so welcome um we're doing the lecture today on our anti-depressants and anxolytics here the objectives you can check out on your own um so let's talk about depression first and then we'll segue into discussions of uh anxolytics and how to treat that because we'll see there is quite a bit of crossover between the two um depression anxiety they tend to be pretty common bedfellows uh as we're going to see and so um we'll find that a lot of the treatment may be somewhat similar as we get into it so uh very common disorder depression uh we've been able to treat it for quite some time now i've had drugs since the 50s and fortunately as time has gone on we've been able to develop safer and safer medications and one kind of throughput that I'll sort of make mention of now we'll kind of see this pop up over and over again is that um you know with depressed patients the big risk is always you know self harm suicide things like that and so um with the older medications that we had back in the day they were highly toxic meaning someone could overdose on them and kill themselves quite easily and so largely nowadays um we have much more selective agents things are going to be much safer uh even in overdose and so that's going to be to the benefit of these patients and we'll talk through the different classes and kind of look at the comparative safety amongst the bunch of them and and again this is not just going to be you know if you don't work in behavioral health you're never going to run into this you'll see this everywhere uh and as a primary care person you may be the person taking care and managing their depression so we need to be uh aware of it know how to treat it things like that and again um your therapy typically needs to be aimed at both treating depression and anxiety because the two tend to coexist quite frequently and can sort of worsen each other and so each indivi individual will be a little bit different from that standpoint and it's kind of difficult to determine what's going to be the most effective therapy for every single patient because uh one of the big problems you're going to run into is that there's placebo effect do you know I can give someone a placebo that they think is active drug they take it they think they're doing something good for themselves they think "Oh yeah I do feel better." When maybe the drug would have you know this placebo it shouldn't do anything but the mind is quite powerful and so we need to be kind of thinking about that as what can make studies sometimes difficult to discern what is going to be the best treatment because again there's a lot of interpatient variability the placebo effect you know all that we need to contend with so we also want to make sure that we're ruling out other like secondary causes for depression that may be um easier to treat or easier to fix so for instance if they're having issues like inflammatory conditions or hypothyroidism there's things we can do for that um which may help secondarily with helping the depression uh but certain medications can certainly be playing a role here and we always want to take a look at the medication list just to make sure there's nothing we can see there which we may transition out of or switch to a different class or whatever the case may be uh I think the isotinone is probably a really good example of that especially younger patients um dealing with anxiety and depression uh certain anticonvulsants or even hormones can affect patients so for example like cortical steroids um oral contraceptives these all may be playing a role and every patient may respond a little bit differently and so you can't necessarily predict which patient is going to have you say this birth control is going to cause worse depression for this one but may help for another patient so it's a lot of variability there and then again um a lot of patients may be underdiagnosed or maybe undertreated and that's where we do run into concerns about things like suicide attempts um obviously that's very important to me in my practice because toxicology one of the big things we do see quite often are going to be patients who try to harm themselves and so we need to also consider not just like what medications they're taking for depression but also like what were they taking for their hypertension what were they taking for X Y and Z cuz they may be overdosing on those substances too um and so that's always going to be a concern when looking at their medication list to see what possibly could be there uh if one were to try to harm themselves now with anxiety there's several different conditions that fall under this sort of uh banner here i'm not going to get really into the specifics between say like generalized anxiety versus specific phobias or OCD um generally speaking they're going to be managed very similar to one another so I'm not really going to get into the weeds from that standpoint um and then again these are going to be uh be instituting therapy once we start to see patients kind of normal function their activities of daily living start to be impacted by anxiety and as I mentioned it's very commonly associated with depression so by treating one you can oftenimes treat the other as well which is kind of a nice twofur there so why do people get depressed um besides having to take a pharmacology class um we don't really know the actual pathophysiologic you know the neurochemistry of it we have no clue we do have a decent idea of what's happening here so for example there's this monoamine theory and when I say monoamines I'm really referring to uh dopamine nor epinephrine and then serotonin and so there was this really old school drug called resurfine back in the day for hypertension and basically how this treated your high blood pressure was by causing you to release a lot of your monoamines and basically deplete yourself of things like norepinephrine and whatnot and so from that drug they realized that a lot of patients were developing depression after using it and so they're like well it must be because of this lack of monoamines so if we give the patient more serotonin or we give them more norepinephrine obviously this will fix the depression and kind of not it's not the really the full story because even if we give you a medication like a selective serotonin reuptake inhibitor yeah that'll boost your serotonin levels right away but it doesn't fix your depression right away and sometimes it can take several weeks it really takes like four to six weeks before you really see full effect out of these anti-depressants so we boosted the monoamines but we don't see a fix for a couple of weeks there's something else happening here when that's what we don't know it could be changes in terms of like gene transcription protein production receptor modulation who knows we don't know but basically what we can do is boost up these neurotransmitters and we know eventually we should get some effect on their mood and that hopefully we'll treat their depression so no final theory but we deal with what we got anyway so our goals here are to reduce symptoms if they're having acute depression try to get them back to sort of normal levels of functioning and then try to prevent any further episodes from happening and you'll see these different phases of treatment here where early on they're maybe in this kind of acute phase maybe the patient's had some kind of crisis or something like that to where maybe they're getting more kind of acute care um hopefully within the first six to 12 weeks we should see remission of symptoms and then we'll be sort of like in a continuation slashmaintenance phase to try to prevent um recurrent episodes from happening here for some people they may be more episodic in terms of depression like maybe they have you know the death of a loved one or something like that um for some people they may require lifelong therapy especially if they've had say you know two or three or more episodes that probably indicates someone needs to stay on therapy for their lifetime um just to prevent future recurrences here and again adherence and patient education super super important um compliance is something that's going to be challenging because patients you know they'll they'll say "Hey take this medication