Mirtazapine – A Multifunctional Drug: Low Dose for Akathisia

Abstract

CNS Spectrums should be commended for drawing the attention of clinicians and researchers to the concept of multifunctional drugs. 1 Multifunctional drugs are agents with multiple therapeutic effects at different doses, depending upon their potency at diverse pharmacologic targets. 2 Quetiapine, trazadone, and doxepine are examples of multifunctional drugs. 1,3 Thus, quetiapine at high doses exerts dopamine (D) 2 and serotonin (5-HT) 2A receptor antagonism and is used as an antipsychotic and antimanic agent. In contrast, quetiapine, like doxepine, at very low doses acts as a potent histamine (H) 1 receptor antagonist exhibiting robust hypnotic properties. Similarly, trazodone at low doses antagonizes 5-HT 2A , H 1 , and α 1-adrenergic receptors that account for its sedative and hypnotic therapeutic effects. Trazodone in doses 3-5 times higher exerts an additional inhibitory effect at the serotonin transporter and becomes an antidepressant. 3 Mirtazapine is a widely used antidepressant and anti-anxiety medication. In therapeutic doses (range 30-90 mg/day) mirtazapine is characterized by a potent pre-synaptic α 2-adrenergic receptor blockade which accounts for its antidepressant activity. Low-dose mirtazapine predominantly antagonizes 5-HT 2A/2C and H 1 postsynaptic receptors. The preponderance of the 5-HT 2A receptor antagonism over D 2 receptor blockade was put forward as a putative explanation for the low propensity of atypical antipsychotic agents to induce extrapyramidal side effects (eg, akathisia, parkinsonism, acute dystonia). 4 Owing to its marked 5-HT 2A antagonistic properties, the addition of low-dose mirtazapine to typical antipsychotics that exert predominant D 2 receptor antagonism, was suggested to test this hypothesis. When given QD, low-dose mirtazapine (15 mg) revealed a robust antiakathisia effect comparable to that of propranolol, the "gold standard" for akathisia, 5 mirtazapine's H 1 , α 2 and 5-HT 3 antagonistic effects are unlikely to play a role, since antihistamines, α 2 and 5-HT 3 antagonists are apparently ineffective in the treatment of akathisia. 6 Notably, mirtazapine administered in higher doses (≥30 mg/day) may induce akathisia in susceptible individuals, 7 putatively due to stimulation of adrenergic neurotransmission via α 2 auto-receptor blockade. It seems that mirtazapine is unique in its dose-related bi-directional effect on akathisia: low doses have an anti

Conformational and Functional Effects Induced by D- and L-Amino Acid Epimerization on a Single Gene Encoded Peptide from the Skin Secretion of Hypsiboas punctatus

“…According to Stahl [1], multifunctional drugs are agents with more than one therapeutic mechanism and it has been observed that almost all existing drugs have more than one known pharmacological target when higher doses exceeding the remedial recommendations are administrated. Fine-tuned with Paracelsuś legendary quote, the multifunctional concept of a drug depends upon a given concentration to reveal its multiple pharmacological activities.…”

Gabapentin enacarbil for antipsychotic induced akathisia in schizophrenia patients: a pilot open-labeled study

“…The drugs that caused akathisia were aripiprazole (n=5), risperidone (n=1), paliperidone (n=1), CLZ (n=1), and perospirone (n=1). From the onset of akathisia to the end of the study, the patients did not take any of the following drugs, which may be considered therapeutic agents for akathisia: propranolol, 20 , 21 mirtazapine, 22 , 23 mianserin, 22 trazodone, 24 cyproheptadine, 25 , 26 zolmitriptan, 27 clonidine, 28 dopamine agonists, 28 and vitamin B6 supplement. 29 MT evaluated all the patients.…”

Insomnia: Therapy and Role of neurotransmitters

“…Only for the treatment of the major depressive disorder is mirtazapine currently approved [47]. In insomnia patients, a daily dose of 30 mg is usually prescribed; higher doses may reduce the drug's sleep-inducing properties [48]. Tricyclic antidepressant: Doxepin Doxepin (Pernix Therapeutics' Silenor) is a sedating tricyclic antidepressant (TCA) that has a high affinity for histamine (H1) receptors.…”