Hi, welcome to HubBytes. I'm Sunil Regge, Consultant Psychiatrist. Today I'll be taking you through the mechanism of action and psychopharmacology of Mirtazapine and providing some insights about the use of Mirtazapine in clinical practice. This video is not to be construed as medical advice. Mirtazapine is considered as a NASA. There are two components to this, the NA component as you can see and the SSA. The SSA component stands for specific serotonin antagonism. So let's start with that one. The specific serotonin antagonism that occurs with mirtazapine is that it antagonizes the 5-HD2A receptor. Now you might remember that this receptor was covered in the video with SSRIs. The 5-HG2A receptor is situated in the limbic system, it's situated in the reticle activating system and it's also situated in the basal ganglia. Now mirtazapine by antagonizing this receptor results in anti-anxiety properties as it antagonizes the 5-HG2A receptor in the limbic system. The 5-HG2A receptor antagonism in the basal ganglia treats akathisia and therefore mirtazapine is evidence based in the treatment of akathisia. It also does not lead to emotional blunting and releases dopamine because 5-HD2A antagonism releases dopamine in the frontal and subcortical areas. And this is something we've covered in the mechanism of action of antipsychotics as well. Then it blocks or antagonizes the 5-HD2A receptor in the reticular activating system. So it's one of the agents that promotes slow wave sleep, the other one being agamelotin. So interestingly... The other sedative effect of mirtazapine is linked to the antihistaminergic effect and this is where it provides this additional sedative property but also one additional property which is weight gain. The next receptor is the 5-HG2C receptor. The 5-HG2C receptor is responsible for sexual function, and by antagonizing it, mirtazapine can be used as a treatment for sexual dysfunction that can occur with SSRIs or SNRIs, but independently used, it does not lead to sexual dysfunction. And finally the 5-HT3 antagonism. The 5-HT3 receptor is situated in the gut and also in the nausea, the vomiting center in the hypothalamus. So by antagonizing it you get some good anti-nausea properties as well. Now these SSA Receptor antagonism tends to occur at lower doses usually, so somewhere between 15 to 30 milligrams. Now that doesn't mean of course that you don't get the NA effect, but just generally you tend to get these at lower doses. It also has a noradrenergic component and that occurs through alpha-2 presynaptic antagonism. Now we know that presynaptic receptors, so again these are important aspects that you can go through which we covered in the SSRI video on this channel. So, alpha-2 adrenergic receptors, when they're autoreceptors, essentially when you activate an autoreceptor, it acts as a brake. When you antagonize it, you lift the brake and the neurotransmitter is released. So mirtazapine releases noradrenalin in the prefrontal cortex by antagonizing the alpha-2 presynaptic autoreceptor. So you get release of norepinephrine from the locus coeruleus. Interestingly, It also antagonizes the alpha-2 presynaptic heteroreceptors that are situated on serotonergic neurons and therefore releases serotonin. Now, interestingly, mirtazapine is associated or can be associated with serotonin syndrome, but not to the same extent as SSRIs or SNRIs. And in clinical experience, I've been able to combine it successfully with SSRIs, SNRIs, which is evidence-based strategy in the treatment of treatment-resistant depression or severe depression without the risk of serotonin syndrome. However, there are case studies where serotonin syndrome has occurred with the use of mirtazapine. And this is because of the alpha-2. receptor antagonism on the heteroreceptors on the serotonergic neurons in the dorsal raphe nucleus where the serotonergic neurons are situated. So technically, yes, serotonin is also elevated. So now what we've got is we've got elevation of serotonin, we've got elevation of norepinephrine, and we've also got this specific serotonin antagonism. it also increases dopamine and this occurs because by increasing serotonin it then goes and agonizes or is an agonist at the 5-HT1A receptor and the 5-HT1A agonism is known to increase dopamine in the prefrontal cortex. So essentially mirtazapine acts as a broad spectrum antidepressant and this effect you tend to get at higher doses. So we'll talk about dosing and how I use it in clinical practice. So when we come to the clinical practice, Low dose mirtazapine can be very very useful for example 7.5 to 15 milligrams to provide sedation anti-anxiety properties because 5-HT2A antagonism in the limbic system so can be quite useful say for example in a patient that's not sleeping for example or has anxiety low dose mirtazapine can be very useful. I also tend to use it in the consultation liaison setting for patients say for example with cancer or have significant nausea it can really help with anxiety. And interestingly, the 5-HT3 receptor tends to also help with the nausea in cancer patients. So as we know, anti-nausea medications such as ondansetron is a 5-HT3 antagonist. Mirtazapine provides inherent 5-HT3 antagonism, so can be used as