Tetracyclic Antidepressants


Mianserin, Mirtazapine 


  Issues for Surgery


Risk of withdrawal symptoms if omitted (see Further Information).

Risk of serotonin syndrome if continued (see Interaction(s) with Common Anaesthetic Agents and Interaction(s) with other Common Medicines used in the Perioperative Period).

Risk of central nervous system (CNS) depression if continued (see Interaction(s) with Common Anaesthetic Agents and Interaction(s) with other Common Medicines used in the Perioperative Period).

For mianserin – potential potentiation of vasopressors if continued (see Interaction(s) with Common Anaesthetic Agents).

For mirtazapine – theoretical risk of QT-interval prolongation if continued (see Interaction(s) with other Common Medicines used in the Perioperative Period).


  Advice in the Perioperative period


Elective and Emergency Surgery

Continue – check sodium levels pre-operatively (see Further Information).

Inform anaesthetist patient is taking mianserin1 – presumably due to potential interactions with vasopressor drugs (see Interaction(s) with Common Anaesthetic Agents).

Post-operative Advice

If a long nil by mouth (NBM) period is anticipated, or if there are concerns with enteral absorption, advice on alternative preparations / routes should be sought from a Psychiatrist.

Monitor electrolytes, particularly sodium, if risk factors for hyponatraemia (see Further Information).

Monitor full blood count if any signs of bone marrow depression (see Further Information).


  Interaction(s) with Common Anaesthetic Agents


Vasopressors

Tricyclic antidepressants (TCAs) are known to potentiate the effects of vasopressors (see Tricyclic Antidepressants monograph), whereas the evidence of an interaction between mianserin and vasopressors is sparse. The pressor response to noradrenaline was largely unchanged in 5 patients taking mianserin; however, a 71 year old women taking mianserin was noted to develop hypotension following spinal and general anaesthesia, which was refractory to multiple boluses of ephedrine but an excessive vasopressor response was observed following a small dose of adrenaline2.

Mianserin, unlike TCAs, does not prevent peripheral uptake of noradrenaline; however, in view of the above report some caution with mianserin and concurrent vasopressors is advised2.

CNS Excitation (Serotonin Syndrome)

Some opioids act as weak serotonin reuptake inhibitors (SRIs) and can precipitate serotonin syndrome in conjunction with other serotonergic medication. Symptoms of serotonin syndrome have been reported in patients taking mirtazapine with tramadol2 but may occur if concomitant use of mianserin or mirtazapine and the following3: -

  • fentanyl
  • methadone
  • pentazocine
  • pethidine
  • tapentadol
  • tramadol

Patients should be monitored closely and the possibility of serotonin toxicity considered if altered mental state, autonomic dysfunction or neuromuscular adverse effects are observed with concomitant treatment3.

Central Nervous System (CNS) Depression (also see under Interaction(s) with other Common Medicines used in the Perioperative Period)

Mianserin and mirtazapine have CNS depressant effects which may be additive with other medicines that also have CNS depressant effects such as2, 3:-

  • benzodiazepines
  • inhalational anaesthetics and intravenous anaesthetics
  • local anaesthetics
  • opioids

(Consult British National Formulary for available drugs in each class)


  Interaction(s) with other Common Medicines used in the Perioperative Period


CNS Excitation (Serotonin Syndrome) (also see under Interaction(s) with Common Anaesthetic Agents)

Tramadol
Serotonin syndrome has been reported in patients receiving concomitant mirtazapine and tramadol but could also be expected to occur with mianserin. Mianserin and mirtazapine lower the seizure threshold; concurrent use with tramadol, which also lowers the seizure threshold, may have an additive effect on the risk of seizures. Concomitant administration of mirtazapine and tramadol has also been associated with an increased incidence of restless legs2.

