- To Change Your Mind - Details Matter
Tips on Medication Management: Finding The Top and Bottom of The Therapeutic Window
Every Brain in Any Recovery: Another Reportable Oversight
January 19, 2008SPECT Imaging Notes: More On “Celiac Brain” Hypofunction
January 29, 2008Why are we having so many Black Box Warnings for the use of psychiatric medications?
Find the Level
Simple answer: Many do not aim for, do not measure, and indeed don't consider that mercurial Therapeutic Window.
And the good news in this regard: it actually isn't hard to find or measure, it just takes a little more time.
The Therapeutic Window represents the body's ability to metabolize the medication effectively. Several easy rules apply here:
Dosage Just Right
– If the medication is just right in dosage and duration you will feel that you are simply floating through that effective opening no problem, and no, or very few, “side effects.”
Dosage Too Much – Top
– If the medication is too much, too high a dosage, you will have signs of toxicity, and will hit the top of the window – bump your head on the top of that window.
– Simply feels like you are toxic, it's just too much. You shouldn't feel stoned or drugged.
– Confusion, disorientation, cognitive stress, anxiety, self expression diminishes.
– With some stimulants you can feel moody and depressed all day – and relieved in the evening as they have a shorter 1/2 life with an expected duration of less than 12-14 hrs. If you feel better when they are gone from your system, – this is a big hint.
– With stimulants too high, especially some of the stimulants, you might feel buzzed, an uncomfortable intensity, too overly attentive, with angry and sad mood swings. With the methylphenidate [‘Ritalin-like'] products you may feel “stoned” if they are beyond the top of the window.
– If you feel these kind of symptoms for the first couple of days after starting a new med, usually no problem. If symptoms continue, urgency is called for and an adjustment is very likely necessary, – see your doc.
Read on for notes on the bottom of the window:
Dosage Too Little – Bottom
– If the medication is too little, too low in dosage, it doesn't appear to be working at all, you can't get into the window, and your chin keeps hitting the sill at the bottom.
– The medication simply isn't working – no side effects, no therapeutic effects, no effects whatsoever.
– Sometimes you may feel just a hint of progress during a portion of the day, but then loose the effectiveness in the PM. – Even with SSRIs at an insufficient dose they may show improvements only a brief portion of the day. Dose and expected duration of effectiveness [DOE] are inseparable measurements.
– Appropriate dosing will often determine duration of effectiveness through the day.
– DOE: Expect to loose effectiveness when the medication is only set to deliver effect over a portion of the day, as most stimulants.
– The objectives, the targets for treatment, spelled out in that first interview, show no improvement.
Brief notes on metabolism, metabolic rate, and other conditions that react poorly to the medication in question:
– New genetic studies show that many do not metabolize drugs at the same rates. Studies show that less than 50% of the population metabolizes medications at an average rate.
– Pharmacogenetic studies [regarding, in this particular case, 2D6 metabolic pathways] show that 5-7% of the population are very fast metabolizers and require more than expected doses to turn the therapeutic tide.
– Metabolism is not completely dependent on body size, and the old adage that body size, larger weight or height, suggests a need for more medications, is outdated.
– Also outdated is the cookie cutter dosage suggested by some based upon age. Each dose for each person must be reviewed at every medication check – Each individual's Therapeutic Window will tell the tale. Drug dosing, sometimes suggested on preliminary reports, can be misleading. Simply go low and slowly with everyone at the outset. Often psych medications are under and overdosed through the process of not establishing specific improvement criteria.
– With stimulant medications used for ADD: the top of the window can look like the bottom of the window, creating an apparent need for more medications in the real context of too much. Said another way, too much medication can diminish focus and attention.
Noted repeatedly at CorePsychBlog: Drug interactions clearly effect the therapeutic window.
– As we have been regularly reporting here at CorePsychBlog: Metabolic issues, such a gluten sensitivity, bowel and liver problems also challenge the expected rate of metabolism.
– And see more here at Genelex on pharmacogenetics for antidepressants and antipsychotics.