it's going to make you feel better oh it's going to take like six weeks." And then in the meantime they're also like getting all the side effects from the drug so like maybe they're having like sexual dysfunction or they're gaining weight and they're just like "Well what the heck like why am I taking this med it's making me feel worse about myself." And then then maybe it's going to work eventually so they'll just stop taking it and you can ask them and they'll probably say "Yeah of course I'm taking the med like I'm supposed to." And they're really not so it can be a challenge and of course I was just meeting with a student uh one of my advises on on rotations now and um they're on their they did their internal medicine rotation and they're like so boring all it is is compliance compliance compliance it's like exactly because the patients are compliant they don't stick with these things unfortunately even though it is in their best interest there are non-farmacologic therapies and these can be synergistic with our medications um doing things like psychotherapy um TMS has been relatively new in the grand scheme of things we're using different magnetic stimulation um to help manage this but even things like electrocombulsive therapy ECT has been used in the past and uh used sometimes even today although somewhat somewhat rarely now well let's get into the drugs because that's what you're here for so like I mentioned we can't really predict who's going to have a good response to these medications here like you see like a third of people just like respond to placebo on its own which is like okay well you know that makes it difficult to determine okay what are the drugs doing are they actually all that effective um and studies do appear that's the case but again keep in mind the mind is quite powerful and so sometimes you don't know is it the placebo response is the drug actually working sometimes hard to tell um how we're going to make our decision in terms of what drug we're going to use maybe uh including facts such as like what have they been on previously like what do they respond to um what kind of you know side effects do they get from the medications they might have been on previously what kind of drug drug interactions um you know what is their current state of mind like are they in an acute crisis or is it more just kind of a generalized sort of depression all of that patient preference all these things we're going to be considering here and so we're going to classify our anti-depressants either based off of their chemical structure so like when I say a tricylican depressant that's referring to the chemical structure or uh it'll be based off the presumed mechanism of action so when I say an SSRI that means a selective serotonin reuptake inhibitor that basically tells you what the drug does it blocks reuptake of serotonin um we'll get into more details here in just a moment um but at least it helps to maybe not maybe not clue us into like how the drug specifically works to treat depression but it at least gives us a clue in terms of what type of side effects might we potentially see as I mentioned takes like between two to six four to 6 weeks to see full therapeutic effects however side effects will happen immediately we'll talk about what some of those more common ones tend to be and we will see some failure rate with these anti-depressants here some of it could be related to sort of like an intrinsic resistance the patient may have uh could be related to inadequate dosage or maybe the patient wasn't on it for long enough or just non-compliant so maybe because they're having adverse effects or maybe they can't afford the medication or any number of reasons take a pick and like I said you know some people do have this placebo response and and some people will have kind of natural remission of their symptoms on their own anyway but for those people who are going to be having more consistent more you know persistent symptoms here um this is where we're going to see a drug therapy tends to shine and so while the different classes of anti-depressants don't necessarily have major differences in terms of overall efficacy that we can tell the side effects are very very different and that can include both the therapeutic doses where patients are taking it normally absolutely can be a difference in terms of overdoses so you know when I hear someone has a TCA overdose I'm going to be infinitely more concerned for that patient than if someone has like an SSRI overdose their world's different in terms of degree of severity in terms of overdose and so we need to be cognizant of that because one of the things we're going to run into across all these meds is they can carry an increased risk for suicidality i'll talk about why that is here in just a little bit but it seems oxymoronic it's like oh I'm going to give you this medication to make you feel better but also you might want to commit suicide like doesn't sound good um but we'll talk about some of the mechanisms for that here and and what it is so um starting out we're going to go historically from our older medications which tended to have more side effects more drug food interactions you know worse safety side effects you know and overdose and whatnot up to our newer agents here and so first off we're going to talk about the monomine oxase inhibitors then the TCAs then we'll get into our SSRIs and then finally the SNRIS i'll go through the mechanisms more uh uh thoroughly here in just a moment so here are two different synaptic junctions here we are going to have a noradinurgic neuron on the upper side here which I'm assuming is showing up on my slide yes I see my mouse moving okay so we have a noradeneric neuron up here and then we have the serotonurgic neuron here down the bottom and so obviously norineric means it's going to be releasing norepinephrine and then the serotonin is releasing serotonin or 5HT so what these drugs are going to do is in the case of something like an S SRRI so a selective serotonin reuptake inhibitor it's going to be able to inhibit specifically just this serotonin transporter because normally the neurons like to be economical with their neurotransmitters like to recycle what they can so after you release serotonin into the syninnapse where it can interact with these kind of postsaptic receptors you will see some reabsorption here through these cert transporters ssris are going to inhibit this directly similarly with norepinephrine you're going to have some reuptake happening here as well and so you'll notice the SSRI just work on serotonin whereas the SNRIs and TCAs are going to work at both so SNR means selective norepinephrine reuptake inhibitor these are going to work at both of these this enhances the amount of neurotransmitter in the syninnapse thus getting more receptor modulation here then something happens and then patients aren't depressed anymore again we don't know the full story but that's roughly how the drugs are working the other means of which we can try to enhance the neurotransmitter amount in the syninnapse is going to be through the actions of blocking monoamine oxidase which you can see here um monomine oxidase is usually necessary for metabolism of things like norepinephrine and serotonin so by blocking this you're going to end up seeing higher amounts of neurotransmitter and thus you get a similar effect to the SSRIs TCAs and SNRIs we go through here so generally speaking the actions are meant to enhance norepinephrine and serotonin and we don't know the full mechanism as I mentioned there but we will possibly see changes in certain uh gene transcription factors you might see um modulation of like how many receptors are available things like that something happens though downstream and patients tend to feel better they have less depression um full story we don't know anyway so getting into the first class here we have the monoamine oxidase inhibitors and so um this actually first started out back in the 50s as a drug used for tuberculosis so it hypniz it and they realize that okay have all these patients you have tuberculosis in these big sanitariums and um oh they're taking this drug and they're feeling better because I imagine if I had tuberculosis I might feel