10-fold overdose, we conclude that isolated mirtazapine ingestions of this magnitude require no acute intervention other than short term (about 6 h) observation." [Abstract]

Bremner JD, Wingard P, Walshe TA.
Safety of mirtazapine in overdose.
J Clin Psychiatry 1998 May;59(5):233-5
"INTRODUCTION: We report 6 confirmed cases of substantial overdose with mirtazapine, a new antidepressant compound, that occurred up to January 1997 in the United States during postmarketing surveillance or in the clinical trials. RESULTS: In 6 patients, the mirtazapine doses ranged from 10 to 30 times the maximum recommended dose, and there were no serious adverse effects of overdose. Two patients at special risk, a 90-year-old man and a 3-year-old child, took higher-than-usual doses without serious sequelae. The 4 patients who combined other central nervous system (CNS) depressants with mirtazapine appeared to experience more CNS depression. One patient who ingested 60 mg of alprazolam had clinically significant respiratory depression in the emergency room but recovered fully within 24 hours. CONCLUSION: After an overdose of substantial multiples of mirtazapine that exceed the maximum recommended daily dosage, the new antidepressant mirtazapine appears to be safe in a limited number of cases." [Abstract]

Thase ME.
Antidepressant treatment of the depressed patient with insomnia.
J Clin Psychiatry 1999;60 Suppl 17:28-31; discussion 46-8
"Stimulation of serotonin-2 (5-HT2) receptors is thought to underlie insomnia and changes in sleep architecture seen with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This is the reason why hypnotics or low-dose trazodone are commonly coprescribed at the initiation of the treatment with either the SSRIs or SNRIs. On the other hand, antidepressant drugs with 5-HT2 blocking properties, such as mirtazapine or nefazodone, alleviate insomnia and improve sleep architecture. In depressed patients, mirtazapine produces a significant shortening of sleep-onset latency, increases a total sleep time, and leads to a marked improvement in sleep efficiency. Antidepressants with preferential 5-HT2 blocking properties are therefore a good treatment option for depressed patients with marked insomnia."
[Abstract]

Davis MP, Dickerson ED, Pappagallo M, Benedetti C, Grauer PA, Lycan J.
Mirtazepine: heir apparent to amitriptyline?
Am J Hosp Palliat Care 2001 Jan-Feb;18(1):42-6
""What's new in therapeutics?" will examine and evaluate drugs that may have a place in hospice, palliative, and long-term care. Mirtazepine will be examined and evaluated. Mirtazepine is a potential alternative anti-depressant with multiple additional benefits. It is an atypical anti-depressant, which has both noradrenergic and specific serotonergic receptor antagonism (NaSSa), and a unique pharmacological profile." [Abstract]

Brannon GE, Stone KD.
The use of mirtazapine in a patient with chronic pain.
J Pain Symptom Manage 1999 Nov;18(5):382-5
"Antidepressant drugs that act on serotonin and noradrenergic systems may be analgesic. The newer antidepressant mirtazapine (Remeron) has activity on noradrenergic and serotonergic transmission and is approved for the treatment of a Major Depressive Disorder. This paper describes a case that suggests that mirtazapine may also be useful in the treatment of chronic pain." [Abstract]

Wobrock T, Schwaab B, Bohm M, Schafers HJ, Wanke K, Supprian T.
[Pharmacotherapeutical approaches to insomnia patients with cardiac diseases and after heart transplantation]
Z Kardiol 2001 Oct;90(10):717-28
"For short-time treatment, medication with benzodiazepine hypnotics may be useful. If the problems of drug dependence and rebound insomnia are taken into consideration, treatment with non-benzodiazepine hypnotics offers more safety and comfort. If insomnia is part of a depressive syndrome, pharmacotherapeutical intervention with antidepressive sedative medication is required. With regard to cardiac disease, treatment with mirtazapine, nefazodone or trazodone should be preferred because of the chinidine-like effect of tricyclic antidepressants (TCA)." [Abstract]

Blier P.
Pharmacology of rapid-onset antidepressant treatment strategies.
J Clin Psychiatry 2001;62 Suppl 15:12-7
"The firing of 5-HT neurons in the raphe nuclei is driven, at least partly, by alpha1-adrenoceptor-mediated excitatory inputs from NE neurons. Inhibitory alpha2-adrenoceptors on the NE neuroterminals form part of a feedback control mechanism. Mirtazapine, an antagonist at alpha2-adrenoceptors, does not enhance 5-HT neurotransmission directly but disinhibits the NE activation of 5-HT neurons and thereby increases 5-HT neurotransmission by a mechanism that does not require a time-dependent desensitization of receptors. These neurobiological phenomena may underlie the apparently faster onset of action of mirtazapine compared with the SSRIs." [Abstract]