Listen: Audio On The Top Of The Window
If you have any to add please drop a comment here and we can make this a reference posting.
cp
26 Comments
CP – Sorry to be off topic on the written post — just listened to your “Ghost Child” CinchCast at right – which inspired a thought I wanted to run by you. Do you think that Harold Levinson’s success with anti-motion sickness medication/vitamin protocols, similar to that used by the astronauts before space flights” with ADDers with sensory/motor issues and a childhood history of chronic ear infections might be explained (or further built upon) by your immune system dysregulation insights? Besides my own ADD coaching manual, his DSM-IIIR-based “Total Concentration” was one of only five *required* texts (among a longer list of “suggesteds”) from Day-1 of my ADD Coach training. Although I did not resonate to all of his content, at the time, his was one of the few non-medical books discussing the importance of developing classifications based on what he referred to as “mechanisms of origin” vs. “superficial descriptions.” I appreciated his even-handed willingness to investigate and provisionally accept otherwise demonized interventions (like the Feingold Diet – “couldn’t hurt – worth trying”), his emphasis on understanding the mechanism of action of neurotransmitters coupled with his belief in the need for protein, and I wanted my students exposed to a cogent, well-supported explanation of a non-“main stream” theory of ADD to serve as a clear contrast with the nut-jobs I knew they would come across going forward. It also served as excellent background for our discussion on inadvertent statistical sampling error (“Hey, my kid’s never had an ear infection — maybe I’ll take him to that inner ear guy!” NOT) – I wanted my coaches to be trained to THINK about cognitive deficits and to be prepared to read studies yet unpublished “keeping their brains engaged.”But SUDDENLY I’m thinking it might bear an additional, closer look with your information as background. Am I totally off-base here, or might it be worth my time to embark on a concentrated reread?Interested in hearing your thoughts on the matter.Madelyn Griffith-Haynie, SCAC, MCC – (blogging at ADDandSoMuchMore and ADDerWorld – dot com!)
Mads,
You, girl, are so right on it! Got it, as they say. One of my fav questions is about ear infections and, yes, many of those folks have a big prob with executive function disorder – the pfc is not working right, but many simply don’t meet criteria for ADHD – the appearance diagnosis.
Immune testing does turn the tide in about 80% of those cases, see it *every day* in my offices and even on the phone consults in Taiwan!
I am so pleased that we found one another out here, appreciate your thinking and mission, and very much look forward to walking down that trail with you this next year!
cp
what do you mean by feeling stoned on methylphendate products concerta feel weird when it kicks in
When MPH products [methylphenidate] are dosed too high the “stoned” feeling is one of being out of it, and can’t focus, dull and mentally off – as if toxic on something, just not getting it the way you should, about two beats off of the conversation. The AMP top is more often one of agitation and anger, irritation and racing thoughts as described in this CinchCast: http://icin.ch/4A4Jc
[…] This post was mentioned on Twitter by Dr Charles Parker. Dr Charles Parker said: ADHD Meds: The Therapeutic Window cannot be neglected http://bit.ly/JH0gt #ADHD #antidepressants #Brain #neuroscience […]
Dr. Parker,
What a blessing to find your website today! Our son has ADHD as a result of a right hemispherectomy he had almost 4 years ago. He is 9-years-old and is extremely impulsive and hyperactive without medication. He has tried Ritalin, Concerta, the Daytrana patch (which worked great, but caused major skin irritation and he started pulling it off at school…oh no!), Vvyanse (sp?) and is now on Intuniv. The first week or so on Intuniv he did really well focusing at school and he stopped picking his cuticles and nose (something he was doing to the point of having infections near his nail beds, which is why we stopped the Ritalin — 15 mg 3 times a day). Another reason we stopped Ritalin was it was not working as well (within 2 or 3 hours he was hyperactive again and picking his cuticles more). He has also gained 8 lbs since being on Intuniv, which is great, as he was not gaining weight on the Ritalin and he is in the 40th % for weight. He has been on Intuniv for over 4 weeks now (3 mg now) and has major insomnia. He did not have this before taking Intuniv. His teachers have also noticed he is not focusing as well and doesn’t seem to have much interest in school work, which is not like him at all. He sleeps great from 8 to midnight and then wakes up, says he is having bad dreams and can’t get back to sleep until 3 or 4. He is currently taking 3 mg in the morning. We have tried 2 mg at noon and 1 mg at bedtime. We have also tried giving the entire dose at bedtime (we do not cut the pills; we have both the 1 mg and 2 mg doses), but he still wakes up. Other medications he is taking are: 10 mg Baclofen for musle spasms 3x/day and Prevacid for GERD 15 mg 1x/day.