a little depressed but they still these patients had a better mood so okay well that's interesting let's try to further develop this and from there we have drugs like phenoline isocaroxazit and then transpipramine and so these are going to be irreversible inhibitors of monomine oxidase A and B key term there irreversible inhibitor that's going to be important here in just a moment and so it's going to be able to affect the metabolism of serotonin norepinephrine and a little bit of dopamine here as well um keep in mind that we have certain precursors in our diet that eventually will turn into these mono monomines and so we can run into issues where if I have a lot of say diet coming in of food that has high amounts of something called tyramine which is a precursor to these monoamines uh and I'm also inhibiting the metabolism this can end up leading to way too much of these in particular like norepinephrine serotonin and that's going to lead to certain side effects and so that's going to be an important drug food interaction we'll talk about here in a moment so like I mentioned phenine transpramine are two of the main ones here is actually used in Parkinson's disease um so we'll cover in that section so big things you're going to notice here um some of which are going to be more ubiquitous to all of these different um anti-depressant different classes we'll talk about um for this one though postural hypotensions fairly common so again make sure patients aren't going to be undo like fall risk for example you see some weight gain here and then a lot of sexual side effects this is going to be pretty um common to all the classes is the sexual side effects and that can be a big reason for patients wanting to discontinue therapy is because if it's causing you know uh problems with their significant other for example u they may want to stop taking the medication the other thing you're going to see here is this hypertensive crisis and this is most likely going to be happening when patients are taking um the MAI in addition to consuming foods or drinks that have high amounts of tyramine in them and I'll show you that list here in just a moment if they're on other medications it can increase their blood pressure u they may start to have things like you know diaperis and stiff neck and this you know kind of really sky-high blood pressure and this can lead to things like stroke can lead to death um and so we need to be really cautious when using these and educate patients appropriately on what kind of things to avoid give that list in a moment um keep in mind this can even happen for up to two weeks after they stop taking the medication that's because it's an irreversible inhibitor so they stop taking it today they can still have effects up to two weeks later and that's including if you put them on other anti-depressant drugs or other hypertensive medications things like that um treatment is largely supportive and giving them anti-hypertensives like nitropide or nicopine or things like that so the foods with which we need to be careful of that are high in tyramine content are going to include um kind of what I refer to as like the bougie foods meaning they're like fancy foods you might find at like dinner parties the kind that I don't really get invited to anymore um and so this means things like aged cheeses aged meats um things like red wine for example like Keianti or cherry fava beans in particular are really high in tyramine and so these would be contraindicated in patients who are taking mais because it has too much of the precursor you then produce that into these monomines and now you're blocking the breakdown of them too so you get way too much um things like MSG soy sauce all of this should be avoided for these patients so because of the challenge with these drug food interactions it was kind of difficult to work with the medication which is fortunate because we have other classes that have been developed since that time back in the 50s other drugs that can interact with the MAIs would include things like your amphetamine type drugs like you might see for uh ADHD for example cocaine uh decongestions like pseudafed uh can all potentially cause uh this increased risk for this hypertensive crisis to occur there from there we then get into our TCAs or the tricyclic anti-depressants and these are actually derived from the pheninoines which we discussed in the section for um schizophrenia which I believe we already talked about um and so these are going to have some similar actions to those as we get into it and these are going to work instead of blocking monomine oxidase they're going to inhibit the re-uptake of serotonin and norepinephrine so they do a little bit of both uh these were considered first-line therapy although that was you know back like in the 80s maybe in the early 90s um these have largely been replaced by the SSRIs just because the side effect profile is quite vastly different night and day difference here um and these drugs can be potentially quite deadly either if a kid gets into it or if an adult overdoses on these um they can be quite fatal and in fact in talking to some of my mentors in toxicology they said back in the 80s um they basically had a bed ready in the ER at any time um one of the critical care beds ready just for anytime you might see a TCA overdose because they were so frequent they would come in and they got so so sick that they needed to have something available for the patients when they inevitably arrived which is unfortunate but nowadays it's much much safer the other thing you'll see TCA is being used for as well can be things like insomnia you may see this for certain types of like pain conditions um bedwedding for example at night can be another use case for these drugs um you so different places you may see this being used so available agents in the TCA category does include moxipene emotalene clamipramine dipramine docipinine and then norpalene um so again big class but uh still certainly in use today just not quite as much as it was back in the day um the problem with these TCAs is the fact that they have a lot of other actions in the body they don't just affect that reuptake of serotonin and norepinephrine um but they have a lot of other receptors they play with which is what leads to some of the danger and the side effects you can run into so in particular they're going to have strong anti-uscerinic action so we've talked about this pneummonic before but you see things like man as a hater blinds a bat you know dries a bone so um sedation is quite common with these um leading to help with insomnia but also the side effect of you know maybe you're more fatigued and shouldn't be driving a car and things like that um and overdose that can be taken to an extreme and see things like you know seizures can develop as a result of overdose here we also end up seeing some cardiac conduction issues um so arhythmias can be a possibility for patients especially in overdose um since it can block sodium channels and can affect your QRS interval for example uh can block alpha receptors so that then leads to hypotension that you can see uh sexual dysfunction weight gain so a lot of different things that it's doing here um and it also kind of looks a little similar to this thin kind of typical antiscychotics uh first generation type of drugs here uh and so as a result of that um it was kind of what we had was the best thing we had at the time there's not any really dietary interactions like you see the mais but we just kind of had to accept the fact that there's yes risk with using these drugs or depression um but other than that you know you're just leaving your patients untreated which is not a great situation to be in either so then we get into the SSRI which are now kind of considered gold standard for treatment of uh depression and anxiety as we'll get into it and these are um nice because they're very clean in terms of their mechanism instead of affecting alpha receptors and sodium channels in the heart and all these different places these just work on the serotonin reuptake transporters so they block 5HT reuptake you get higher concentration the syninnapse and then something happens and then the patient's depression's treated um so