Garcia-Sevilla JA, Ventayol P, Perez V, Rubovszky G, Puigdemont D, Ferrer-Alcon M, Andreoli A, Guimon J, Alvarez E.
Regulation of platelet alpha 2A-adrenoceptors, Gi proteins and receptor kinases in major depression: effects of mirtazapine treatment.
Neuropsychopharmacology. 2004 Mar;29(3):580-8.
"Major depression is associated with the upregulation of alpha(2A)-adrenoceptors in brain tissue and blood platelets. The homologous regulation of these receptors by G-protein-coupled receptor kinases (GRKs) might play a relevant role in the pathogenesis and treatment of depression. This study was designed to assess the status of the complex alpha(2A)-adrenoceptor/Galphai/GRK 2 in the platelets of depressed patients (n=22) before and after treatment with the antidepressant mirtazapine, an antagonist at alpha(2A)-adrenoceptors (30-45 mg/day for up to 6 months). A second series of depressed suicide attempters (n=32) were also investigated to further assess the status of platelet GRK 2 and GRK 6. Platelet alpha(2A)-adrenoceptors and Galphai protein immunoreactivities were increased in depressed patients (49 and 35%) compared with matched controls. In contrast, GRK 2 content was decreased in the two series of depressed patients (27 and 28%). GRK 6 (a GRK with different properties) was found unchanged. In drug-free depressed patients, the severity of depression (behavioral ratings with two different instruments) correlated inversely with the content of platelet GRK 2 (r=-0.46, n=22, p=0.032, and r=-0.55, n=22, p=0.009). After 4-24 weeks of treatment, mirtazapine induced downregulation of platelet alpha(2A)-adrenoceptors (up to 34%) and Galphai proteins (up to 28%), and the upregulation of GRK 2 (up to 30%). The results indicate that major depression is associated with reduced platelet GRK 2, suggesting that a defect of this kinase may contribute to the observed upregulation of alpha(2A)-adrenoceptors. Moreover, treatment with mirtazapine reversed this abnormality and induced downregulation of alpha(2A)-adrenoceptor/Galphai complex. The results support a role of supersensitive alpha(2A)-adrenoceptors in the pathogenesis and treatment of major depression." [Abstract]

de Boer TH, Nefkens F, van Helvoirt A, van Delft AM.
Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan.
J Pharmacol Exp Ther 1996 May;277(2):852-60 [Abstract]

Haddjeri N, Blier P, de Montigny C.
Effects of long-term treatment with the alpha 2-adrenoceptor antagonist mirtazapine on 5-HT neurotransmission.
Naunyn Schmiedebergs Arch Pharmacol 1997 Jan;355(1):20-9 [Abstract]

Haddjeri N, Blier P, de Montigny C.
Effect of the alpha-2 adrenoceptor antagonist mirtazapine on the 5-hydroxytryptamine system in the rat brain.
J Pharmacol Exp Ther 1996 May;277(2):861-71 [Abstract]

Berendsen HH, Broekkamp CL.
Indirect in vivo 5-HT1A-agonistic effects of the new antidepressant mirtazapine.
Psychopharmacology (Berl) 1997 Oct;133(3):275-82 [Abstract]

Nakayama K, Sakurai T, Katsu H.
Mirtazapine increases dopamine release in prefrontal cortex by 5-HT(1A) receptor activation.
Brain Res Bull. 2004 Apr 30;63(3):237-41.
"Mirtazapine has a low affinity for 5-HT(1A) receptors but shows 5-HT(1A)-agonistic-like effects in behavioral pharmacology test. However, there is to date no clear evidence that mirtazapine enhances 5-HT(1A) neurotransmission. The object of the present study was to assess the effects of mirtazapine on dialysate levels of dopamine and 5-HT in the medial frontal cortex of freely moving rats and to determine whether this drug could modulate 5-HT(1A) neurotransmission. In vivo microdialysis was used to study the effects of mirtazapine on extracellular dopamine and 5-HT levels, and the effect of the 5-HT(1A) antagonist WAY100,356 on extracellular dopamine level increased by mirtazapine in the rat prefrontal cortex. Mirtazapine (4-16mg/kg, i.p.) produced a dose-dependent increase in extracellular dopamine levels in the medial prefrontal cortex (mPFC) of freely moving rats without modifying those of 5-HT. In the presence of the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazineyl]ethyl]-N-(pyridinyl)-cyclohexane-carboxamide (WAY100,635; 0.3mg/kg; i.p.), the influence of mirtazapine on cortical levels of dopamine was markedly attenuated. These results indicate that mirtazapine induces the enhancement of the output of cortical dopamine mediated via blockade of alpha(2)-adrenergic receptors and facilitation of post-synaptic 5-HT(1A) function." [Abstract]

Devoto P, Flore G, Pira L, Longu G, Gessa GL.
Mirtazapine-induced corelease of dopamine and noradrenaline from noradrenergic neurons in the medial prefrontal and occipital cortex.
Eur J Pharmacol. 2004 Mar 8;487(1-3):105-11.
"The novel antidepressant mirtazapine has been shown to increase extracellular noradrenaline and dopamine in the medial prefrontal cortex. Our previous studies indicate that extracellular dopamine in the cerebral cortex originates largely from noradrenergic terminals, such release being controlled by alpha(2)-adrenoceptors. Because mirtazapine inhibits alpha(2)-adrenoceptors, the possibility that it might corelease dopamine and noradrenaline was investigated. By means of microdialysis, the effect of mirtazapine on extracellular dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and noradrenaline in the medial prefrontal cortex, densely innervated by dopaminergic and noradrenergic neurons, and in the occipital cortex, receiving equal noradrenergic but scarce dopaminergic projections, was compared. Basal extracellular concentration of noradrenaline was similar in both cortices, while dopamine in the occipital cortex was only about 50% lower than in the medial prefrontal cortex, reflecting noradrenergic rather than dopaminergic projections. The intraperitoneal (i.p.) administration of mirtazapine (5 and 10 mg/kg) increased extracellular dopamine, DOPAC and noradrenaline to approximately the same extent in both cortices, an effect totally suppressed by the alpha(2)-adrenoceptors agonist clonidine (0.15 mg/kg, i.p.). To exclude the possibility that mirtazapine-induced increase in dopamine might result from reduced dopamine removal from extracellular space, noradrenaline and dopamine uptake mechanisms were blocked by perfusing 100 microM desipramine into either cortex. The combined i.p. administration of mirtazapine (5 mg/kg) and the local perfusion of desipramine produced an additional increase in extracellular dopamine, DOPAC and noradrenaline in the medial prefrontal cortex and occipital cortex compared with the increase produced by either drug given alone. The results suggest that mirtazapine by inhibiting alpha(2)-adrenoceptors produces a corelease of noradrenaline and dopamine from noradrenergic terminals in the cerebral cortex." [Abstract]

