I'm Dr John Cru and today I'm going to be talking about combination medications for ADHD so as usual I'll start with the take-home message and then after minute or two I will launch into the main message if you have questions you can type them into the comment period and I'll launch right into it so combination for medication is combining different agents different phac pharmacologic agents so I'm not talking about here combining talking therapies most often cognitive behaviorally based and medications there's a good role for that and that's valuable to do here I'm talking about combination medications so one this is fairly commonly done two the FDA does not has not approved any F any ADHD medication for use with others it doesn't ban that use but as only all the medications that have been explicitly approved for treating ADHD are explicitly approved for using as solo agents three most of the research out there is just descriptive it's just telling us how frequently combination therapy happens what which drugs it's most common with what combinations are most common which patient populations within the ADHD Community are more likely to receive this but there are a few randomly controlled studies and a little other evidence looking at two particular combin ations One is using atomoxetine stratera plus a stimulant and the other body is of research is looking at guanosine or Alpha 2 Agonist agents in combination with the stimulant and my distillation of both of those Bodies of Evidence is that there is some evidence that those combinations can lead to enhanced benefits so greater control of ADHD symptoms and they do not appear to increase any medication side effect risks or problems and you know there are some studies not where it's not clear that there's actually an added benefit from that combination but overall there's some support for some so I'm going to launch into the main topic main Talk itself why would you need to combine medications aren't stimulants powerful enough aren't they dangerous enough themselves you want to be adding something else to it so part of it is that even though stimulants are clearly all the research would suggest the intervention that's most likely to result in substantial symptomatic relief and relief symptoms to the greatest extent there's very few people who get total relief of all their ADHD symptoms from stimulant medications now I would argue that part of that at least is that we're talking about about not just a neurochemical deficit or problem but a circuitry and connectivity how the brain is wired and I don't think any medication is likely to completely eradicate that but there are certainly people who get some many people get substantial relief but have room for more relief from their symptoms so the thought is combining a stimulant usually and and most of this can talk about combining nonstimulants together but most of this is talking about combining stimulant medications so the rationale for adding on something is that you can get a stronger effect you can just hit dopamine or norepinephrine you know twice as strong or more potently with two different effects or that you may get some Synergy from having using agents that are working in two different ways so again most of our our stimulants are strongly promoting the release and availability or re-uptake and and availability of dopamine and norepinephrine but we have another class of drugs Alpha 2 agonists primarily guanine which is working on a different alpat 2 receptor is a neopine phrine receptor but this isn't just causing More release from the cell bodies it's modulating cells that are actually usually getting glutamate neurot receiving glutamate input and modulating how the cell processes that glutamate input so there maybe again complimentary or synergistic approaches from using different classes of medications together another area is that even though we have a range of stimulants that operate over different periods of time some are immediate release some are intermediate acting some are long acting often the intermediate or long acting just don't work perfectly well to cover the day or cover the period of time that someone needs adequate relief from their ADHD symptoms so there can be benefit particularly to adding on a short acting stimulant also some people might need additional boost beyond their Baseline boost during specifically difficult tasks so augmentation with a short eing stimulant can happen there and in the reverse picture sometimes adding on an agent like atomoxetine can help cover the end of the day periods when the primary stimulant is wearing off or subsiding in its action so those were all sort of augmenting or getting more complete relief a related topic but a slightly different one is some people can't tolerate the full dose of a stimulant because of their side effects and again adding on a combination agent may help get them to that same symptomatic relief level with fewer side effects because the augmenting agent is milder in terms of side effects or in particular and we'll talk a little bit about this with guanosine secondary augmenting agent itself May modulate someone's brain so that they can tolerate a bigger dose of the stimulant or they couldn't tolerate for so two other big reasons to go for combination therapy is that the stimulants themselves can cause side effects that are problematic so one is insomnia is common in ADHD to begin with but we know that there are some many individuals with ADHD actually sleep better and have more regular sleep awake Cycles when they are taking their stimulant but there are some individuals who clearly have insomnia worsened by a stimulant medication and augmentation either with sleep agents specifically or with mapine which is a sedating anti-depressant have been shown to be helpful in that situation there's other side effects of stimulants such as ticks can be associated with taking stimulants which can be improved by anticho discs so there may be reasons to add on an agent just to combat primarily a side effect or adverse effect or what some would call an Associated condition and then the fourth reason for combination therapy is we know that individuals with ADHD are more likely than the general population to have any number of