A case report has been published in which mirtazapine reduced visual hallucinations in a patient with Parkinson's disease psychosis (PDP). This is in alignment with recent findings that inverse agonists at the 5-HT2A receptors are efficacious in attenuating the symptoms of Parkinson's disease psychosis. As is supported by the common practice of prescribing low-dose quetiapine and clozapine for PDP — doses too low to antagonise the D2 receptor, but sufficiently high doses to inversely agonise the 5-HT2A receptors.
Mirtazapine is sometimes prescribed as an appetite stimulant for cats experiencing anorexia due to medical conditions such as chronic kidney disease. It is especially useful for treating combined poor appetite and nausea in cats.
Efficacy and tolerability
In clinical studies, mirtazapine has been found to be an effective antidepressant with a generally tolerable side-effect profile relative to other antidepressants.
In general all antidepressants, including mirtazapine, require at least a week for their therapeutic benefits on depressive and anxious symptoms to become apparent. Unlike most antidepressants, however, mirtazapine has demonstrated itself to have a faster onset of antidepressant action, with an initial reduction in affective symptoms being seen within the first week of treatment, and the maximal change in improvement occurring over the course of the first two weeks.
In general, some antidepressants, especially SSRIs, can paradoxically exacerbate some peoples' depression or anxiety or cause suicidal ideation. Despite its sedating action, mirtazapine is also believed to be capable of this, and for this reason in the United States and certain other countries it carries a black box label warning of these potential effects.
Mirtazapine is considered to be relatively safe in the event of an overdose, although it is considered slightly more toxic in overdose than most of the SSRIs (except citalopram). Unlike the TCAs, mirtazapine showed no significant cardiovascularadverse effects at 7 to 22 times the maximum recommended dose. Case reports of overdose with as much as 30 to 50 times the standard dose described the drug as relatively nontoxic, compared to TCAs.
Twelve reported fatalities have been attributed to mirtazapine overdose in literature. The fatal toxicity index (deaths per million prescriptions) for mirtazapine is 3.1 (95% CI: 0.1 to 17.2). This is similar to that observed with SSRIs.
All affinities listed were assayed using human materials except those for α1-adrenergic and mACh that are for rat tissues, due to human values being unavailable.
Though not known to have ever been screened at this site, it is possible that mirtazapine may act on the 5-HT6 receptor as well. Supporting this speculation is the fact that its analogue mianserin (which, regarding structure, can also be called 6-desazamirtazapine) has been shown to have high affinity for 5-HT6 and does not produce cAMP accumulation (indicating it is an antagonist).
Antagonism of the 5-HT2 subfamily of receptors and inverse agonism of the 5-HT2C receptor appears to be in part responsible for mirtazapine's efficacy in the treatment of depressive states. The 5-HT2C receptor is known to inhibit the release of the neurotransmitters dopamine and norepinephrine in various parts of the brains of rodents, notably in reward pathways such as the ventral tegmental area. Accordingly, it was shown that by blocking the α2-adrenergic receptors and 5-HT2C receptors mirtazapine disinhibited dopamine and norepinephrine activity in these areas in rats. In addition, mirtazapine's antagonism of 5-HT2A receptors has beneficial effects on anxiety, sleep and appetite, as well as sexual function regarding the latter receptor. The newest research however has shown that mirtazapine is actually an inverse agonist of the 5-HT2C receptor. 5-HT2C inverse agonists have been shown to inhibit mesoaccumbens dopamine outflow attenuating the rewarding properties of various substances like morphine. This inhibition of dopamine may be stronger than thought as substances with 5-HT2C inverse agonist properties may have more activity to regulate dopamine neurotransmission than ones with competitive antagonism. With its newly understood properties of 5-HT2C inverse agonism, it is being investigated and shown to lower drug seeking behaviour, conditioned place preference and the rewarding effects of substances such as methamphetamine in various human and animal studies. It is also being investigated to help in substance abuse disorders with withdrawal effects and remission rates. but some studies have shown mixed benefit.
Antagonism of the 5-HT3 receptor, an action mirtazapine shares with the approved antiemeticondansetron, significantly improves pre-existing symptoms of nausea, vomiting, diarrhoea and irritable bowel syndrome in afflicted individuals. Mirtazapine may be used as an inexpensive antiemetic alternative to ondansetron. Blockade of the 5-HT3 receptors has also shown to improve anxiety and to be effective in the treatment of drug addiction in several studies. In conjunction with substance abuse counseling, mirtazapine has been investigated for the purpose of reducing methamphetamine use in dependent individuals with success. In contrast to mirtazapine, the SSRIs, SNRIs, MAOIs, and some TCAs increase the general activity of the 5-HT2A, 5-HT2C, and 5-HT3 receptors leading to a host of negative changes and side-effects, the most prominent of which including anorexia, insomnia, sexual dysfunction (loss of libido and anorgasmia), nausea, and diarrhoea, among others. As a result, mirtazapine is often combined with these drugs to reduce their side-effect profile and to produce a stronger antidepressant effect.
Mirtazapine is a very strong H1 receptor inverse agonist and, as a result, it can cause powerful sedative and hypnotic effects. After a short period of chronic treatment, however, the H1 receptor tends to desensitize and the antihistamine effects become more tolerable. Many patients may also dose at night to avoid the effects, and this appears to be an effective strategy for combating them. Blockade of the H1 receptor may improve pre-existing allergies, pruritus, nausea, and insomnia in afflicted individuals. It may also contribute to weight gain, however. In contrast to the H1 receptor, mirtazapine has very low affinity for the mACh receptors, although anticholinergic side effects like dry mouth, constipation and mydriasis are still commonly seen in clinical practise.
Like many other antidepressants, mirtazapine has been found to have antinociceptive properties in mice. However, unlike most other antidepressants, though similarly to venlafaxine, these effects are mostly mediated through downstream modulation of the endogenous opioid system, of which in the case of mirtazapine the μ-opioid and κ3-opioid receptors are mainly involved. Interestingly, while virtually all antidepressants differ little in their maximal effectiveness in the treatment of major depression, mirtazapine and venlafaxine have demonstrated superior efficacy in treating severe types of depression such as psychotic depression and treatment-resistant depression. It has been suggested that this may be due to their unique influence on the opioid system, which is a property that has been hypothesized to somehow give them an advantage over other antidepressants in cases of severe depressive symptomatology.
Mirtazapine is typically prescribed in doses for humans of 15 mg, 30 mg and 45 mg. However, clinical doses as high as 120 mg have been reported in the medical literature.
According to information from the manufacturers, mirtazapine should not be started within two weeks of any MAOI usage; likewise, MAOIs should not be administered within two weeks of discontinuing mirtazapine. However, a single study regarding the combination reported that it does not result in any incidence of serotonin-related toxicity. In addition, a case report claimed that mirtazapine can actually be used to treat serotonin syndrome. Mirtazapine in combination with an SSRI, SNRI, or TCA as an augmentation strategy is considered to be relatively safe and is often employed therapeutically, with a combination of venlafaxine and mirtazapine sometimes referred to as “California rocket fuel”.
Another case report described mirtazapine as inducing hypertension in a clonidine-treated patient, likely due to occupancy of α2-autoreceptors by mirtazapine limiting the efficacy of concurrent clonidine therapy.
Liver and moderate renal impairment has been reported to decrease the oral clearance of mirtazapine by approximately 30%; severe renal impairment decreases it by 50%.
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