Rogoz Z, Wrobel A, Dlaboga D, Dziedzicka-Wasylewska M.
Effect of repeated treatment with mirtazapine on the central dopaminergic D2/D3 receptors.
Pol J Pharmacol 2002 Jul-Aug;54(4):381-9
"The above results indicate that repeated MIR administration did not induce any adaptive change (behavioral and biochemical changes) in the dopaminergic D2/D3 system." [Abstract]

On site link: mirtazapine clinical studies

On site link: mirtazapine and weight gain

On site link: mirtazapine drug interactions/pharmacokinetics

Nierenberg AA.
Do some antidepressants work faster than others?
J Clin Psychiatry 2001;62 Suppl 15:22-5
"The clinical utility of antidepressant drugs is impaired by the delay in onset of their therapeutic action. It is becoming increasingly clear that differences exist between antidepressants with respect to this property, both within and between pharmacologic classes. Post hoc analyses of comparisons between selective serotonin reuptake inhibitors and dual-action antidepressants such as mirtazapine and venlafaxine indicate that the dual-action drugs may have a faster onset of action. At least in the case of mirtazapine, the earlier onset appears to be via a specific antidepressant effect and not an effect on sleep or other accessory symptoms." [Abstract]

Thompson C.
Onset of action of antidepressants: results of different analyses.
Hum Psychopharmacol 2002 Jun;17 Suppl 1:S27-32
"Because the value of antidepressants is hampered by their delay in onset of action, considerable attention has been focused on developing a drug that acts more rapidly. However, although specific studies are now ongoing, there have been no peer-reviewed prospective onset of action trials published in the literature to date. Some data are currently available from post-hoc pooled analyses and numerous methods have been developed for evaluating the onset of action; these include the time to response, the time to onset of therapeutic effect, pattern analysis and survival analyses. Such an analysis of four large-scale, double-blind studies has provided evidence for an earlier onset of action with mirtazapine than with the SSRIs (fluoxetine, paroxetine and citalopram). Significant differences were seen between mirtazapine and the SSRIs after 1 week of treatment. This effect was consistent across the four different methodologies and appears to be due to a specific antidepressant effect rather than an early effect on, for example, sleep. These findings await confirmation from specifically designed prospective onset of action studies." [Abstract]

Szegedi A, Muller MJ, Anghelescu I, Klawe C, Kohnen R, Benkert O.
Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression.
J Clin Psychiatry. 2003 Apr;64(4):413-20.
"OBJECTIVE: Current clinical knowledge holds that antidepressants have a delayed onset of efficacy. However, the delayed onset hypothesis has been questioned recently by survival analytical approaches. We aimed to test whether early improvement under antidepressant treatment is a clinically useful predictor of later stable response and remission. METHOD: We analyzed data from a randomized double-blind controlled trial with mirtazapine and paroxetine in patients with major depression (DSM-IV). Improvement was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score reduction of > or = 20%. Stable response was defined as > or = 50% HAM-D-17 score reduction at week 4 and week 6, and stable remission as a HAM-D-17 score of < or = 7 at week 4 and week 6. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Improvement occurred in a majority of the analyzed patients within 2 weeks (mirtazapine: 72.7% of 109 patients; paroxetine: 64.9% of 103 patients). Early improvement was a highly sensitive predictor of later stable response or stable remission for both drugs. NPV approached maximum values as early as week 2 for mirtazapine and week 3 for paroxetine. After 2 weeks of treatment with mirtazapine and 3 weeks with paroxetine, almost none of the patients who had not yet improved became a stable responder or stable remitter in the later course. CONCLUSION: Our results strongly suggest that early improvement predicts later stable response with high sensitivity. These empirically derived data question the delayed onset hypothesis for both antidepressants tested and provide important clinical clues for an individually tailored antidepressant treatment." [Abstract]

Benkert O, Muller M, Szegedi A.
An overview of the clinical efficacy of mirtazapine.
Hum Psychopharmacol 2002 Jun;17 Suppl 1:S23-6
"Mirtazapine is at least as effective as the tricyclic antidepressants and trazodone in a wide range of patient subgroups including in- and out-patients with moderate to severe depression. It also appears to be at least as effective as the serotonin and noradrenaline reuptake inhibitor venlafaxine in the treatment of severely depressed melancholic patients. When compared with the selective serotonin reuptake inhibitors (SSRIs), mirtazapine shows a significantly earlier onset of action. Further analysis of a study comparing mirtazapine with the SSRI paroxetine indicated that early improvement was a highly sensitive predictor of later stable response for both drugs. The positive predictive value of an early improvement was significantly higher during mirtazapine treatment compared with paroxetine. The negative predictive value approached maximum values as early as week 2 with mirtazapine and week 3 with paroxetine. This suggests that the predictability of the response to treatment is better with mirtazapine than with paroxetine." [Abstract]

Keller MB.
Rationale and options for the long-term treatment of depression.
Hum Psychopharmacol 2002 Jun;17 Suppl 1:S43-6
"Depression is a chronic and disabling illness that frequently requires long-term maintenance treatment. The probability of recurrence after recovery is extremely high, especially amongst patients who have experienced previous episodes of depression. Indeed, once a patient has suffered from three episodes of depression, the likelihood that they will have another episode within the next 2 years is more than 95%. Despite this, depression remains an under-recognized and under-treated disease. Mirtazapine has shown sustained efficacy in the long-term treatment of depression, being more effective than amitriptyline and at least as effective as the selective serotonin reuptake inhibitors paroxetine and citalopram. It is also well tolerated over prolonged periods. It should therefore prove suitable for use as maintenance treatment in depressed patients." [Abstract]