other different conditions including depression PTSD anxiety syndromes including social anxiety bipolar disorder so a second psychoactive agent may be useful or even necessary to combat or address that Associated condition research shows that it depends on what population you're looking at in terms of how common combination therapy is so one of the first earlier studies was a 2009 study where they looked at in the US 18,000 individuals with ADHD this was from Insurance Company claims report and they found that of those who were taking stratera atomoxetine 20% were taking another agent as well combination therapy for those on a long acting stimulant 20% 21% were also on another agent as well for those with an intermediate acting stimulant the rate was combo therapy was 27% for short acting stimul therapy their rate was 23% for those taking bupropion while Butrin for ADHD 37% were on another drug as well and the group of drug in this and it was mostly guanosine but they classified it as Alpha 2 agonists more than half 53% of individuals with ADHD who are taking Onin or an alpha 2 other Alpha 2 Agonist were also taking some other type of ADHD medication another claims study data in 2015 by mol and others looked at more than 200,000 kids so much bigger population sample this is also in the US kids between the ages of 6 and 17 so 211,000 kids with ADHD and only about 10% of those kids were on combination therapy but of that group if you were on a short acting stimulant almost half so about 45% of those who were on a short acting stimulant were also on another agent and of the group taking the alpha to agonists more than half so 54% of those individuals were also on a second agent and they compared that group so that was what a children who were insured by a commercial insurer when they compared that to children who were insured by Medicaid so in the US that means low income status so that group was about 125,000 individuals substantially higher percent percentage of individuals with ADHD were on combo therapy so it was almost a quarter 24% rather than just 10% and if you on a short acting stimulant 70% of that group when it was only 45 were also on an additional agent and also the guanosine group the group that was on Alpha 2 agents 64% of those individuals were also another additional agent so in this population and there's some indication that there are higher rates of hyperactivity this may be a more severe group of ADHD people with ADHD symptoms we know that socioeconomic status is associated I'm not saying caused here Associated more severe ADHD so it's not at all clear whether this higher rate of combination treatment was this is actually a more severe or different group of individuals with ADHD or because of socioeconomic status and other factors they were treated differently within the system and got different medications or maybe were less likely to get long acting agents so one other study a little more recent of 20121 study done in Korea this was a much smaller study looking at who showed up at an Outpatient Clinic University based clinic and only 5% of their ADHD patients were getting a combination of medications and that was both atom oxine stratera and methylphenidate now in Korea and in much of Southeast Asia compared certainly to the US there's much more restriction or limitation of amphetamine-based products depends what population you're looking at in terms of how common combination therapy is so what are the benefits of combination therapy or have we shown them so looking at the stratera plus stimulant combination and this is from a metaanalysis by Troyer and Associates children with combined ADHD were more likely to receive combined therapy combination of Strater plus a stimulant and purely inattentive males who were over represented in the ADHD population anyway and children who are over represented in the studies were more often receiving combination therapy the agent most often combined with methylphenidate was draa at oxidine and their assessment was that some of the studies did show that there was Improvement in the combination of the two compared to just stimulant alone or compared to just sta alone if that was done but there were some studies that didn't were unable to show a difference that doesn't mean again there wasn't a difference there it was just unable to show it and also fairly pervasively they did not find any increase in serious side effects from this combination of medications situation where we have some amount of research is looking at guanosine the Alpha 2 Agonist combining that with the stimulant and there's some studies suggesting that particularly inattentive symptoms may be improved by that combination compared to just the stimulant that measure called the CGI it's a global measure of psychiatric health so this is not just featuring ADHD symptoms that there's some Global Improvement and functioning with combination there have been at least one well- conducted pharmacologic study looking at no changes in the profile in terms of how much is released area under the curve or Peak levels or duration so there's no pharmacokinetic interaction between Quan facine and stimulants that are preventing or seriously interrupting the timing or delivery of one drug is not affecting the other and there's at least one study that showed of people who were on stimulants but had poor adherence that just the addition of Bon facine increased the consistency of taking your stimulant medication one of the other questions regarding other than just combining prescription medications together for ADHD that I get a lot of questions is is it okay to combine supplements so things like fish oil or Ginko or jinang and there's even less study or research on those the little bit we have suggests particularly for fish oil Ginko jinang penol that there may be some additional benefit from adding on these agents there have been no health risks or dangers identified so far of combining any of those with stimulants the One supplement that's had studies indicating no particular benefit of adding it to stimulants for ADHD as St John's work there was one preliminary study suggesting it might be helpful but a larger controlled study didn't find any benefit other area where there's not a whole lot of