Topiramate for migraine prophylaxis

About 14% of adults in the UK have migraines. Drugs used in migraine prophylaxis include beta-blockers (e.g. propranolol), 5HT antagonists (e.g. pizotifen), antidepressants (e.g. amitriptyline), antiepileptics (e.g. sodium valproate) and NSAIDs. The antiepileptic topiramate (Topamax-Janssen-Cilag) is licensed for the prophylaxis of migraine headache in patients aged over 16 years. Here we discuss the place of topiramate in migraine prophylaxis.     

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.     

An updated review of antidepressants with marked serotonergic effects in obsessive–compulsive disorder

Introduction: Since the recognition of the effectiveness of clomipramine in treating obsessive–compulsive disorder (OCD), a number of recent empirical studies have confirmed a key role of the serotonergic (5-HT) system in the pathophysiology of OCD. The current study presents a review of the existing double-blind studies testing 5-HT antidepressants in OCD.

Areas covered: A systematic review was performed to identify double-blind, placebo-controlled, randomized clinical trials investigating the efficacy of antidepressants with marked 5-HT effects [clomipramine, selective serotonin reuptake inhibitors (SSRIs), venlafaxine, desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine and vilazodone] in the short-term treatment of OCD. The search provided 29 studies investigating eight different 5-HT antidepressants. While the findings show reliable efficacy of clomipramine and SSRIs in the treatment of OCD symptoms, no double-blind studies were identified investigating the efficacy of desvenlafaxine, duloxetine, mirtazapine, agomelatine, vortioxetine or vilazodone.

Expert opinion: While our results support the effectiveness of older antidepressants with marked 5-HT effects in OCD, it also suggests that newer agents should be tested more comprehensively.     

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.     

Effects of the co-administration of mirtazapine and paroxetine on serotonergic neurotransmission in the rat brain.

The alpha(2)-adrenoreceptor antagonist mirtazapine, which is also a 5-HT(2), 5-HT(3) and H(1) receptors antagonist and the selective serotonin (5-HT) reuptake inhibitor paroxetine are effective antidepressant drugs which enhance 5-HT neurotransmission via different mechanisms. The present studies were undertaken to determine whether the mirtazapine-paroxetine combination could induce an earlier and/or a greater effect on the 5-HT system than either drug alone. Using in vivo electrophysiological paradigms, the firing activity of dorsal raphe 5-HT neurons was decreased by 70% in rats treated with paroxetine (10 mg/kg/day, s.c.) for 2 days and was back to normal after 21 days. In contrast, a 2-day treatment with mirtazapine (5 mg/kg/day, s.c.) did not alter the firing of 5-HT neurons whereas it was increased by 60% after 21 days of treatment. A low dose of mirtazapine (5 mg/kg/day, s.c.x2 days) failed to offset the decremental effect of paroxetine on the 5-HT neuron firing activity, but a higher dose (10 mg/kg/day, s.c.x2 days) did attenuate the decremental effect of paroxetine. In the dorsal hippocampus, neither mirtazapine (5 mg/kg/day, s.c.) nor a paroxetine (10 mg/kg/day, s.c.) treatment altered the responsiveness of 5-HT(1A) receptors to microiontophoretically-applied 5-HT. Both in controls and in rats treated for 2 days with paroxetine alone, the administration of the 5-HT(1A) antagonist WAY 100635 (25-100 microg/kg, i.v.) did not change the firing activity of dorsal hippocampus CA(3) pyramidal neurons. However, WAY 100635 increased significantly the firing activity of these neurons in rats treated with mirtazapine alone but to a greater extent with both mirtazapine and paroxetine for 2 days. After 21 days of treatment, WAY 100635 increased to a greater degree the firing rate of CA(3) pyramidal neurons in rats which received the combination over rats given either drug alone. It is concluded that the mirtazapine-paroxetine combination shortened the delay in enhancing the tonic activation of postsynaptic 5-HT(1A) receptors and produced a greater activation of the postsynaptic 5-HT(1A) receptors than either drug given alone. The present results suggested that mirtazapine may have a faster onset of action than a SSRI, and that the co-administration of mirtazapine and paroxetine may accelerate the antidepressant response and as well as being more effective than either drug alone.     