We are exhausted and want another expert’s opinion on what we should do next. A pharmacist said maybe we should have him try Ritalin SR, but we worry about weight-loss with it staying in his system 8 hours and we are concerned he will start picking again. But we have to get some sleep soon.
Thanks in advance for your help!
Sincerely,
Mary Lou Meier
Mary Lou,
Night presses forward out here, so will make this brief. Your last remarks turn the tide. The GERD is the bell weather as is the eating issue and the muscle spasms. Too easy to think it’s all neurological. Strongly recommend you listen to this CD by Mark Laponis, MD [longevity is always on the table with chronicity] so you can catch the drift of where I am going with the immune system break down topic. We have seen many ‘brain injury’ presentations and they have all done quite well with NeuroScience testing and targeted neurotransmitter precursors… once we know the exact immunity issues.
In a word, I really don’t think you will have a lot of success until you get those specifics on the table… been there done that.
cp
Dr. Parker, My doctor started me on 70mg Vyvanse on Monday, Jan. 24th. I don’t think I’m getting the results I should. I can focus (for hours) but I have zero motivation to do anything other than mess with the computer. I spent something like 4hrs writing a letter to PayPal obsessed with formatting it. And while doing other PC stuff I discovered Microsoft Office templates and themes, a theme builder program and Vista themes. Since starting Vyvanse I have done nothing but mess around with customizing stuff on the computer. I haven’t even showered. The focus is a welcome addition but for me focus without motivation doesn’t provide much results. Lastly, I’ve been quite tearful. Do you have any idea what may be going on? I truly appreciate your time and it’s wonderful you have this blog. I’m definitely going to read through everything you have to say about ADHD. Again, thank you Doctor.
Kim,
You are very likely coming out the Top of the Window… over focused, but almost over thinking, and I’ll bet your DOE is more than 14 hr with appetite decrease and sleep issues present – tell me if I’m wrong.
Take a look at this link on the Top of the Therapeutic Window. Another hint: started you too high right off the bat, with no time to adjust. Suggest using the water titration with your docs approval and start lower, work slowly up to the right DOE, then use that specific dose.
cp
Dr. Parker,
I have found your comments to be quite useful. I’ve been taking Vyvanse 60mg for about 8-9 months if I had to guess, and I originally started Vyvanse at 50mg almost exactly a year ago. I haven’t missed too many doses, but occasionally I’d miss a day – in rare instances, a few days in a row – and would continue the next day with little to no side effects, though on occasion I would experience 2-3 days of abdominal cramps after resuming the dosing. After about 6 months or so I began to only feel effects of the drug for about 2-4 hours after my dose, immediately following a long comedown with opposite effects (feeling spacey/out of it, depressed, antsy and moody/agitated – I very rarely felt any of this pre-V). Is this the top of the window, or the bottom in disguise? Despite the negative effects, V has almost completely cured my anxiety and anxiety attacks. He upped my dose to 60mg after telling him the effect was short and the comedown longer. Seemed to only increase intensity of the focus and social euphoria, not extend it. On top of that, it made my OCD worse – there was intense focus on little random OCD-like movements/routines. I normally only had slight OCD, but upping it added new “ticks” (mainly involving blinking or vocal cord noises). I should note that neither the pre-Vyvanse nor post-Vyvanse OCD was ever inhibiting and most people don’t seem to take notice, it’s just aggravating.
One more important note I know will make a big difference in this diagnosis: Since I still have a short 2-4 hour DOE, I’ve been taking the pill at around 5 or 6pm rather than noon like I did on 50mg. As you mentioned in a comment, I fall into the category of people who have somewhat attention-demanding evening routines and it’s really helped my focus incredibly at the time of day I need it to – but generally kept me to only about 4-5 hours of sleep a night. I’ve always been a night owl, never had insomnia problems, but I know dosing too late in the day has affected me negatively. Little to no sleep gives me an even more weak, shorter DOE; 6+ hours at night gives a higher & intense peak effect, but only 2-4 hr DOE and still a long comedown. It’s driving me crazy!