Fawcett J, Barkin RL.
Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression.
J Affect Disord 1998 Dec;51(3):267-85
"Mirtazapine has been evaluated in a worldwide clinical development program involving approximately 4500 patients. Controlled clinical trials involving almost 2800 mirtazapine-treated patients have demonstrated the compound to be effective for the treatment of moderate-to-serve major depression. Mirtazapine was consistently superior to placebo, and equivalent in efficacy to the tricyclic antidepressants amitriptyline, doxepin and clomipramine, but with an improved tolerability profile. Mirtazapine has shown a rapid onset of action in patients with predominantly severe depressive illness in a comparative study against fluoxetine. Mirtazapine has a unique tolerability profile, since the specific postsynaptic 5-HT2 and 5-HT3 receptor blockade of mirtazapine provides early antidepressant effects without causing unwanted serotonin-related side-effects. Transient somnolence, hyperphagia and weight gain are the most commonly reported adverse events, which may be attributed to the antihistaminic (H1) activity of mirtazapine at low doses. Somnolence, the most commonly reported side-effect, appears to be less frequent at higher dosages. Mirtazapine also demonstrates important anxiolytic and sleep-improving effects, which may be related to its pharmacodynamic properties. In addition, mirtazapine does not appear to be associated with sexual dysfunction. Mirtazapine has shown no significant cardiovascular adverse effects at multiples of 7 to 22 times the maximum recommended dose." [Abstract]

Hirschfeld RM.
The use of mirtazapine in difficult-to-treat patient populations.
Hum Psychopharmacol 2002 Jun;17 Suppl 1:S33-6
"Patients who have failed previous antidepressant treatment present substantial clinical management challenges. Similarly, elderly patients require special attention. Three recent studies have shown that mirtazapine has a role to play in the management of these patients. Mirtazapine has proved effective in the treatment of patients who were resistant or intolerant to selective serotonin reuptake inhibitors (SSRIs) and the switch to mirtazapine could be made immediately without the necessity for a taper period. In a double-blind study in patients who were resistant to SSRI treatment, mirtazapine had a more rapid onset of action than sertraline. Mirtazapine has also proved effective in elderly depressed patients and again showed a faster onset of action than another of the SSRIs, paroxetine." [Abstract]

Aslan S, Isik E, Cosar B.
The effects of mirtazapine on sleep: a placebo controlled, double-blind study in young healthy volunteers.
Sleep 2002 Sep 15;25(6):677-9
"Mirtazapine improved the variables related to sleep continuity when compared with placebo. It increased the sleep efficiency index, while decreasing the number of awakenings and their duration. The slow wave sleep time was increased, while the stage 1 sleep time was decreased significantly. There was no significant effect on rapid eye movement sleep variables. CONCLUSION: Our findings suggest that mirtazapine has considerable effects on slow wave sleep. Further studies are recommended to investigate the efficiency of antidepressants, in respect to the effects of 5-HT2 blockade on slow wave sleep." [Abstract]

Winokur A, DeMartinis NA 3rd, McNally DP, Gary EM, Cormier JL, Gary KA.
Comparative effects of mirtazapine and fluoxetine on sleep physiology measures in patients with major depression and insomnia.
J Clin Psychiatry. 2003 Oct;64(10):1224-9.
"BACKGROUND: Sleep complaints are common in patients with major depressive disorder (MDD). Both MDD and antidepressant drugs characteristically alter objective sleep measures. This study compares the effects of mirtazapine and fluoxetine on sleep continuity measures in DSM-IV MDD patients with insomnia. METHOD: Patients (N = 19) received initial baseline polysomnography evaluations over 2 consecutive nights. Subjects were randomly assigned to either fluoxetine (20-40 mg/day) or mirtazapine (15-45 mg/day) treatment for an 8-week, double-blind, double-dummy treatment trial. Single-night polysomnograms were conducted at weeks 1, 2, and 8, with depression ratings assessed at baseline and weeks 1, 2, 3, 4, 6, and 8. Statistical analysis was performed by repeated-measures analysis of variance followed by Dunnet's post hoc analyses. RESULTS: Patients receiving mirtazapine (N = 8) had significant improvement in objective sleep physiology measures at 8 weeks. Improvements in sleep latency, sleep efficiency, and wake after sleep onset were significant after only 2 weeks of mirtazapine treatment. No significant changes in sleep continuity measures were observed in the fluoxetine group (N = 11). Both groups improved clinically in mood and subjective sleep measures from baseline, with no differences between groups. CONCLUSION: These data demonstrate the differential effects of mirtazapine and fluoxetine, with significant improvement in favor of mirtazapine, on objective sleep parameters in MDD patients with insomnia." [Abstract]

Schittecatte M, Dumont F, Machowski R, Fontaine E, Cornil C, Mendlewicz J, Wilmotte J.
Mirtazapine, but not fluvoxamine, normalizes the blunted REM sleep response to clonidine in depressed patients: implications for subsensitivity of alpha(2)-adrenergic receptors in depression.
Psychiatry Res 2002 Jan 31;109(1):1-8 [Abstract]