Attenuation of hypothalamic-pituitary-adrenocortical hyperactivity in depressed patients by mirtazapine

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 α₂-receptors and at postsynaptic 5-hydroxytryptamine (5-HT)₂, 5-HT₃ and histamine H₁ 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. Electronic Publication     

The effect of mirtazapine augmentation of clozapine in the treatment of negative symptoms of schizophrenia: a double-blind, placebo-controlled study

The development of therapeutic strategies to effectively treat negative symptoms remains one of the primary goals in the treatment of schizophrenia. Mirtazapine is the first of a new class of dual action compounds, the noradrenergic and specific serotonergic antidepressants (NaSSa), whose activity is related to the enhancement of noradrenergic and serotonergic transmission by a presynaptic alpha2 antagonism and postsynaptic 5-HT2 and 5-HT3 antagonism, respectively. This study was a 8-week double-blind, randomized, placebo-controlled trial of 30 mg adjunctive mirtazapine to clozapine therapy in 24 patients with DSM-IV schizophrenia. The main finding at the end of the trial was a significant reduction on the Scale for the Assessment of Negative Symptoms (SANS) total scores in the mirtazapine group compared to placebo (P<0.01) with a significant improvement on the SANS subscales avolition/apathy and anhedonia/asociality. The Brief Psychiatric Rating Scale total score at week 8 showed superiority of mirtazapine over placebo. These findings suggest a potential role for mirtazapine as an augmentation strategy in the treatment of negative symptoms of schizophrenia.     

Tolerability and safety aspects of mirtazapine

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.     

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.     

Discriminative stimulus properties of antidepressant agents: a review

Though drug discrimination techniques have proven invaluable in characterizing the interoceptive properties of drugs of abuse, antipsychotics and anxiolytics, with the exception of some fragmentary data with tricyclic agents, surprisingly few studies have been undertaken with antidepressants. Nevertheless, the preferential dopamine (DA) reuptake inhibitor, bupropion, elicits a robust discriminative stimulus in rodents. Moreover, in rats trained on a two-lever FR-10 schedule for food reward, the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram, and the noradrenaline (NA) reuptake inhibitor (NARI), reboxetine, elicit discriminative stimuli at doses that selectively elevate extracellular levels of 5-HT and NA, respectively. In generalization tests, mixed inhibitors of 5-HT and NA reuptake, such as venlafaxine, substitute for both citalopram and reboxetine, while SSRIs substitute for citalopram but not for reboxetine. Intriguingly, selective NARIs appear to substitute both for reboxetine and for citalopram though, owing to long-term instability of the citalopram cue, the latter observation will require confirmation. Bupropion and the atypical antidepressant, mirtazapine - a 5-HT2/alpha2-adrenoceptor (AR) antagonist devoid of affinity for 5-HT and NA reuptake sites - substitute for neither citalopram nor reboxetine, indicating that 'antidepressant' effects per se do not account for their interoceptive properties. Moreover, mirtazapine abolishes the citalopram cue, an action mimicked by the selective 5-HT2C antagonist, SB242,084. The discriminative stimulus elicited by reboxetine is blocked by the alpha1-AR antagonist, prazosin. In contrast, it is not significantly attenuated by the alpha2-AR antagonist, RX821,002, nor by betaxolol or ICI118,551, antagonists at alpha1- and alpha2-ARs, respectively. These observations indicate that 5-HT2C receptors and alpha1-ARs contribute to the discriminative stimulus properties of SSRIs and NARIs, respectively. The present article reviews the literature devoted to the discriminative stimulus properties of antidepressant agents as training drugs, focusing in particular upon novel data with citalopram and reboxetine. In addition, several open questions and future research directions are evoked. It would be of considerable interest to extend such drug discrimination studies to other classes of antidepressants or potential antidepressants, including venlafaxine, mirtazapine and antagonists at neuropeptide (corticotropin releasing factor1 and neurokinin1) receptors.     

The use of triptans in the management of menstrual migraine

Many women experience headaches, including migraine, in association with their menstrual cycles. Although definitions vary, menstrual migraine generally refers to migraine without aura that occurs within several days prior to and several days after the onset of menses.Although menstrual migraine has been reported to be more difficult to treat than other types of migraines, there is no evidence from controlled clinical trials to support this assertion. Thus, the pharmacological treatment of menstrual migraine should be similar to that of other types of migraines, except with respect to the use of hormonal manipulations to treat menstrual migraine.Serotonin 5-HT(1B/1D) receptor agonists (triptans) are effective for the acute treatment of both menstrual and non-menstrual migraines. When used as acute therapy, a triptan should be administered early, when the headache is still mild in severity. Ideally, an acute therapy will provide rapid and complete pain relief with no disability. Some patients may require preventive therapy for menstrual migraine based on suboptimal response to an adequate trial of acute therapy. Patient diaries that record headache onset, relationship to the menstrual cycle and treatment response through three complete cycles will allow accurate prediction of the onset of menstrual migraine; this information is also needed to make decisions about timing of intermittent preventive therapy. The goals of intermittent preventive therapy are to reduce the frequency, duration and intensity of menstrual migraine attacks.Clinical studies show that triptans are effective when used as either acute therapy or as intermittent preventive therapy for menstrual migraine. Sumatriptan and zolmitriptan have been evaluated in prospective, randomised, controlled trials for acute treatment. Retrospective analyses and open-label studies also support the use of other triptans as acute therapy. In addition, sumatriptan, frovatriptan, naratriptan and zolmitriptan have been evaluated as intermittent preventive therapy in prospective studies. Thus, data from clinical studies indicate that triptans are effective for the treatment of menstrual migraine.     