How can I fix this? The past week I’ve been taking it 2 hours earlier at 4pm to eventually get my dose time to noon. Vyvanse reduces my appetite dramatically, and my doctor said taking it with lunch would be OK as long as I was getting 6+ hours of sleep. But how should I handle the dose change? Should I take it an hour earlier each day until it’s at noon? Or should I immediately start at noon? My doctor hasn’t been too helpful when I tell him about the OCD, depression and short DOE and I have no idea what to do, when this medicine works it’s changed my life!
Zach,
The subtlety of this presentation makes it difficult to draw an exact bead on what is going on – but it sounds like you are doing it incorrectly to me, and likely to your doc if you talked to him about the evening dosing etc.
1. Going off and on and GI upset: very likely no protein breakfast. I’ll bet your protein intake in general is short from what it should be, and your neurotransmitter pool is down.
2. Sound like the top of the window to me. Onset should be 1/2 -3/4 hr max. Long onset I always think too much. Thinking you are ok with the dose is also often a part of the presentation of being to much.
3. Read my new book [Patient’s Guide for ADHD Medications] when it comes out on sleep, Chapter 12, am working to finish it up, will be out soon. Your sleep is contributing to your problems and you are relying on Vyvanse to fix the inadequate sleep – which it is not designed to do!
4. Late PM doses almost always mess with the sleep onset.
5. You are feeling crazy because you are chasing the dragon, and need to slow down, and restart at a lower dose. You will know the dose is right when you have that time noted here on the onset.
6. You might do better with a lower dose 2X/day to cover your evening if you go past the 10-12 hr DOE it can provide if correctly adjusted.
7. The theme here is simple: If you are struggling just measure neurotransmitters/amino acids, period… – and assess specifically what is going on, so that imbalances can be precisely corrected.
cp
[…] DOE [somewhere over 12 hr with some folks]. Said another way, sounds like you are coming out of the Top of the Therapeutic Window. These findings in the office are less common, as many adults have done well in specific work […]
I am currious to find out if a combination of Strattera and Adderall ir could be used effectively and safely. The reason I’m asking is because both medications improve different symptoms of my ADHD. Strattera Pros: improved my mental accuity, short-term memory, and it was consistent the whole day with just one dosage in the morning. The cons with Strattera were that I had become apathetic/detached, general loss of interest, my personality was flat, groggy, decreased libido and my creativity decreased greatly. When I first transitioned off Strattera to Adderall ir, I noticed that most of the Strattera side affects were gone. Even my focus was better on the adderall, but it seems the Adderall is not really helping me in the areas that I had improved in with the Strattera. In addition the adderall was inconsistent throughout the day.
I need consistency in these areas throughout the whole day, because I’m in sales which often requires me to be on calls or entertain clients until later at night–well after the adderall wears off. I’ve followed your dosing directions by figuring out the DOE and Therapeutic Window. I’ve thought about Vyvanse, but that won’t cover me if I have to be “on” for 18 hrs.
Kevin,
Right, Vyvanse won’t cover you for 18 hrs [would likely be an overdose with side effects], but if you wish to take Vyvanse, you might delay taking it to later in the day, then set the objective for the 12-14 hr DOE as fits with your work experience when you have properly titrated it with your doc. Don’t take it too late, will keep you unpredictably awake. Finding the window is quite easy if you simply pay attention to the DOE.
Usually Strattera performs almost exactly as you described, but often without the positive effect. My guess, subject to your review with your doc, is that the IR Adderall wasn’t dialed in sufficiently to cover the desired time slot for the day. When the IR is topped at it’s best dose, metabolically tightened up for the best efficacy – should be in the range of solid 6hr DOE. This procedure will, of course, leave you with the problem of multiple dosing and some work to get the AM and PM doses down, as they do, quite often, differ [I suspect it has something to do with the variables of acid base balance and bowel transit time changes – but have no specific references – only makes intuitive sense].
The good news is that the AMP molecule is OK with your 2D6, and the only challenge before you, as it is with everyone walking in the door, is understanding and correcting the DOE for max efficiency.
I have some students and professionals like yourself, who, because of the evening requirements, go with a good aerobic exercise in the AM, a cup of Starbucks, and a dose in the 9 AM range which will give you about 11-12 midnight range as your DOE objective. Remember, the closer you go to 12 Noon for the dose, the more apt the med will be to last too long and interfere with sleep.
