SNRIs, Serotonin Antagonists and SSRIs – Antidepressants

00:00 In terms of the new class of drugs called the serotonin- norepinephrine reuptake inhibitors, take a look here. So now these drugs are getting more and more specific to act on either norepinephrine or serotonin and this group of drug acts on both relatively equally. So in terms of the profile, they are similar to the tricyclic antidepressants but because they're more specifically have fewer side effects peripherally. Now, SNRIs do not have a blocking effect on the peripheral tissues and in particular they don't have blocking effects on the postsynaptic neuron like the other drugs. A classic SNRI is Cymbalta. It's a very widespread drug used almost everywhere in the world. It's used in major depressive disorders. It's also interestingly used in neuropathic pain. So many of my patients who are diabetic who have neuropathic pain are on this drug. The most popular antidepressant in Canada is venlafaxine or Effexor or Effexor XR. It is a heavily prescribed drug because it has relatively few side effects and it has less affinity for norepinephrine than duloxetine. The side effects do include an increased blood pressure. The side effect profile is similar to the newest class of drugs which is called the SSRIs, which we'll talk about later. There are some withdrawal symptoms. So, if a patient misses even 1 dose, you can see withdrawal symptoms develop. So, the drug company developed Effexor XR, which is the extended release version of this drug which somewhat mitigates that disadvantage but it's still there. So it's important that this drug be used in those patients who are very compliant or very adherent to medication regimens. Let's talk about the serotonin antagonists. The acronym is SA or 5-HTA but we used SAs more now.

02:13 Now, you can notice here that we're no longer talking about the norepinephrine receptor system. Right? We're now focusing on serotonin. So this is a relatively targeted activity against the serotonin receptor, which is a G protein-mediated event. These are located in the neocortex of the brain. This results in better anti-anxiety activity and better antidepressant activity as well. So the SAs block the serotonin 2A receptor. As I said before, it's a G protein coupled receptor, it's located in the neocortex, it's a short-acting drug so we often have to prescribe it 2 or 3 times a day. These are some of the examples. Now this particular drug, I'm not even going to mention it because it's not used because of its severe interaction with cytochrome system, but trazodone is a very commonly used SA. It's used as a sleep aid.

03:15 Many of my patients are on it. It's quite effective and it seems to be a lot better than the benzodiazepines which it replaced. Let's move on to the newest group of drugs, the selective serotonin reuptake inhibitors or the SSRIs. Sometimes these are called serotonin specific reuptake inhibitors with the same initials. Now it causes allosteric inhibition of the serotonin receptor itself. It has minimal or zero effects on the norepinephrine uptake and it binds at a different site to the serotonin receptor than the serotonin itself does, the nice thing about SSRIs with the minimum side effects. This results in great anti-anxiety activity and great antidepressant action with minimal peripheral symptoms. These are a list of the SSRIs and if you only want to remember one, you can remember the top one but in general all of these will come into your hands at some point during your practice. Now in terms of the effectiveness, these drugs have the same effectiveness as the tricyclic antidepressants and fewer, almost minimal side effects. In terms of toxicity and overdose, you will see patients develop headache, nausea, anxiety, and agitation. They often complain of jitters. They're shaking like a leaf if they overdose. And they sometimes can also develop extrapyramidal side effects. This means akathisia, dyskinesias, dystonic reactions, and we're going to be talking a little bit about dystonic reactions in our Parkinson's disease lecture and we also mentioned dystonic reactions in our autonomic nervous system lecture. In terms of drug interactions with the SSRIs, with fluoxetine which is commonly known as Prozac, it inhibits the cytochrome system and so therefore you're going to have interactions with multiple drugs. So this fluoxetine will increase the level of dextromethorphan, of propranolol, of tamoxifen, and of the tricyclic antidepressants.

05:35 Now fluvoxamine, also called Luvox, inhibits the 1A2 subunit of the cytochrome system.

05:43 And citalopram, which is Celexa, affects the cytochrome system as well but it affects fewer drugs because it actually acts in a more rare isoenzyme. While we're talking about the SSRIs, I want to talk about something called serotonin syndrome. Serotonin syndrome was first described as a reaction between monoamine oxidase inhibitors and the SSRIs. It is a life-threatening condition. Here's how it presents. In terms of the central nervous system stimulation, so there is severe muscle rigidity, myoclonus, and hyperreflexia. You get hyperthermia and you get seizures and mydriasis. In terms of the cardiovascular symptoms, you get tachycardia and an unstable blood pressure and in terms of the gastrointestinal system you can get increased bowel sounds and complaints of diarrhea. The serotonin syndrome has a mnemonic called MADAMS TIPS. So I'm just going to go through them for you.

06:51 M is mental status change which I mentioned before, A is agitation, D is diarrhea, A is ataxia or the inability to walk properly, myoclonus is M, and shivering. And in terms of TIPS; there is tachycardia, increased reflexes, pyrexia, and sweating.