these are much safer in overdose and they also tend to be much more tolerable in terms of side effects it really has kind of changed the game uh in significant ways uh agents in this category will include agents like satalopramg esatalopram which is just the left-handed version of satalopram lluoxitine fluoxamine peroxitine and then certillene the main ones you're going to run into there and so in terms of side effects they really don't have a lot when it comes to things like you know alpha effects or histimeic effects which is good that's a nice change from the TCAs there you see less weight gain although you do still see some common side effects including GI upset uh sexual disturbances is still common with these uh and then things like headache and insomnia so patient may have like some sleep disturbances associated with these important things to note um when patients are using ethos you want to make sure they don't stop taking them uh cold turkey or have any kind of abrupt discontinuation uh because you can get sort of a withdrawal phenomenon so patients can become sort of uh adapted to having these SSRIs around and then when you cut them off cold turkey they can having kind of rebound issues like sleep disturbances anxiety headaches uh can feel pretty miserable for the most part um so one thing we can do is either do I try to taper down on the dose gradually or if we can give agents with longer half- livives or things with like active metabolites like fluoxitine that can help to provide kind of like a nice kind of natural curve down in terms of drug levels thus patients may not have as much withdrawal symptoms to deal with there um other than that you know for some people this will help improve their anxiety will help to treat it for others you may see a little bit worse in symptoms so it really kind of depends on the agent how the patient's going to respond to it um other than that the other big thing to note here as well can include QT prolongation that you see with satalopram and then esatalopramg um again not usually big concern a normal dosing but certainly an overdose and in fact I actually had a a call at the poison center not too long ago um for a young lady who had overdosed on her satalopramg uh and the doc was looking for guidance in terms of like when they could medically clear the patient so they could then send them over to psychiatric care um it was interesting cuz I my first question was it was a teleoprame so I said well it's a QTC and um they go oh it's a 480 which is not like terribly prolonged like usually a 440 is considered to be like sort of like a normal a little bit longer in women um and I was like well do we have any like historical baseline is that her normal is that new for her uh and so he went back to go check and then sure enough the previous EKG had a count of like 420 or something i was like "Okay well now we're we're pretty higher up versus where we were originally and I don't think we can really you clear the patient at this point we'll probably need to admit and observe just to make sure because you don't want to like clear them send them over to psych and then they you know die from torsads um partway through their visit." So again that this does occur the other thing to note here and and this blackbox warning is going to apply to basically all anti-depressants so this not just for SSRIs but for all of these are the fact they carry a blackbox warning for suicidality and so again it sounds oxymoronic because you're like well this is supposed to fix their depression not cause them to commit suicide and we see this more so in like children and adolesccents young adults um and the question is like well why does this happen why is it you know you're handing them a prescription and then you know they may be likely to either overdose themselves or try to commit some other kind of self harm uh and part of it is thought to be through this process called acthesia this kind of this um kind of this restlessness this kind of uh you have this anxious energy that you can't get out like you have ants in your pants kind of feeling and so you know some depressed patients part of their disease is that they don't have a lot of energy so they may have thoughts of self harm they may have plans of how they might harm themselves but they just don't have the energy to carry it out well when you started these anti-depressants one of the first things you'll get back is some of that energy you may still feel depressed but now you have like maybe some energy to actually enact some of these plants and so this is why it's so critical especially with like TCAs for example you take a whole bottle of TCAs I mean that can be quite deadly so um it was a huge risk that we knew we just needed to be really cautious and monitor for and so um not only that but if you have like someone who's like has maybe undiagnosed bipolar disease and you then unmask their manic episodes that could potentially lead to risk for suicidality um so again applies to any of them make sure people like around them are aware of what you know kind of warning signs to look out for things like that just to prevent any undue um risk for these patients to go on and then try to harm themselves moving on then from the SSRIs we get into the SNRIS and so these are going to be agents that work to block the reuptake of the serotonin and norepinephrine that sounds kind of like the TCAs but these are also clean like the SSRIs in fact they just affect those two receptors or those two transporters they don't really affect you know muscerinic receptors and histamine receptors and all that so from that standpoint they're much better from a side effect profile than the TCAs and so these are a little bit newer too um so these are typically utilized for depression but you can also see these being used for treatment of things like fibromyalgia or other peripheral neuropathies that can occur um due to that reuptake of norepinephrine um kind of helps to modulate some pain circuits and so that can help to um treat some of those neuropathic type of pain there available agents in this category will include venlaxine desinlifaxine which is the right-handed version of venlaxine duloxitine miliperin and levomin which should be the left-handed version and so GI disturbance is probably a little bit higher than the SSRIs you still see the sexual dysfunction and you could expect to see some increases in blood pressure due to that reuptake of inhibition of norepinephrine uh especially like venoxaxine you can see that sometimes and then with duloxitine you get a little bit of anticolinergic actions there some some constipation dry mouth so additional things you want to be looking out for from that standpoint uh next up you also have some mixed serotic agents here so now you know most individuals you'll probably be starting off with like an SSRI or SNRI MAI are kind of reserved for as patients that are um you know really not treated well with other medication classes kind kind of like a last line kind of deal um we also have some kind of miscellaneous agents here which may be used as more like a second third line type of option for some patients here um first of which we have here is called trazadone um the fazadone is not really used so much because it caused a lot of liver issues so trazone is the main one and then veazadone is a newer uh in this category here and so what this is going to do is one block reuptake of serotonin similar to your SSRIs um but it can also work as an antagonist of the 5HT2 receptor again how much that provides in terms of clinical response who knows um notably though we can see a lot of sedation with these medications and in fact um in my experience this is what I would see you know in Florida um for the longest time PAS couldn't write for control substances neither could nurse practitioners and so if you wanted to write for something for sleep these were kind of the strongest things you could do that weren't controlled substances and so um you see a lot of prescriptions uh for insomnia for treat you know treatment by PAS and nurse practitioners um not the case anymore now you can get your DA license if you like but you still may see it used for that specific purpose there and then um other