Involvement of 5-HT(2C) receptors in the anti-immobility effects of antidepressants in the forced swimming test in mice.

Several recent studies have demonstrated that 5-HT(1A), 5-HT(1B) and 5-HT(3) receptors were implicated in the mechanism of action of antidepressants in the mouse forced swimming test. Despite extensive evidence for a role of 5-HT(2C) receptors in depression, the precise role of these receptors in the effects of clinically established antidepressants was not directly investigated in the mouse forced swimming test. This work was aimed at exploring interactions between several doses of Ro 60-0175, a recently available, full and selective 5-HT(2C) agonist, and antidepressant drugs in the mouse forced swimming test. Spontaneous locomotor activity was measured as an index of intact sensorimotor functions and the dose-effect of Ro 60-0175 alone, as well as interactions with several antidepressants, such as tricyclic antidepressants (imipramine, desipramine and maprotiline) and selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, fluvoxamine and sertraline), were studied in the mouse forced swimming test. There was no intrinsic antidepressant-like effect of Ro 60-0175, but an impairment in locomotor function was detected when using doses higher than 4 mg/kg in the mouse. There was a synergistic effect of low doses of Ro 60-0175 with sub-active doses of imipramine, paroxetine, citalopram and fluvoxamine; an antagonism between the highest dose of Ro 60-0175 and the active doses of paroxetine and fluoxetine was also detected. There is evidence that 5-HT(2C) receptors may be involved in the action of antidepressants which are able to boost the concentration of serotonin in the synapse, i.e. SSRIs and imipramine     

The effect of stimulation and blocking of histamine H2 receptors on the turnover of the serotonin in different parts of the alimentary tract and the brain of the rat

In the experiments performed on Wistar rats it was found that histamine (0.05 and 0.5 mg/kg i.p.) caused an acceleration of the turnover of serotonin (5-HT) in the stomach. After the lowest dose of ranitidine (3 mg/kg i.p.) a decrease in the rate of 5-HT turnover in the stomach was observed, whereas the higher doses (15.0 and 30 mg/kg i.p.) accelerated the turnover of this amine. In the duodenum, both doses of histamine accelerated the turnover of 5-HT, however, ranitidine in all doses induced a reduction in the rate of 5-HT turnover in this part of the alimentary tract. In the intestine, both doses of histamine enhanced the turnover of 5-HT but after all doses of ranitidine a decrease of the turnover was observed. The blockade of histamine H2 receptors with ranitidine did not completely abolish the effects of histamine on the 5-HT system, in the parts of the rat digestive system studied which suggests also an indirect activity of other receptors in presented observations. In the rat brain, an acceleration of the turnover of 5-HT after both doses of histamine was found. However, ranitidine only reduced the rate of 5-HT turnover at the lowest dose. In animals treated with ranitidine (15 mg/kg i.p.) for three days, histamine did not produce any change in the turnover of 5-HT in rat brain. These experiments show, that in the alimentary tract a relationship exists between histaminergic and serotoninergic systems.     

Effects of methysergide, pizotifen and ergotamine in the monkey cranial circulation.

Internal and external carotid vascular resistances were measured, in anaesthetized monkeys, to asses the direct cranial vascular effects of i.v. methysergide, pizotifen and ergotamine, and their effects on the cranial vascular responses to the constrictors 5-hydroxytryptamine and noradrenaline and the dilators histamine, prostaglandin E1 and bradykinin. Methysergide reduced responses to 5-HT, and tended to potentiate the external carotid responses to noradrenaline. Pizotifen blocked responses to histamine; it tended to reduce internal carotid responses to 5-HT, but it potentiated external carotid 5-HT responses. Ergotamine reduced responses to 5-HT and noradrenaline, but this was probably related to its cranial vasoconstrictor effects, especially in the external carotid circulation. Methysergide induced weak transient cranial vasoconstriction and pizotifen had no direct effects. These findings may be relevant to the therapeutic actions of these drugs in migraine, since the doses used approximated to those used clinically.     