Hope this helps,
cp
[…] have been writing about the burn rate, the Therapeutic Window, and the Signature Individuality of biological-metabolic rates for more than two years, lecturing […]
thanks for your encouraging comments on our MentalHealthCamp project!
i was really happy to read this post. the fact that people react differently to medications and doses at different times and under different circumstances is often completely ignored. the human body is an incredibly complex organism, each with his or her own biochemical fingerprint.
thank you for your great work!
Isabella,
Many thanks for your kind remarks, please do keep me posted – so much to share out there, and I appreciate connecting with those of you who are pulling together protocols for even better communication.
cp
Jackie B,
I have paused for a moment in the foyer to put my dancing shoes on…
What I am about to tell you is from my own experience, and is documented somewhat indirectly in the drug interaction book on my website bookstore [Cozza and Armstrong], but has not found it’s way to the literature yet.
I say “indirectly” because Vyvanse is not in there, only AMP as a class is documented.
Amphetamines “as a class” run up through [are “substrates” of] 2D6, just as Strattera does. The interaction, the drugged effect with the Strattera and Paxil, as your doctor suggested, is predictable, did happen, – but is, from my own personal experience, not manageable *for the long run.* – Often works for short bursts, maybe 2-6 weeks, then the fog with the Strattera rolls in, out the top of the window. Right on the objective, but with duration over time, the objective is lost to the narrowing of the window. The DOE becomes almost completely unpredictable, and therefore not a useful tool in the necessary careful titration.
The reason, from my own experience, is that the therapeutic window narrows with this intentional or unintentional drug interaction. -[another post on this soon, since this narrowing of the window phenomena appears to be coming up quite frequently, here and with second opinions]
Said in a slightly more technical way: Since the rate of metabolism is itself unpredictable, and that unpredictability is modified in a relatively unpredictable way by using one drug to augment another, the process often becomes unglued and unravels.
AMPs “as a class” are 2D6 substrates, and, yes, the last pass on AMP metabolism is through the kidney, but before the kidney it passes through Phase 1 metabolism: CYP450.
My thought in this matter, subject of course to your doc’s approval, would be to open that therapeutic window with a different, cleaner antidepressant, one that is more clearly open on 2D6 than Paxil or Prozac, both significant inhibitors of 2D6, and therefore on my not-a-favorite list.
The next likely question has an off label answer, in that most antidepressants have no clear indication in children and adolescents with the FDA: Which antidepressant? Here is where I put on my shoes and carefully pass the ball back to your doc.
In my office under most circumstances I would use Effexor XR [very clean on 2D6], but this space does not give enough of a forum for all the variables, the history and necessary review. I would stay, at this moment, with the Vyvanse, expect the window to open with a cleaner 2D6 antidepressant, and then after could more successfully titrate the stimulant dose with the DOE.
Having said all of that – one more caveat: As much as I do like Vyvanse, it’s not for everyone, as some individuals genetically have a harder time with AMP molecules, period.
For those next changes I turn to your doc to see what he/she says.
Interesting question, more posts on these issues from back about a year ago here on this blog. Google “2D6” on CorePsychBlog for remarks on AMP in general, pre-Vyvanse.
Thanks,
Chuck
Dr. P,
I just read your fascinating drug interactions section, and have a new question about taking Vyvanse and Paxil together.
Background – my 14-year old daughter w/adhd could never handle the stimulants (anger or dysphoria) and Strattera was ok but not optimal in terms of efficacy, or even DOE. So in the fall our doc added Paxil in the hopes of actually using the 2D6 pathway to improve the Strattera performance. Unfortunately, side effects increased, particularly sedation and brain fog, with little added benefit. So, in December we switched from Strattera to Vyvanse, leaving the Paxil (15mg) as is so we would not be changing too much at once.
The Vyvanse has been less irritating than past stimulants and more effective than Strattera, but we have been finding trouble finding that therapeutic window: the low dose stops working in the mid-to-late afternoon (leaving her more impulsive and hyper than she ever was) yet the higher doses (which definitely last longer) create anxiety, social paranoia and obsessive nail biting.