notable things here too is that trazen in particular can block alpha receptors so this may lead to dizziness hypotension risk for fall so be cautious there and then as a result of that alpha blockade as well um there is some risk for privatism and so it would be the sort of like unintended or unintentional erection uh more than four hours that is considered a urologic emergency because you can cause long-lasting tissue damage nerve damage um so it does need to be one of those things you referred straight to the ER and get urology on board in some cases they may need to do things like needle aspiration um or they may apply some medications and drainosy to treat that um but that's a notable one there i remember one time I had a um fellow who had tried to commit suicide travis was one of the medications on board and um the medical resident or not medical res medical student um was doing the physical exam and whatnot and she was just like this guy's got an erection i was like uh oh yeah transit of course that's what what causes that so um pretty typical thing to see there okay next up we have buproprion and this one's neat because this one does not work through the traditional mechanisms and really doesn't affect serotonin at all and what it does is block the reuptake of norepinephrine and then dopamine so that's what differentiates this one and so um because of that it's been seen to be utilized for things like addictive conditions like um you know for smoking sensation for example because it's thought to kind of like reset the reward pathway a little bit remember that reward pathway is going to be triggering a dopamine release um you know if you gamble and win big or if you have sex or you do heroin you know you trigger that reward pathway through that dopamine this is thought to help kind of rewire that a little bit so that way patients don't feel as much of that sort of psychological craving for these things and so you may see this being used for things like overeating disorders and other addictive sort of disorders but for depression this is we like this one pretty well and the big claim to fame for this one though is that it has the least amount of sexual dysfunction uh versus the other classes so if you have a patient who is complaining about problems in the bedroom for example or wherever they happen to have those activities um you would end up potentially switching them from like an SSRI over to be propriant that's a big reason why you'll see that quite frequently um not everyone but for some um in overdose these can be dangerous or this one can be dangerous since it can lead to some seizures and arrhythmias so we want to be cautious for that if you ever had a someone with like a wellutran overdose for example there uh next one here we have is called Mortazipine or Rimmeron this one's going to be working as an antagonist of these alpha 2 auto receptors basically this um kind of works like the opposite of clonedine where you end up seeing an increased release of things like norepinephrine and serotonin and has some kind of miscellaneous effects of these 5HT2 and three receptors um notably this one because it blocks histamine you may see some somnolins and weight gain associated here um so a little bit worse side effect profile than you might see this is like another one you might see it's like a second or third line type of medication vioxitine is a newer agent here this one's going to be working as an SSRI and also can work as sort of a partial agonist antagonist at several different receptors don't memorize this but you can see just the wide variety of different serotonin receptors that are out there um for this one again sexual dysfunction tends to be quite common some diarrhea um and then if you have patients who are slow metabolizing uh SIP 2D6 enzymes present they may accumulate the drug leading to worsened side effects there uh then we get into the NMDA receptor antagonist so this is kind of like bleeding edge of treatment for depression and so this is where we get into discussion of ketamine and then the drug esetamine as well which is the anantimer of ketamine and so ketamine has been used um for real long time as a sedative both in veterary medicine and then in human medicine and in fact we would use this all the time uh in patients who have say for instance like a dislocated uh joint or if they had say a fracture that need to be reduced um you would have patients come to the ER we give them a dose of ketamine um they kind of have you know it's kind of knocked out sort of effect and then they'd wake up in like 20 minutes so really good as an anesthetic sort of agent here but what we've sort of seen and we've kind of developed this from research done in uh veterans uh specifically at like the VA for example and treatment for things like PTSD um they were doing these kind of guided ketamine sessions with them and ended up being really effective and so I think you know use of psychedelics and other agents that affect uh NMDA receptors are going to be probably like you know pretty pretty up and coming here in the in the future um but what we're seeing here is that we're using much smaller doses of ketamine than what you would use to like knock the patient out and then usually there's some kind of guided sort of um therapy to go along with this um with a healthcare provider um usually that's given either IV or orally and then esetamine has an intraasal option there as well um keep in mind because these are sedatives you do need to do this in a monitored setting although there has been um since the pandemic there was sort of an explosion of like teleaalth medicine and uh there are things like at home ketamine sessions you can do typically do it online with a healthcare practitioner sort of monitoring but uh that's been sort of a recent development there this is a controlled substance it's a C3 um so there could be some risk for misuse or abuse of the medication and other than that you expect to see sedation most commonly um and this can also cause sort of a dissociative like effect and how I describe that is because you're blocking these um NMDA cu lumate receptors it kind of causes like a mind out of body type of experience where the body may be sending signals to the brain but the brain's not getting them they're just not there um so for instance when we're giving anesthetic doses of ketamine to like say children who are having a joint put back in place you know you can tell them hey you know what do you like to do for fun they're like I love baseball like imagine you're playing baseball with your favorite player you knock him out and they wake up and they're like "That was amazing i had the best time." Like you know I was playing with this guy and it was it was fantastic i don't know any baseball players so I don't want to embarrass myself um but they get this like really kind of dissociated effect and again when they're knocked out you know they're you're doing painful things to them but that signal is never making it up into the brain and so that's why it works so well as an anesthetic um use at these kind of lower doses I can kind of expect to see that kind of a slight dissociation where maybe patients are able to gain like kind of better perspective on their issues or problems things like that so it's been an interesting development over time and again not every patient will undergo ketamine therapy but it could be an option especially if they failed things like you know multiple trials of SSRIs and SNRIs and and whatnot there um here's a good uh article from a couple years back which I think is interesting to talk about some of the um benefits and the downsides of using at home therapy and um you know some of the the you know trials and tribulations patient may experience and providers uh go through with these things here so just something to consider all right so all these drugs potentially carry the risk anything enhancing serotonin has the risk of causing serotonin syndrome and so it's kind of a term that will be used but you're not really sure like what the heck it is and basically there's four cardinal sort of features of serotonin syndrome uh first of which is some degree of altered mental status whether they're agitated sedated it's just