Radhakishun FS, van den Bos J, van der Heijden BC, Roes KC, O'Hanlon JF.
Mirtazapine effects on alertness and sleep in patients as recorded by interactive telecommunication during treatment with different dosing regimens.
J Clin Psychopharmacol 2000 Oct;20(5):531-7
"This double-blind study compared mirtazapine's effects on alertness and sleep between parallel groups treated for 2 weeks according to a fixed regimen of 30 mg at bedtime (N = 69) and one that increased in dose from 15 to 30 mg at bedtime after the first week (N = 71). These patients with depression used an interactive telephone/computer system for daily alertness and sleep recordings on self-rating scales before and during treatment. Efficacy (17-item Hamilton Rating Scale for Depression [HAM-D], Clinical Global Impression Scale [CGI]) and safety assessments were made by participating psychiatrists. Both groups' alertness ratings were subnormal at baseline and even lower after the first dose. The ratings recovered after the second dose and increased progressively to levels 18% higher than those at baseline by the end of treatment. Patients receiving the fixed dose reported earlier sleep onset and longer duration. Similar mean changes in HAM-D scores (approximately -40%) and frequencies of CGI responders (>50%) occurred in both groups. The regimens were equally well tolerated. Somnolence, the most frequent side effect, was reported by only 10% of each group during the first week and by fewer patients during the second. Mirtazapine in fixed and ascending nocturnal dosing regimens was found to facilitate sleep, but it does not generally reduce daytime alertness. The fixed regimen seems preferable because of its greater effects on sleep." [Abstract]

Ruigt GS, Kemp B, Groenhout CM, Kamphuisen HA.
Effect of the antidepressant Org 3770 on human sleep.
Eur J Clin Pharmacol 1990;38(6):551-4
"The effect of a single dose (30 mg) of Org 3770 (metirzapine) on human sleep was assessed in a double blind, placebo controlled, cross over study in 6 young, healthy male volunteers. The sleep stage classification was based on visual scoring of 24 h electroencephalographic recordings according to the criteria of Rechtschaffen and Kales. Org 3770 30 mg p.o. given 2 h before bedtime had a sleep promoting action in all subjects, resulting in a shortened time to the onset of sleep. Bedtime waking and dozing (Stage 1) were reduced in favour of deep, slow wave sleep (Stages 3 and 4). Org 3770 increased the latency of REM sleep with respect to Stage 2 sleep in all subjects. It also caused a minor reduction in waking periods during REM sleep and a lower frequency of awakenings after periods of movement. No effect of Org 3770 was observed in reaction and vigilance tests on the post treatment day. The observed effects of Org 3770 on normal human sleep suggest that it might ameliorate the sleep disturbances encountered in endogenous depression, which are characterized by a reduction in slow wave sleep, an increase in nighttime awakenings and shortening of REM sleep latency." [Abstract]

Palazidou E, Papadopoulos A, Sitsen A, Stahl S, Checkley S.
An alpha 2 adrenoceptor antagonist, Org 3770, enhances nocturnal melatonin secretion in man.
Psychopharmacology (Berl) 1989;97(1):115-7 [Abstract]

Winokur A, Sateia MJ, Hayes JB, Bayles-Dazet W, MacDonald MM, Gary KA.
Acute effects of mirtazapine on sleep continuity and sleep architecture in depressed patients: a pilot study.
Biol Psychiatry 2000 Jul 1;48(1):75-8
"Six patients meeting criteria for major depressive disorder and scoring > or =4 on the three Hamilton Depression Rating Scale sleep items were studied. Polysomnographic evaluations were performed at baseline and after 1 (15 mg at bedtime) and 2 weeks (30 mg at bedtime) of open-label mirtazapine treatment. RESULTS: Mirtazapine significantly decreased sleep latency and significantly increased total sleep time and sleep efficiency from baseline levels during week 1, with similar results observed after week 2. Mirtazapine did not significantly alter rapid eye movement sleep parameters. Clinically, Hamilton Depression Rating Scale and sleep disturbance ratings improved after treatment. CONCLUSIONS: Mirtazapine significantly improves sleep continuity in major depressive disorder patients with poor sleep quality at weeks 1 and 2 of treatment, while preserving sleep architecture." [Abstract]

DAVID W. CARLEY, and MIODRAG RADULOVACKI
Mirtazapine, a Mixed-Profile Serotonin Agonist/Antagonist, Suppresses Sleep Apnea in the Rat
Am. J. Respir. Crit. Care Med. 160: 1824-1829, December 1999.
"Serotonin enhancing drugs, including L-tryptophan and, more recently, fluoxetine and paroxetine, have been tested as pharmacologic treatments for sleep apnea syndrome. Although some patients have demonstrated reduced apnea expression after treatment with these compounds, this improvement has been restricted to nonrapid eye movement (NREM) sleep, with some patients showing no improvement. This study reports the effects of mirtazapine, an antidepressant with 5-HT1 agonist as well as 5-HT2 and 5-HT3 antagonist effects, on sleep and respiration in an established animal model of central apnea. We studied nine adult male Sprague-Dawley rats chronically instrumented for sleep staging. In random order on separate days, rats were recorded after intraperitoneal injection of: (1) saline, (2) 0.1 mg/kg +/ mirtazapine (labeled as Remeron), (3) 1 mg/kg mirtazapine, or (4) 5 mg/ kg mirtazapine. With respect to saline injections, mirtazapine at all three doses reduced apnea index during NREM sleep by more than 50% (p < 0.0001) and during REM sleep by 60% (p < 0.0001) for at least 6 h. In association with this apnea suppression normalized inspiratory minute ventilation increased during all wake/sleep states (p < 0.001 for each state). The duration of NREM sleep was unaffected by any dose of mirtazapine (p = 0.42), but NREM EEG delta power was increased by more than 30% at all doses (p = 0.04), indicating improved NREM sleep consolidation after mirtazapine injection. We conclude that mirtazapine, over a 50-fold dose range, significantly reduces central apnea expression during NREM and REM sleep in the rat. The efficacy of this compound to suppress apnea in all sleep stages most probably arises from its mixed agonist/antagonist profile at serotonin receptors. The implications of these findings for the management of sleep apnea syndrome must be verified by appropriate clinical trials." [Full Text]