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.     

The effect of some new antidepressants on apomorphine-induced hypothermia in mice

Imipramine-like tricyclic antidepressants antagonize hypothermia induced by apomorphine in mice (Lapin & Samsonova 1968; Schelkunov 1968, 1977; Fuxe & Sjöqvist 1972; Maj et al 1974; Puech et al 1978); this phenomenon has been used by some authors as a test for the antidepressant activity. Therefore, we have examined the effect of some new antidepressants in this test, especially as some of them differ in their mechanism of action from imipramine-like drugs. The drugs used were: nomifensine, an inhibitor of the dopamine and noradrenaline (NA) uptake (Hunt et al 1974; Schacht & Heptner 1974), two specific inhibitors of 5-hydroxytryptamine (5-HT) uptake, femoxetine (FG 4963) (Buus Lassen et al 1975) and poroxetine (FG 7051) (Petersen et al 1977), two other antidepressants whose main characteristic was the blockade of central 5-HT receptors, i.e. mianserin (van Riezen 1972) and trazodone (Baran et al 1979). We also included pizotifen, a drug used in migraine prophylaxis (see Speight & Avery 1972) but exerting an antidepressant effect (Standal 1977; Banki 1978) and a potent central anti 5-HT activity (Dixon et al 1977; Przegalinski et al 1979). For comparison, the effect of four tricyclic antidepressants (imipramine, desipramine, amitriptyline and chlorimipramine) was also studied.     

The effect of risperidone on the mirtazapine-induced changes in extracellular monoamines in the rat frontal cortex

BackgroundThe aim of our study was to understand the mechanism of clinical efficacy of the combination of an antidepressant and risperidone in drug-resistant depression.MethodsWe studied the effect of an antidepressant (mirtazapine) and risperidone (atypical antipsychotic), given separately or jointly on extracellular levels of dopamine (DA), serotonin (5-HT) and noradrenaline (NA) in the rat frontal cortex. The animals were given a single intraperitoneal injection of risperidone (1 mg/kg) and mirtazapine (10 and 20 mg/kg). The release of monoamines in the rat frontal cortex was investigated using a microdialysis in freely moving animals, and monoamine levels were assayed by HPLC with coulochemical detection.ResultsRisperidone increased the cortical extracellular levels of DA, 5-HT and NA. Similarly, mirtazapine dose-dependently increased the cortical extracellular levels of the monoamines studied. A combination of mirtazapine either at the higher dose (20 mg/kg) or at both doses (10 and 20 mg/kg) with risperidone produced a significant effect on DA and NA release, respectively compared to the effect of any drug given alone. The increase in the DA (but not NA) release induced by mirtazapine plus risperidone was partly blocked by the selective 5-HT_1A antagonist WAY 100635 (0.2 mg/kg).ConclusionsOur data indicate that the increase of cortical extracellular levels of DA and NA by combined administration of mirtazapine and risperidone may be of crucial importance to the pharmacotherapy of drug resistant depression, and that, among other mechanisms, 5-HT_1A, 5-HT_2A, α₂-adrenergic and histamine H₁ receptors may play some role in this effect.     

Dysphoric mania induced by high-dose mirtazapine: a case for 'norepinephrine syndrome'?

The antidepressant mirtazapine antagonizes central presynaptic alpha2-adrenergic auto- and heteroreceptors resulting in increased central norepinephrine and serotonin activity. Histamine H2 receptors are also antagonized, as are postsynaptic serotonin 5-HT2 and 5-HT3 receptors, leading to serotonergic activity primarily via 5-HT1A receptors. Based on the case report of a patient who developed mania with higher than recommended dosage of mirtazapine, we review the literature on the atypical nature of manic symptoms with mirtazapine. Eight subjects, including those in our study, were identified as having developed mirtazapine-induced mania with atypical features, consisting of dysphoria, irritability, insomnia, psychomotor agitation and abnormal gait. Predisposing features may have included the presence of underlying brain dysfunction and certain selective serotonin reuptake inhibitor-mirtazapine combinations. Dysphoric mania with atypical features may be induced by mirtazapine, providing support for a common hypothesis such as 'central norepinephrine hyperactivity' as the basis for development of mania with mirtazapine.