altered hyperothermia autonomic instability which means their blood pressure heart rate are going to be off normal and then this increase in muscle tone and in particular you're going to see like clonus like in the lower limbs for example there um and this can occur with any serotonin active drug so SSRIs SNRIs MAIs um you'd see this most commonly with MAIS especially if they're having a high tyroine containing food in their diet you're most most likely to see this here and so other things you can expect to see sweating related to their hyperothermia you can expect to see their blood pressure heart rate's all over the place um you can see clonus and rarely risk for things like reviolyis just if the muscles are kind of too tight and locked up they can potentially cause muscle damage there and treatment is largely supportive so we'll hydrate the patient really well give them you know things like cooling like either use cooled IV fluids or we'll give them um evaporative cooling where you kind of like spritz the patient down and put a fan on them um uh to help you know kind of evaporate the extra heat away there is an anti-erotonin drug we could use called stipproepadine this isn't done very often but could be a potential option there okay so when considering agents here like I mentioned if we can utilize something that has a long halflife or something that um has active metabolites for example like fluoxitine this will help to prevent withdrawal symptoms in patients who may be non-compliant so that could be a concern uh for some people if you kind of have a feeling like I'm not really sure if this patient is going to keep taking it regularly um this might be one reason why you choose this option versus some of the other ones there um just because the withdrawal symptoms can be pretty um pretty uncomfortable and unpleasant for the patient there um keep in mind as patients are taking these chronically you will see tissue buildup chronically so um even though you're maybe switching patient from one drug to another there could still be a decent amount of tissue buildup um that you may see some lingering effects from the medications there and so um you may need to do something where like if you're switching drugs that taper down on one and then eventually start tapering up on the other just to make sure the patient's not left completely untreated but not having uh too big a risk for things like serotoninergic toxicity there and then um for patients with liver dysfunction you may see uh very extended half- livives for these drugs here so it could be something to consider uh if they have a history of cerosis in terms of therapeutic monitoring um there's nothing we can really do in terms of levels to help us because there's not really any good correlation between drug level and drug effect um instead what we will do is just give it time if by 6 weeks we're not really seeing anything and the patient's been compliant then we can say "Yeah this is probably not the med for you." By four weeks you should start to see something at the very least patient start to feel a little bit better um however you know at that point six weeks if nothing's going on just change out the med you could try going you know different meds within the same class you could say go from say certuline to peroxitine for example or you could just switch up the category altogether so you could go from say certuline to um duloxitine or go to vinlaxine or some other option in say like the snri category there new agents tend to be a little bit safer in terms of having fewer phicinetic interactions um however just look it up if you're not sure uh if you're going to be and again you might not be seeing the patient for their depression specifically but you're seeing them for they're coming in for a migraine into the ER and they happen to be taking these medications just be cautious and make sure if you're adding anything onto the profile there's not going to be any significant interactions um that may lead to you know therapeutic problems with your patient like I said TCAs are pretty extensively metabolized through various uh enzymes like SIP 2D6 384 so just double check before you start prescribing there and then any drug that can enhance serotonin can contribute to risk for serotonin toxicity and serotonin syndrome um so this can include things like lenazalid for example as an antibiotic like if you're treating say uh MRSA for example or methylene blue which is a dye you sometimes find in surgery i had one time a patient was having uh was getting parathyroidctomy done and we actually got a call at the poison center from a surgery center which is very odd like we don't get calls from surgeons ever um but basically no one had screened this patient's profile they're going in for a parathyroidctomy and they were using the dimethylene blue because it preferentially gets uptaken into the parathyroid so it leads the surgeon to have a better idea of where the parathyroid tissue is at and he cuts that out and then you're done um but no one had looked at this up and so the patient had been on anti-depressants they got the methylene blue during the surgery and all of a sudden they started to see patients temperature going up heart rate's going up the patient's limbs are kind of getting stiffer and basically they're inducing serotonin syndrome right in the middle of surgery which is like oopsie that's not good um so treated the patient got them through it and got their parathyroids taken out but but it can't happen um things like tripans you might use for migraines all of these things are going to be something which can potentially cause this toxicity so ideally we like to have some kind of like wash out period between their uses although may not be clinically you know reasonable like if someone has an infection they need lenazid for I'm not going to wait 2 to 5 weeks to treat that I need to use lazid right now you just may consider like discontaining anti-depressant uh at the current time just to avoid whatever interaction you can i mentioned QT prolongation in particular with drugs like cylop and esatalop um this becomes a problem as soon as you start increasing the number of QT prolonging medications so if we're going to be on multiple multiples of these definitely check a QT or certainly any kind of overdose with anti-depressants check an EKG because again you're very likely to see some kind of change there and then just be cautious with sedatives alcohol bzodasipines because they can cause some synergy there uh so if you're taking like trazadone plus alcohol that can be quite sedating much more so than the patient might even expect and uh I know I don't talk about herbal supplements too frequently but this is an important one for a variety of reasons here we have St john's wart and this has been shown to be effective for mild cases of depression this could be something you may consider for patients who um want to use a more natural route of treatment or maybe hesitant to use phicotherapy or have some kind of bad experience this may be something they can consider and so it works for depression because it has this active component called hyperin which is MAI basically and has some ability to block the reuptake of you know serotonin and or epinephrine here um fairly well tolerated for the most part but the notable notable thing here two things is one this is a really strong inducer of SIP 3A4 and peak like a protein this is important because it's going to lead to decreased levels of a lot of other medications so say for instance someone was taking say oral birth control and they were taking St john's word at the same time this is going to lead to a patient chewing through that estrogen more quickly leading to potential ovulation leading to potential pregnancy not great um a lot of other medications are affected here so again when in doubt just look it up just do the extra 10 seconds it takes to do a quick check and then this can also enhance serotonin toxicity in particular if you're going to use this with like other anti-depressants for example that's where you can run into some problems all right um special populations in the elderly this is oftenimes overlooked and can be mixed up with things like dementia Alzheimer's etc