Thase ME.
Treatment issues related to sleep and depression.
J Clin Psychiatry 2000;61 Suppl 11:46-50
"For a significant minority, SSRIs can have negative effects on sleep patterns resulting in insomnia that requires concomitant sedatives or anxiolytics. By contrast, agents that block the serotonin type 2 (5-HT2) receptor have beneficial effects on depressive insomnia. For example, a recent 8-week study comparing the effects of nefazodone and fluoxetine on sleep disturbances in outpatients with nonpsychotic depression and insomnia found that fluoxetine was associated with approximately a 30% increase in the number of nocturnal awakenings whereas nefazodone was associated with about a 15% decrease, a net difference of 45%." [Abstract]

Nutt DJ.
Care of depressed patients with anxiety symptoms.
J Clin Psychiatry 1999;60 Suppl 17:23-7; discussion 46-8
"Anxiety frequently coexists with depression, either as a comorbid anxiety disorder or as anxiety symptoms accompanying a primary depressive disorder. Effective therapy for the treatment of depressive illness must include a consideration of anxiety symptoms, since anxiety has been estimated to be present in up to 96% of patients with depressive illness. Available data also indicate that depressed patients with significant anxiety may be at greater risk for suicide. Of particular clinical importance are symptoms of somatic anxiety: they are present in up to 86% of depressed patients, and the failure to treat them effectively can diminish the ability of a patient to function. Since the overall prognosis for recovery from a major depressive episode is less than optimal in patients with significant anxiety, treatments that can provide an effective and early relief of both depressive and anxiety symptoms are of paramount importance. Drugs with serotonin reuptake inhibition (such as selective serotonin reuptake inhibitors [SSRIs] or serotonin-norepinephrine reuptake inhibitors [SNRIs]) may produce transient increases in anxiety symptomatology presenting as jitteriness, agitation, insomnia, and gastrointestinal symptoms when treatment is initiated. Mirtazapine has intrinsic receptor-blocking properties (in particular, serotonin-2 [5-HT2] receptor blockade) that can be linked to an early relief of anxiety symptoms during the treatment. The available data show that mirtazapine is superior to placebo in depressed patients with high baseline anxiety and/or agitation. Furthermore, mirtazapine was statistically significantly superior to both citalopram and paroxetine in alleviating anxiety symptoms early in treatment as assessed by changes from baseline on the Hamilton Rating Scale for Anxiety or the Hamilton Rating Scale for Depression anxiety/somatization factor, respectively. Mirtazapine provides early and effective relief of both depressive and anxiety symptoms, reducing the need for polypharmacy. These therapeutic actions of mirtazapine persist throughout the course of treatment." [Abstract]

Montgomery SA.
Safety of mirtazapine: a review.
Int Clin Psychopharmacol 1995 Dec;10 Suppl 4:37-45
"The clinical trial development programme of mirtazapine (Org 3770), performed in Europe and the United States, demonstrated an outstanding safety profile of this compound. The evaluation of the safety was based on data from all patients who took at least one dose of study medication during studies comparing mirtazapine with placebo, amitriptyline or other active comparators. A general indication of mirtazapine's safety is the significantly lower percentage of patients (65%) who complained of any adverse clinical experiences compared with the placebo- (76%) or amitriptyline-treated group (87%). Moreover, drop-out rates due to adverse clinical experiences were significantly lower than in the amitriptyline-treatment group. Mirtazapine has virtually no anticholinergic, adrenergic or typical selective serotonin reuptake inhibitor (SSRI) side effects. The only significantly higher incidences versus placebo were seen in the adverse clinical effects of drowsiness (23% versus 14%), excessive sedation (19% versus 5%), dry mouth (25% versus 16%), increased appetite (11% versus 2%) and weight increase (10% versus 1%). These complaints were typically mild and transient in nature, and decreased over time despite increased doses of mirtazapine. In contrast, significantly higher incidences of headache (5% versus 10%) and weight decrease (2% versus 6%), symptoms commonly seen in depressed patients, were recorded in the placebo-treated patients. Also, typical SSRI adverse events, such as nausea, vomiting, diarrhoea and insomnia, and symptoms of sexual dysfunction were registered less frequently in mirtazapine-treated patients than in the placebo-treated patients. Approximately 10% of the mirtazapine-treated patients in the clinical trial programme were older than 65 years. The pattern of adverse clinical experiences seen in this group of patients is fully in line with that seen in the overall patient population. The analysis of vital sign indices, i.e. blood pressure and heart rate, showed that no changes occurred with mirtazapine treatment; this pattern was fully comparable to that seen with placebo. Furthermore, very low incidences of clinically relevant changes in laboratory indices, such as the liver enzymes alanine aminotransferase and aspartate aminotransferase or neutropenia, were recorded in each treatment group. Mirtazapine has a very low seizure-inducing potential: only one case was recorded in a patient with a history of seizures during previous treatment with clomipramine. The low seizure-inducing potential combined with a lack of cardiotoxic properties allows safety in an overdose of mirtazapine, even in elderly patients. The only symptom seen in the patients taking an overdose of mirtazapine alone or in combination with other drugs was excessive but transient somnolence, which resolved spontaneously within a few hours. In conclusion, the new antidepressant mirtazapine offers clinicians a unique combination of strong efficacy and good safety." [Abstract]