So after reading your earlier posts, my question is: could it be the Paxil really messing up the Vyvanse picture? BTW, our doc was going to have her next try taking Vyvanse 30mg TWICE a day (morning and afternoon) to try to increase the DOE without the side effects — but is very open to input and would consider dropping the Paxil if that is a likely culprit. Your experience in this area would be invaluable!
Peter,
Your history strongly suggests a problem with every stimulant molecule and modification thereof. Methylphenidate and Amphetamine molecules all appear to suffer the same consequence… rapid toxic-like effects.
This appearance almost always is associated with metabolic challenges, likely bowel or general GI, seen in the North [GERD] or South [IBS, Constipation, etc] or both. These issues clearly need more investigation.
-Sounds like you need to have a workup with your doc for gluten sensitivity or other significant metabolic problems, as your metabolic system is too sensitive to even disproportionately small doses.
Hope this helps, – please let us know what your find out.
Chuck
Rhei,
Thanks for your kind comments. The path is never direct, but the markers will keep you going in the right direction.
Chuck
Betsy-
Your careful discussion about the top and bottom of the window with your daughter does help flesh out the nuance of *too much at the top* with Adderall – and the dulling too much can cause on any med.
Vyvanse most often does a better job with the top and the *dulling* there, but at 8 Hr DOE, appears to be too short, and therefore slightly insufficient. I suggest you ask your doc about going to 70 mg as most of the time that works to carry on for, in her case probably 12-13 Hrs DOE.
But your brief review does leave me with a caveat… It does sound a bit like she is a slow metabolizer [genetic – 2D6?], or is suffering with some other primary metabolic slowing pattern such as a bowel issue, that could diminish the liver clearance.
Please take a look at these issues with your doc and let us know how those observations work.
Hope this helps,
Chuck
This will be a big help for me and to my family members. Thank you! I can advice them about the proper medication. Keep on posting so that I have something to share with my relatives and surely we’re going to be healthy if we follow this.
Thanks for your article.
I was recently diagnosed with ADHD-Innattentive type. Concerta and Vyvance made my heart race even at low dose. Strattera removes anxiety and makes me more alert, but not better focused. Focalin at 2.5mg is the first one that actually works. But, my psychiatrist said I could take Strattera and Focalin at the same time (25mg x 2 of Strattera). I’ve had side-effeccts but too soon to blame any interaction. Could there be one?
Hi Dr. Parker,
I wrote some while back about my 15-year-old daughter on Vyvanse after 8 years on Adderall IR.
She had tried Adderall XR at some point and the dose got too high, marked by slo-o-wed mentation and weekend homework output (always verrry slow, anyway). I wrote this down: when meds were likely at peak, she sat for two and a half hours and wrote (not distracted, but actually on task) exactly 23 lines. She was in fifth grade. Later in the evening (meds wearing off), she sat and wrote 57 lines in 45 minutes. She was herself again, and for her age that was a reasonable rate (her prolific style has been the bane of her academic life, though — there are penalties for the children who are born observers and writers!).
Now, the only times I thought she was taking too much (i.e., at the top of the window and beyond), she has been slower. Never agitated, buzzed, etc. Sense of humor missing. She herself says, however, “I know I would not have any friends if it weren’t for medication.”
Now, on Vyvanse: she is still noticing a fall-off at 8 hours. I know with Adderall, a higher dose to start often made it last longer, but one can take only so much, it would seem, without blowing out the top of the window.
I know you cannot advise me directly about this youngster, but as a matter of science, is it likely that if someone fading out cognitively at 8 hours, it could be illuminating — and potentially beneficial — to increase, with her doctor’s approval, the dose by a small increment to observe cognitive phenomena as well as DOE?
While Vyvanse so far is available in 30, 50 and 70 mgs. and she takes 50, it might be necessary to divvy up the powder to keep the increase small.
Any ideas? I am also keen to know what your patients do even when they obtain 14 hours’ of coverage, with the last 2 hours and more, if they need stimulant for sleep?
Thanks for your time and your excellent blog. It’s informative and the comprehensive approach is of course exactly what is needed in this world.
Betsy Davenport, PhD
Beautiful, clean summary, Dr. P! Thank you.
This is so helpful for patients to read before they ever begin medication treatment.
Unfortunately, too many physicians just don’t know what it means to “start low, titrate slow.”
Gina