INTRODUCTION

Mirtazapine is one of the antidepressants that increase both noradrenaline (NA) and serotonin release. This effect is mediated by blockage of noradrenergic alpha-2 auto- and heteroreceptors and inhibition of serotoninergic 5-HT2A and 5-HT3, and histaminic H1 receptors (1). The recommended dose of mirtazapine for the treatment of depression is 30-45mg/day, within which range acts as a disinhibitor of serotonin and NA and antagonist of alpha-2. Nevertheless, the dose range of 3.75-15mg is usually sufficient for insomnia as the latter only requires the blockade of H1 receptors (2).

Although the underlying mechanism has not yet been elucidated, all antidepressants has the potential to cause development of manic episodes (3).

Previous studies and case reports have suggested tricyclic antidepressants, monoamine oxidase inhibitors and selective serotonin reuptake inhibitors among the antidepressants with highest risk for developing manic episodes (4-6). In particular, mirtazapine needs special attention as implied by many case reports that suggested the occurrence of manic episodes under mirtazapine combination therapy, or in an add-on setting for sleeping problems in mixed depressive disorders, or after discontinuance of the drug (7-10).

This mini-review aimed to evaluate the case reports that could be reached when screening using the keywords “mirtazapine”, “manic shift”, “mania”, and “hypomania” in PubMed, Google Scholar, PsychINFO, and Cochrane search engines. Among the case reports published until August 2017, those in English or accessible in full text were examined. Afterwards, a patient developing manic shift after a two-day course of mirtazapine therapy during his hospitalization in Department of Psychiatry of Gulhane Training and Research Hospital was introduced to point to potential risk factors.

Case Reports on Mirtazapine Use and

Discontinuance

The literature search showed nine reports where manic or hypomanic episode was described during mirtazapine treatment and two reports where manic episode was described after it was discontinued. These patients who developed manic episodes were classified in four groups based on pharmacological differences and manic episodes:

1.Manic episode after mirtazapine monotherapy (n=4)

2.Manic episode during therapy with ≥30mg/day mirtazapine added on to SSRI (n=2),

3.Manic/hypomanic episode during therapy with <30mg/day mirtazapine (n=3),

4.Manic episode after mirtazapine discontinuance (n=2).

1.Manic shift after mirtazapine monotherapy

The first group was characterized manic symptoms observed during mirtazapine monotherapy (<30mg/day) used for depression. In two cases that aged 42 and 66 years old, fluoxetine and escitalopram were used before mirtazapine monotherapy was initiated, where the latter was tapered and fluoxetine was abruptly discontinued prior to mirtazapine (11,12). The other case was antidepressant-naive before mirtazapine, yet received a higher dose (45mg/day) (13). The most distinguishing feature of these three cases was the time to the manic episode. It was shown that higher dose of mirtazapine monotherapy led to accelerated development of manic episode when initiated before fluoxetine cessation and not allowing for a washout period. Another case to be considered in this group in terms of antidepressant monotherapy was a 43-year-old female patient with major depression. This case started with venlafaxine treatment where no response led to switching into mirtazapine after discontinuance and appropriate washout period. As no improvement was seen after titration up to 45mg/day after 4 weeks, topiramate 400mg/day was added. And finally when mirtazapine was escalated to 60mg/day, symptoms of mania were reported to be observed (14).

2.Manic episode during therapy with ≥30mg/day

mirtazapine added on to SSRI

The second group of case reports were those receiving mirtazapine in antidepressant doses combined to SSRI therapy. It was reported that the drug was added onto fluoxetine or paroxetine, where manic/hypomanic symptoms occurred within 45 days in average, and that hypomanic symptoms were spontaneously resolved after mirtazapine discontinuance and manic symptoms with valproate and clonazepam treatment (15,16).

3.Manic/hypomanic shift during therapy with

<30mg/day mirtazapine

The third group described manic/hypomanic episodes where mirtazapine doses were below the antidepressant level (<30mg/day). The first case initiated 15mg/day of mirtazapine in addition to high-dose sertraline treatment (250mg/day), (17). The other 68-year-old male patient was followed up with post-stroke depression (9). Ten-day course of mirtazapine that was initiated after paroxetine discontinuance was reported to trigger hypomania symptoms, which could be relieved with carbamazepine and haloperidol. The last case was a 15-year-old adolescent patient. The most interesting feature of this manic episode triggered by 22.5mg/day of mirtazapine regimen was that no other treatment had been used. Extra intervention was needed to relieve this episode, including lithium and haloperidol after mirtazapine cessation (18).