Nutt DJ.
Tolerability and safety aspects of mirtazapine.
Hum Psychopharmacol 2002 Jun;17 Suppl 1:S37-41
"The tolerability and safety profile of the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine reflects its unique pharmacological profile. The 5-HT(2) blocking effect contributes towards its anxiolytic effects and benefits on sleep, as well as preventing the sexual dysfunction that may occur with non-specific stimulation of the serotonin system by drugs such as the selective serotonin reuptake inhibitors (SSRIs). In addition, 5-HT(3) blockade by mirtazapine helps to prevent nausea and vomiting. Weight gain is the most commonly reported side-effect of mirtazapine, although there is evidence to suggest that this is not a significant problem during long-term treatment. In conclusion, mirtazapine has a good tolerability and safety profile that demonstrates several benefits over other antidepressants." [Abstract]

Roose SP.
Tolerability and patient compliance.
J Clin Psychiatry 1999;60 Suppl 17:14-7; discussion 46-8
"Currently available antidepressants interact with several types of receptors, which may explain both wanted and unwanted effects of these drugs. These effects are different and distinctive, and knowledge about them may help clinicians understand differences between compounds in terms of their tolerability profiles. Given roughly comparable efficacy, tolerability profile is the critical determinant in selecting an antidepressant medication for a particular patient. In addition, tolerability is inseparably linked to patient compliance, both in acute and long-term treatment, and ultimately to overall success of treatment. Refinement in pharmacologic profiles of all newly introduced antidepressants resulted in overall advantages in tolerability in comparison with older tricyclic compounds. However, differences in receptor interactions between antidepressants are directly reflected in tolerability (adverse event) profiles. Among new antidepressants, mirtazapine and the selective serotonin reuptake inhibitors share favorable overall tolerability and safety, especially with respect to low premature termination rates because of adverse events, cardiac safety, and safety in overdose. However, the different pharmacologic profile of mirtazapine is reflected in its different tolerability profile. Because of interactions with the histamine (H1) receptor, mirtazapine may be related to transient initial somnolence and weight gain in some patients. Its serotonin-2 (5-HT2)-blocking properties may account for lack of sexual dysfunction, insomnia, nervousness, and agitation. Mirtazapine's 5-HT3-blocking properties are unique among all currently available antidepressants and may account for lack of gastrointestinal adverse events." [Abstract]

Biswas PN, Wilton LV, Shakir SA.
The pharmacovigilance of mirtazapine: results of a prescription event monitoring study on 13554 patients in England.
J Psychopharmacol. 2003 Mar;17(1):121-6.
"Mirtazpine is the first noradrenaline and serotonin specific antidepressant. We monitored the safety of mirtazapine as reported in primary practice in England.The exposure data were provided by monitoring the dispensed prescriptions issued between September 1997 and February 1999. Questionnaires sent to GPs provided outcome data. Drowsiness/sedation and malaise/lassitude were the most frequent ADRs (116, 71 respectively) and had the highest incidence density (per 1000 patient-months) in the first month of treatment (58.1, 27.8 respectively). Agitation (73), aggression (70), rash (20), hallucinations (13) and abnormal dreams (31 were unlabelled AES while abnormal liver function tests (12), syncope (8), abnormal behaviour (4) and visual disturbance (3) were labelled AES possibly due to mirtazapine use. Serious suspected ADRs reported were facial oedema (5), allergy (3), bone marrow toxicity (2) and myelodysplasia (1)." [Abstract]

Vanina Y, Podolskaya A, Sedky K, Shahab H, Siddiqui A, Munshi F, Lippmann S.
Body weight changes associated with psychopharmacology.
Psychiatr Serv 2002 Jul;53(7):842-7
"The antipsychotic drugs chlorpromazine, clozapine, and olanzapine are often associated with weight gain. Among antidepressants, amitriptyline and mirtazapine are known to cause weight gain. However, reductions are sometimes observed, and each antidepressant has its own unique weight-effect profile. Mood stabilizers, especially valproate-related products, are also associated with weight gain." [Abstract]

Hirschfeld RM.
Management of sexual side effects of antidepressant therapy.
J Clin Psychiatry 1999;60 Suppl 14:27-30; discussion 31-5
"Although much attention has been paid to sexual dysfunction associated with the selective serotonin reuptake inhibitors (SSRIs), many other commonly used psychotropics are associated with a variety of sexual dysfunction, including haloperidol, benzodiazepines, stimulants, and drugs of abuse. With regard to SSRIs, sexual dysfunction occurs in 50% or more of such patients, which is substantially higher than the rates reported in the Physicians' Desk Reference. The reason for this discrepancy is that patients will not spontaneously report sexual problems and must be questioned about such problems directly. A variety of strategies exist to manage antidepressant-induced sexual dysfunction, including waiting, reducing the antidepressant dose, use of drug holidays, use of adjunctive pharmacotherapy, and switching antidepressants. Use of an antidepressant with a low prevalence of sexual side effects, such as bupropion, nefazodone, and mirtazapine, may also be considered." [Abstract]

Gregorian RS, Golden KA, Bahce A, Goodman C, Kwong WJ, Khan ZM.
Antidepressant-induced sexual dysfunction.
Ann Pharmacother 2002 Oct;36(10):1577-89
"DATA SYNTHESIS: Sexual dysfunction is a relatively common adverse effect of many of the antidepressants in common use today. Rates of sexual dysfunction observed in clinical practice may be higher than those reported in the product information for several agents. Selective serotonin-reuptake inhibitors (SSRIs) appear to be the class of antidepressants most likely to cause sexual dysfunction. Published studies suggest that between 30% and 60% of SSRI-treated patients may experience some form of treatment-induced sexual dysfunction. Bupropion and nefazodone appear to be much less likely to cause sexual dysfunction (</=10% of patients). Mirtazapine also appears to be associated with a low rate of sexual adverse effects. Panel results largely reflect the consensus of the literature." [Abstract]