rigorous research at all is that when someone has a comorbid condition is it appropriate is it helpful to use an additional agent and I would say particularly in my practice even though the stimulants and other ADHD agents May themselves have anti-depressant properties I've certainly seen people who continue to have depression in the setting of being on a stimulant or being on onine or being on stratera and very often adding an SSRI or more often I'd add an snri is helpful for allevia depression in that setting more often I would use an snri something like d oxidine symbola because to me it makes sense if it helps you lower the rate of or lower the dose of your stimulant that may be beneficial in terms of reducing chronic lifelong side effects and snris are probably more effective anti-depressants and pure ssris in terms of complete alleviation or reduction of symptoms in terms of just response rates so far the data suggests they're roughly similar even though and I've talked about this before anxiety can be alleviated in a setting of ADHD by stimulants or treatments targeting the ADHD because having your brain respond in a way that's more reliable consistent predictable and controllable can reduce anxiety but there's certainly many people with social anxiety or other anxieties on ADHD medication and those ADHD medications can actually exacerbate anxiety so very often adding an SSRI or an SS snri to a stimulant can help in that situation with comorbid OCD and again I have talks on that adding an SSRI or an anticho can be helpful as I mentioned previously for tick disorders getting an anti-yo can be helpful when I Was preparing ing for this talk I actually decided to just look at the last 100 patients I treated with ADHD so I this is not a systematically done study I just wanted to see how often I was using combination medication so out of that 100 I do have five people who were not on any medication for their ADHD using primarily CBT DBT and other behavioral approaches 41% I on a single agent some of those were on a single formulation of a stimulant some of those were on a single formulation of a agent like buproprion or duotine or guanosine and more than half so 54% of my individuals that I'm working with for ADHD were on more than one agent very often so that included people who are on two different stimulants a short acting and an immediate and then a acting or who might be on a stimulant and guanine might be on a stimulant and duotine or bupropion or atomoxetine so I have a variety and I did not systematically study it I think a majority of those who were on combination were on combination because they had a comorbid condition but have people in all the categories I outlined earlier so the next question is how do you combine medications so my thoughts here are one is you should be targeting ahead of time what symptoms what you're trying to improve if you're adding on a second agent should have a good idea what are we looking for is it or help with sustain detention is it for help with being less impulsive in certain situations is it reducing hyperactivity is it to get better coverage in the evening than you have so be aware of what you're actually trying to achieve when you're adding on a second agent second point is I'm not the biggest fan of using ADHD scales particularly to diagnose ADHD but I think this is one of their most useful applications is and again we have many different ADHD symptom scales usually based on the 18 DSM criteria even though these are trying to be specific for ADHD they are influenced by other things going on someone's life but they can be a useful way to track whether adding on medication or adding on a second medication is leading to symptomatic Improvement and if you do those scales I'd recommend doing them at the same circadian time of day because circadian rhythms affect attention and other executive functions and also be aware that even though these scales were designed to monitor ADHD and track that I've had people who were using using them and when the election results came by recently or leading up to the election results either anxiety depression other mood factors changed their ADHD scores I don't think it fundamentally changed the extent to ADHD but it changed how they responded on a scale that's supposed to measure ADHD so the third principle when adding on a second agent is start with the low dose and monitor what the results are so not just symptomatic reduction but what are you seeing in terms of side effects benefits again sometimes a benefit is that you can lower the dose of the stimulant that you're on and there is some growing evidence that some of the uncommon but highly undesirable effects of stimulant are related to dosage I mean that there's been assumption that that's been true for years but we're getting more data so specifically cardiac X specifically rates of psychosis seem correlated with the bigger dose you're on so these specific instances where I found combination therapy particularly useful and these are not novel to me these are many other ADHD treaters describe this as well so one is that certain individuals who stimulants just rub them up too much feel too jittery too overactivated and can't even tolerate a low dose many of those individuals after a few several weeks of being stabilized on guanosine can actually calor a stimulant much more than they were able to initially so that combination often works well and also certainly use a short acting stimulant to help extend the life of an intermediate or long life stimulant in a somewhat related fashion I have a handful of people who are in addition to their daytime stimulant are taking a low dose often of methylphenidate but I have at least one person who takes 5 milligrams of at all right before bedtime because that helps them control Coral their thoughts and put themselves to sleep and again I certainly have worked with a lot of people where using an SSRI or more often an s SAR to treat anxiety where depression is absolutely helpful and essential to addressing the combination of anxiety depression and ADHD so that's all I have to say for today stay healthy stay happy and I'll be available for questions and answers about this either in the written comments or my weekly Q&A session