4.Manic shift after mirtazapine discontinuance

The last group was those developing manic episode after mirtazapine cessation. There were two case reports in this group. The first case, a 65-year-old female patient, was being followed up with major depression and developed hypomanic episode two days after discontinuance of mirtazapine that she received for 35 days (19). The second case was a male patient who was diagnosed with bipolar disorder 20 years ago and received 800mg/day of lithium and 15mg/day of mirtazapine for the last six months. This patient also developed mania seven days after mirtazapine cessation, where the episode could only be resolved with olanzapine 10mg/day added on to the lithium treatment (20).

Case Report Manic Shift After Two-Day

Course of Mirtazapine

Secondary to his wife’s infidelity, 31 years old male patient was diagnosed with major depression after having feelings of unhappiness and anhedonia, complaints of continuous crying and inability to sleep, and thoughts of self-harm; and hospitalized to Gulhane Training and Research Hospital. Past medical history showed venlafaxine 75mg/day due to obsessive compulsive disorder two years ago and then sertraline 75mg/day for anxiety disorder. These modalities were reported to help him to resolve symptoms and he discontinued the drugs voluntarily. It was determined that sertraline 100mg/day was started again in another institution for recurring depression symptoms that started three months ago, although no improvement was recorded during 12 weeks of sertraline regimen, for which he applied to our hospital. Further query of medical history revealed no finding that favored bipolar disorder or any period implying hypomanic/manic symptoms. Initial mental state examination noted a depressive affect, worthlessness and incapability predominance in the content of thought, a plaintive tone of voice, decreased speech and appetite, and difficulty to get off and maintain to sleep. After admission, mirtazapine 15mg/day was added onto sertraline 100mg/day. At the end of day 2, patient was observed to have increased speech, elevated affect, and flight of ideas, upon which manic shift was determined and antidepressant treatment was discontinued. Treatment was re-arranged to valproic acid 1000mg/day and 300mg/day of quetiapine. Observing that manic symptoms disappeared thoroughly at the end of third week, the patient was discharged with the current treatment.

DISCUSSION

The cases presented in this mini-review and our case disclose developing of manic/hypomanic symptoms associated with mirtazapine treatment. One of the common points observed in these cases was that the diagnosis was major depression where it was used in antidepressant dose or in combination for depression, and the management did not cover mood stabilizers. In addition, there were also some additional risk factors, including the use of higher doses of antidepressants, organic etiology of depressive symptoms (post-stroke depression, advanced age, or atypical depression in adolescence), (9,17,18) or being triggered after trauma. No risk factor regarding manic/hypomanic shift was established when mirtazapine was initiated in combination with mood stabilizers. A recent study compared patients with bipolar disorders that were managed with either antidepressant monotherapy or combined antidepressant and mood stabilizer therapy, and reported that mood stabilizers were effective in preventing short- and long-term manic shifts (21). This again emphasize the importance of review of bipolar disorders during querying of past medical and family history.

Another remarkable point is that manic episode may develop during treatment with mirtazapine at low doses used for hypnotic-sedative effect, as we just reported in our case. Previous reports defining the rate of manic episode as 0.25 (22), and no observing of manic shift compared to other antidepressants (42.1% for fluoxetine, 30.6% for bupropion, 30.6% for venlafaxine, and 18.8% for nefazodone) in rapid cycling bipolar disorder in a 2008 study (23) may lead to trivialization of this association. This might be attributed to masking of manic/hypomanic symptoms by the hypnotic/sedative effects of mirtazapine.

The most important contribution of our case report to the literature is that it suggests the potential of lower doses mirtazapine therapy to lead to manic shift relatively earlier than that in previous case reports. It is also noteworthy that in the absence of any evidence for bipolar disorder, the symptoms can be quickly controlled by mood stabilizers.

We hope that this case report and its management provides a guidance to physicians who will encounter the same clinical problem in the future.

Informed Consent: Written consent was obtained from the patient.

Peer-review: Externally peer-reviewed.

Conflict of Interest: Authors declared no conflict of interest.

Financial Disclosure: Authors declared no financial support.

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