Hirschfeld RM.
Care of the sexually active depressed patient.
J Clin Psychiatry 1999;60 Suppl 17:32-5; discussion 46-8
"Sexual dysfunction's pharmacologic basis is thought to be stimulation of 5-HT2 receptors. Antidepressant-induced sexual dysfunction, most frequently presenting as a reduction in libido or delayed orgasm, may not pose a large burden for patients in acute treatment. However, in long-term treatment, patients are generally well, and anything that interferes with sexual functioning will be a greater problem and will contribute strongly to noncompliance. Different strategies are advised when dealing with sexual dysfunction in depressed patients treated with antidepressant drugs: waiting for a spontaneous resolution of a problem, reduction in antidepressant drug dosages, drug holidays, adjunctive pharmacotherapy, or switching antidepressants. Perhaps the best way is to avoid sexual dysfunction by starting treatment with an antidepressant with proven acute and long-term efficacy that is devoid of sexual side effects, for example, mirtazapine, bupropion, or nefazodone." [Abstract]

Norinder A, Nordling S, Haggstrom L.
[Treatment of depression and cost efficiency. The cost of a tablet is a poor indicator seen from a socioeconomic perspective]
Lakartidningen 2000 Apr 5;97(14):1693-8, 1700
"Cost-effectiveness calculations comparing mirtazapine with amitriptyline show that it is less expensive to initiate treatment with mirtazapine, both when direct costs are compared and when indirect costs are included. In a comparison between mirtazapine and fluoxetine, initial treatment with fluoxetine is less expensive with respect to direct cost, but these two alternatives are equivalent when indirect costs are taken into consideration. The price of drug is a poor criterion of resource expenditures and of rational pharmacological therapy in the treatment of depression." [Abstract]

Holm KJ, Jarvis B, Foster RH.
Mirtazapine. A pharmacoeconomic review of its use in depression.
Pharmacoeconomics 2000 May;17(5):515-34
"Available data suggest that mirtazapine is a cost-effective alternative to amitriptyline and fluoxetine for the treatment of depression." [Abstract]

Borghi J, Guest JF.
Economic impact of using mirtazapine compared to amitriptyline and fluoxetine in the treatment of moderate and severe depression in the UK.
Eur Psychiatry 2000 Sep;15(6):378-87
"The expected cost of healthcare resource use attributable to managing a patient suffering from moderate or severe depression who discontinues antidepressant treatment, irrespective of the initial treatment, was estimated to be pounds sterling 206 (range pounds sterling 50 to pounds sterling 504) over five months. Using mirtazapine instead of amitriptyline for seven months increases the proportion of successfully treated patients by 21% (from 19.2 to 23.2%) and reduces the expected direct NHS cost by pounds sterling 35 per patient (from pounds sterling 448 to pounds sterling 413). Using mirtazapine instead of fluoxetine for six months increases the proportion of successfully treated patients by 22% (from 15.6 to 19.1%), albeit for an additional cost to the NHS of pounds sterling 27 per patient (from pounds sterling 394 to pounds sterling 420). In conclusion, this study suggests that mirtazapine is a cost-effective antidepressant compared to amitriptyline and fluoxetine in the management of moderate and severe depression in the UK." [Abstract]

Brown MC, Nimmerrichter AA, Guest JF.
Cost-effectiveness of mirtazapine compared to amitriptyline and fluoxetine in the treatment of moderate and severe depression in Austria.
Eur Psychiatry 1999 Jul;14(4):230-44
"In conclusion, this study suggests that despite the differences in acquisition costs, mirtazapine is a cost-effective antidepressant compared to amitriptyline and fluoxetine, supporting the adoption of this treatment in the management of moderate and severe depression in Austria." [Abstract]

Marthi K, Jakobsen S, Bender D, Hansen SB, Smith SB, Hermansen F, Rosenberg R, Smith DF.
[ N-methyl-(11)C]Mirtazapine for positron emission tomography neuroimaging of antidepressant actions in humans.
Psychopharmacology (Berl). 2004 Jan 15 [Epub ahead of print]
"RATIONALE. Many actions of antidepressant drugs cannot yet be studied using positron emission tomography (PET) neuroimaging due to lack of suitable radioligands. We believe that mirtazapine, radiolabeled with C-11, might be suitable for PET neuroimaging of alpha(2)-adrenoceptors in selected regions of the living human brain. OBJECTIVE. To determine the regional central biodistribution and pharmacokinetics of [ N-methyl-(11)C]mirtazapine in humans. METHODS. Five healthy volunteers received an intravenous injection of [ N-methyl-(11)C]mirtazapine for evaluating its metabolism, biodistribution and pharmacokinetics. RESULTS. [ N-methyl-(11)C]Mirtazapine entered the brain readily, with initial clearance from blood to tissue (K(1)) ranging from 0.31 ml/ml/min in amygdala to 0.54 ml/ml/min in thalamus. The rate of metabolism of [ N-methyl-(11)C]mirtazapine in the bloodstream was relatively slow, with 20-40% of [(11)C]-derived radioactivity still present as parent compound at 60 min post-injection. The clearance of [ N-methyl-(11)C]mirtazapine from the tissue compartment (k(2)') ranged from a low of 0.03 min(-1) in amygdala to a high of 0.06-0.07 min(-1) in thalamus and cerebellum. The volume of distribution (V(e)') of [ N-methyl-(11)C]mirtazapine was markedly greater in hippocampus and amygdala (11.3-12.0) than in cerebellum (6.7), with intermediate levels in the thalamus (9.4). CONCLUSIONS. [ N-methyl-(11)C]Mirtazapine has suitable properties for PET neuroimaging. We envision [ N-methyl-(11)C]mirtazapine as a molecular probe for PET imaging of antidepressant actions at sites such as alpha(2)-adrenoceptors in the living human brain." [Abstract]