um and certainly as patients get older we can see some increased risk for suicidality so just be really cautious make sure to look at their entire medication history look for duplications look for um any kind of like phicinetic interactions that could be happening there um and and just be aware they are at risk for some of these more typical side effects just because they don't have as much homeostatic reserve as other patients so they're more likely to see sedation or hypotension or falls whatever the side effect might be associated with the individual classes there in pediatrics certainly this is more prevalent than once thought back in the day and we don't necessarily have as strong evidence in this population as we do for adult patients so largely what we have is extrapolated from adults and then seeing what happens to kids here um be aware of that increased suicide risk um so again screen for that talk to parents let them know what to be looking out for in terms of um you know risk for these things changes in behavior etc um since they tend to be at risk especially early on in treat uh for pregnant and lactating patients here we're going to see um that you know things like postpartum depression are a real deal we just talked about this uh just recently but um we're going to find that uh you know if moms were on SSRIs beforehand during pregnancy they're more likely to relapse so this may be um necessary to continue treating throughout especially if they have like you know recurrent history of um bouts of depression or whatnot maybe just reasonable just to keep them on it um again risk versus benefits are always something you got to weigh uh when it comes to um deciding your pregnant patient drug use so for the most part you're going to start with an SSRI or newer so you could do like an aspenri um we tried to stay away from TCAs as first line just because of the worst in side effect profile so maybe like a second or third line and then MAIS are going to be the last resort there are still some patients who do need it although they're fre fortunately far and few in between just because of the dietary issues you got to think about risk for serotonin syndrome and all that it's just good to stay away from those if at all possible for treatment failure check for compliance check to see they actually were taking the medication they gave it an adequate amount of time they gave an adequate dose to be effective in the first place and as I mentioned you could try switching within the class you could utilize something from a different class to see if they may respond better um keep in mind though that like patients may not be stopping therapy just based off of lack of efficacy it could be side effect profile-wise that it could be causing issues which may lead to patients deciding this med's not for me whether sexual dysfunction whatever the case may be and then we may have cases where we need to add on additional therapy of things like lithium if they have like bipolar disorder atypical antiscychotics especially things like aropiprazole um due to its you know pretty well tolerated sort of nature um this may be useful for the more kind of treatment resistant depression types okay so that does it for this first section here i'm going to go ahead and go straight to the anxolytics i know you're so anxious for me to continue on so let's get into it um so as I mentioned anxiety disorders come in a lot of different flavors here so there's just kind the generalized anxiety um you could have things like social anxiety disorder or panic disorders and all of that um down to specific phobias right uh and so these are largely going to be treated the same and we'll kind of talk through that and so um you know stress anxiety can be a good thing in limited amounts like that's what keeps us like alive and like not doing like really risky things um over you know looking out for predators and things like that but in these patients we're seeing some sort of abnormality where they're getting this sort of unnecessary um sort of increase in this uh stressful you maladaptive response here you're going to seeing a lot of norepinephrine serotonin being released here imbalances in GABA so um we need to kind of try to reestablish you know the normality here and we're in a couple of different ways and so we also need to consider other drug induced reasons for this i mentioned acthesia as being sort of a feeling of anxiety the kind of nervous energy patient can't get rid of um things like stimulants too much caffeine can cause anxiety um you know things like anticolinergics drug withdrawal can do this like ethanol withdrawal or benzo withdrawal um so try to identify these causes first to see if you can identify something easy to fix rather than um trying to treat a whole new problem that's you know is related to the medications you're on or maybe you're missing in the case of withdrawal so treatment is largely supportive i found in my uh history and my time uh the best thing to do for someone who's panicking is to tell them just calm down everyone responsible to that not really but we're going to see if phicotherapy can be very useful here so both we need to be thinking about what to do acutely and then what to do for more chronic management so if patients are having an acute panic attack or they're very acutely anxious then benzoazipines can be useful there because they're going to be useful to help kind of hyperpolarize the neurons to kind of slow everything down it's a it's a literal chill pill right so they can use that for the acute symptoms of anxiety for long-term management this is where the anti-depressants come into play so just like we use them for uh depression these also end up working for anxiety as well which is great because very frequently anxiety and depression are very common bedfellows so your patient likely has a component of both um we'll talk about a few alternatives things as we get into it so anti-depressants are very effective for acute and as well as long-term generalized anxiety disorders here and again plus all the other types as well um things like venifaxine proxitine SSRIs SNRIs are all frequently used uh from this standpoint here these are just examples um if an SSRI or SNR is not working for the patient you can consider utilizing a TCA like a meipamine although just know the side effect profile is going to be worse uh than the SSRIs and whatnot um again we're not really sure of why these work for depression or for anxiety here um thought to maybe be altering some of these stress adapting pathways but it does take weeks so for those patients who having an acute panic issue or anxiety issue um these are not going to be effective for that these need to be started in conjunction with the quick acting meds in order to help make sure we're maintaining the control of anxiety but for more acute things we're going to look at our benzoazipines as being a better u sort of actor there so with benzo we know they're going to bind to the GABA A channels at the benzodasopene receptor site that then allows GABA to more easily bind to and open up those channels so chloride flows in and the hyperpolarizes the neurons and they can shell and again remember that with benzo the dose really does matter so you can get anywhere from anxilyis and then as you steadily increase the dose you're going to be more likely to start to see things like sedation amnesia all the way into basic patients conked out their sleep um so dose is really going to matter here and again we need to educate about drug interactions and things like that since benzo can um be a common player in patients having some of these you kind of therapeutic misadventure so the number of times I've seen patients on opioids and you know Xanax and muscle relaxing and they're drinking do we need to count a lot of patients will end up doing this and so we got to be able to educate make sure they're aware of the dangers of mixing and matching some of these medications here this is a big list drugs like alprazilam tend to be very common used for anxiety some of these you're going to see for like seizure management as well things like you know clinazipam may see more often there um but going through the list we have alprazilam chordizoxide