Methylthioninium chloride (methylene blue)
There have been case reports of serotonin syndrome in patients taking mirtazapine who were also given methylthioninium chloride2. The MHRA advise that methylthioninium chloride should be avoided in patients taking drugs that enhance serotonergic transmission (e.g. mianserin, mirtazapine). If concurrent use is necessary the lowest possible dose of methylthioninium chloride should be given and the patient should be closely monitored for signs of CNS toxicity for 4 hours after administration2, 4. However, this advice is contested in one report which suggests even doses as low as 1mg/kg may be sufficient to inhibit monoamine oxidase-A, thus causing a reaction2.

Other Medications
There is also an increased risk of developing serotonin syndrome when mianserin or mirtazapine is used concurrently with the following2, 3: -

  • granisetron
  • ondansetron
  • linezolid

Monitor patients for symptoms of serotonin syndrome such as fever, tremors, diarrhoea, and agitation. Concurrent treatment should be stopped if serotonin syndrome occurs2, 3.

CNS Depression (also see under Interaction(s) with Common Anaesthetic Agents for information on opioids)

Mianserin and mirtazapine have CNS depressant effects which may be additive with antiemetics that also have CNS depressant effects such as cyclizine, droperidol and prochlorperazine2, 3.

QT-Interval Prolongation

Cases of QT-interval prolongation have been reported during post-marketing use of mirtazapine5. Co-administration with other medicines known to prolong the QT-interval must be based on a careful assessment of the potential risks and benefits for each patient since the risk of torsade de pointes may increase 2.

Medicines that may be used in the perioperative period that are known to prolong the QT-interval include2: -

  • ciprofloxacin
  • clarithromycin
  • domperidone
  • droperidol
  • erythromycin (especially intravenous)
  • granisetron
  • haloperidol
  • loperamide (increased risk with high doses)
  • ondansetron
  • prochlorperazine

The possibility of QT-interval prolongation with concomitant administration of mirtazapine and the above listed medications is only theoretical; however, it may be prudent to monitor ECG with concurrent use if risk factors for QT-interval prolongation also present (increasing age, female sex, cardiac disease, and some metabolic disturbances e.g. hypokalaemia).

Clarithromycin

Clarithromycin is predicted to increase the exposure to mirtazapine through inhibition of CYP3A42. Whilst single surgical prophylactic doses should not pose a problem, monitor for side effects and consider reducing mirtazapine dose if a prolonged course is required2, 3, 5.


  Further Information


Withdrawal

Abrupt withdrawal of mianserin or mirtazapine is not recommended, particularly after long-term administration as withdrawal symptoms may occur. The majority of withdrawal reactions are mild and self-limiting with symptoms including nausea, vomiting, dizziness, agitation, anxiety and headache3, 5.

Hyponatraemia

Hyponatraemia, possibly as a result of inappropriate secretion of antidiuretic hormone (SIADH) has been reported rarely with mianserin and mirtazapine. Caution is required in patients at increased risk of hyponatraemia, such as elderly, or volume depleted/dehydrated patients or patients treated with diuretics1, 5.

Blood Dyscrasia

Mianserin and mirtazapine can cause bone marrow depression. If fever, sore throat, stomatitis or other signs of infection develop during treatment, a full blood count should be checked. If blood dyscrasia is suspected the mianserin or mirtazapine should be stopped (monitor for signs of withdrawal – see above)1, 3, 5.


  References


  1. Summary of Product Characteristics – Mianserin 15mg Film-coated Tablets. Accord-UK Ltd. Accessed via www.medicines.org.uk 26/07/2019 [date of revision of the text December 2018]
  2. Baxter K, Preston CL (eds), Stockley’s Drug Interactions (online) London: Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 20th July 2019]
  3. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. http://www.medicinescomplete.com [Accessed on 20th July 2019]
  4. Summary of Product Characteristics – ProveBlue® (methylthioninium chloride) 5mg/ml solution for injection. Martindale Pharma. Accessed via www.medicines.org.uk 20/07/2019 [date of revision of the text February 2018]
  5. Summary of Product Characteristics – Mirtazapine 15mg Film-coated Tablets. Accord-UK Ltd. Accessed via www.medicines.org.uk 20/07/2019 [date of revision of the text December 2018]