an anti-nausea agent in patients that might be extremely anxious or might have medical issues associated, such as cancer patients, for example. So... At low doses you tend to get quite a prominent anti-stimulant effect and you get this specific serotonin antagonism so it can be a good sleep promoting property, anti-anxiety property and a mild antidepressant effect as well. Now one of the things that I mentioned that it does elevate serotonin but the risk of serotonin syndrome tends to be low and similarly you know the risk of AIDS, hyponatremia due to AIDS that can occur quite a lot with SSRIs or SNRIs tends to be low with mirtazapine because most likely because it has a specific serotonin antagonism so it antagonizes the effect so it does not act as a typical cert transporter inhibitor as the SSRIs tend to do. Okay, so higher doses of mirtazapine. Now one of the things I find in clinical practice is that it's important to recognize this dual aspect of mirtazapine. So at low doses, yes, you can treat anxiety, a little bit of useful in mild depression with insomnia. But if you're treating melancholic depression or the severe end of the spectrum depression, then higher doses are required. And What doses are required here? So here I've often noticed doses above 30 milligrams are required, 45 and even to 60 milligrams. In fact, there is a study that looked at, and this was a naturalistic study that looked at doses of mirtazapine. The mean dose in treatment resistant depression was somewhere around 38 milligrams and the dose range varied from 15 to 90 milligrams. So higher doses of mirtazapine can be used and as we know mirtazapine can be successfully augmented as well and come to what agents you can augment it with. So essentially how do I start mirtazapine? I will start mirtazapine at 15 milligrams at night time, so in a patient with depression 15 milligrams and weekly increases of a Approximately 15 milligrams can be considered, of course, with the right framework. So in an inpatient setting, I can do it faster than in the outpatient setting. Key things to look out for. It is absolutely crucial when prescribing mirtazapine and particularly as you go to the higher doses that mixed states need to be ruled out. Because if you have mixed states present, then side effects such as activation, agitation, akathisia, insomnia, nightmares, etc. can occur as doses go up. So it's absolutely crucial to ensure that the mesolimbic system is not activated, mixed states are ruled out, bipolarity is ruled out because mirtazapine or high doses can have an activating effect. So usually starting at 15 milligrams and depending on the necessity response I can go up to 60 milligrams. But important to note that higher doses may be required. And coming to augmentation, so mirtazapine can be a very useful agent to augment in the severe end of the spectrum of depression. And you can again go to psychscenehub.com and look at the article on melancholic and psychotic depression and look at the augmentation strategies considered. We also know that California rocket fuel, the combination of venlafaxine high dose plus mirtazapine was used in the STAR-D trial at level 4. And this is a combination that is... Evidence based in treatment resistant depression. So what are the augmentation agents that can be used? I've used it with SSRIs, SNRIs, again evidence-based, with vortioxetine plus mirtazapine, agomelatine plus mirtazapine. I've successfully used it in the most severe cases with psychostimulants, both armodafinol and also other stimulants such as dexamphetamine or methylphenidate. So mirtazapine is quite a versatile agent but should be used appropriately. Side effects, sedation and of course because of the anti-histamine effect, weight gain can be a real issue that can limit the use of mirtazapine. So it's an important aspect to take into account when using mirtazapine. Now of course other side effects as you go higher, constipation, dry mouth, all the side effects that can occur as noradrenergic activity goes up and dopaminergic activity goes up. clinicians should take into account. So in summary, mirtazapine is a novel antidepressant. It's quite a unique antidepressant. Clinicians should recognize the dual effects and the noradrenergic dopaminergic effect that the alpha-2 a presynaptic antagonism can provide along with the 5-HD1A agonism increasing dopamine can provide. It does elevate serotonin to a certain extent as well due to the heteroreceptor activity on the serotonergic neurons, but risk of serotonin syndrome tends to be lower and most likely due to this specific serotonin antagonism that occurs on these receptors. But by knowing these three receptors, we can see mirtazapine can be used for as anti-anxiety. It can be used to treat akathisia, it promotes slow-wave sleep, treat sexual dysfunction or no sexual dysfunction, no emotional blunting, 5-HT3 good anti-nausea properties as well. And with mirtazapine, really important to recognize the dual dose range and can be used successfully as an augmentation strategy as well. So I hope that you found this quick video on mirtazapine useful. and can use it successfully in clinical practice. See you in another edition of HubBytes. Take care and stay safe. Bye-bye.