chobazam clinazipam chlorazipate daisopam laopamazzylam oxasopam tasopam and then triazelam there's a lot of them they've been around for a while if you notice I have starred four of these you need to know the whole list you should be able to identify any of these as a benzodasopine but there's four in particular that I know and I'm going to call these the lot loot t benzoazopines whose There's larazzipam oxazopam tmasopam and triazel why do I single those four out well because what we're going to find is is that when it comes to benzoazipines um there's a wide variety of different kinetic concerns for patients especially the elderly in particular and so what you're going to find is is that some of these are going to have hpatic metabolites that are active some of these are more fat soluble and they like to hang out in the body for longer than say like a more water soluble agent here so the four that I've listed here the lot benzo these are preferred in the elderly because they're more water soluble and they don't have a lot of active metabolites they get in and they get out relatively quickly meaning if your patient has renal dysfunction or if they have increased ataposity because they're overweight or if they have a liver dysfunction these are safer to use they don't tend to accumulate in the body like a lot of these other ones like alprazilam or clinazipam for example so in the elderly stick with your lot benzoazipines and you should be good to go you can still see risk for things like you know sedation and itaxia and risk for falls and all that still applies but it's just the drugs don't accumulate and kind of linger around and overstay their welcome that's why we like those there other cases here you can see benzo being used for sedation muscle relaxation agitation seizures a lot of use cases for these very very common like I mentioned depending on the degree of lipopilicity you may see some changes in terms of onset of action um some are available IV so for instance in the hospital we use a lot of like um laorazzipam for seizure management for example we use mazzling a lot for anxilyis it really just you know you'll see clinical practice will sort of kind of dictate that um like I mentioned most benzo are going to undergo some kind of sip interactions here but agents like laorazzipam oxazipam tend to miss that so contribute to that locked group of bins as I mentioned there and then just be cautious of patients liver dysfunction they can tend to accumulate the drug and the the effects will tend to last much longer than you would have expected it to otherwise cns depression is the most common thing you're going to see with this um some tolerance will develop over time so whereas you know the dose it may be very sedated on today a couple weeks from now they may be totally fine with it um you can kind of overcome that by kind of slowly titrating up on the dose to see what they tolerate and then like I mentioned very synergistic with uh other depressants like alcohol I think a very common one um you can see things like memory impairment which sometimes we do it for that reason because if they're going for surgery for example you can use it as sort of a amnestic agent there and that's fine um and then in some cases you may find patients may develop what they call a paradoxical reaction where they get this excitation whereas you expect them to be sleepy but they're like overactive and having a lot of acsia that's usually see in kids but some adults will develop this as well big thing with this is if patients are going to be chronically taking benzoazipines you do not want them to abruptly discontinue use benzo withdrawal similar to alcohol withdrawal can be fatal because as you lose all that GABA activity you're going to start to see the balance switch over to glutamate leading to too much exytotoxicity leading to seizures you don't want that to happen so patient may be very anxious they may have tremors and sweating and may have hallucinations and those seizures can then develop so you want to be really careful there a lot of rebound anxiety as well so we needed to get patients off of these we would want to titrate slowly berron is good for patients who maybe are not good candidates for uh benzo because they benzoines are controlled substances or C4s um if you had a history of like substance abuse maybe you don't want to give them a controlled substance bpron could be a decent option here it's not as effective necessarily and it's probably kind of second line compared to um you know like your SSRIs or SNRI for example here um so overall some patient may see this as a valuable add-on others it may not get much of an effect at all it does take up to two weeks plus for efficacy there so it is a bit of a delay full mechanism we're not really sure part of it thought to be through the sort of serotonin 1A achanism here um hard to know again it's one of those things we're not really fully sure of the mechanism here otherwise it was pretty well tolerated not a huge amount of side effects here but again overall efficacy may be limited uh depending on you the patient how they're going to respond to it okay and then um one other thing we could do for patients is if we have a patient who has a performance related anxiety like you know public speaking for example is one of the most common phobias i used to be deathly afraid of giving any kind of public uh speaking and and funny now that I have a job where like just get paid to do this constantly um and so you know it's funny the other day I said something um but you know it's hard to believe you know I have a job where people pay me just to just talk at them must really like it my wife's like yeah I wish I was one of those people i was like "Well thanks dear that's so nice of you to say." Anyway love my wife but um so if you have like a performance-based anxiety so say like there's a big event coming up or you need to give a speech or play an event or whatever the case may be um a lot of the symptoms of anxiety that may show up um can be managed by the use of beta blockers so if you think about how um say before a big exam or something you may be anxious you may feel tremulous you may be sweating you're tacocardic um you know all that kind of comes across in your personal presentation and so if we can use something like a beta blocker that will block the effects of all those extra catakolamines because you're your sympathetic nervous system is going in overdrive this to block a lot of that so you may still feel kind of nervous but your body's not exhibiting those symptoms so you can speak more confidently you can reduce the tremors and the sweating and your heart rates at a normal rate they're going to be really effective so good for more performance-based type of situations um propanol tennol any of the beta blockers can be used here just list these as sort of examples here um one thing to note make sure they do a test dose prior to the event because you'd hate to have someone who's going to go for uh their their public speaking thing and they take a beta blocker and they pass out because they're you know heart rate's down in the 40s don't want that to happen so take a test beforehand determine their tolerance what type of side effects they may have and then they basically take an hour prior to the performance and that way has time to absorb get in the system and be able to help manage that anxiety there so that could be another thing uh potentially useful for that specific situation so uh generally speaking in terms of approaches to treatment for urgent symptoms we can start off with a short course of benzoazipene so say like 2 to four weeks of a short-term benzo and then we'd also concurrently would like to start an SSRI or SNRI if they're just kind of having a generalized anxiety they're not really feeling any sort of acute issues here or problems then you could just start the SSRI or SNRI they're fine um if they're not having adequate response to therapy and assuming they're being compliant you can switch over to another agent there tch would be kind of considered like a third line type of option uh if necessary so um that does it for this section today so thanks so much for joining me i will talk to you again soon bye