Why are non-stimulants like Strattera less effective than stimulants like Ritalin and Adderall for ADD?

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Why are non-stimulants like Strattera less effective than stimulants like Ritalin and Adderall for ADD?

In: Chemistry
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This is where the dopamine hypothesis for ADHD starts to break down. As a little bit of background, Strattera was approved because the FDA was desperate for a non-stimulant medication for ADHD (I have some more background from a practitioner who was there when Strattera was undergoing FDA evaluation and the BS Eli Lilly pulled once it was approved).

Anyway, the current hypothesis is that stimulants act as stimulants (i.e. cause stimulation) by increasing the concentration of dopamine, serotonin, and norepinephrine in the brain. So the theory was, let’s use other things that increase those same neurotransmitters in the brain but aren’t stimulants. Enter atomoxetine (Strattera), a failed antidepressant that some thought helped for ADHD (spoiler: it didn’t). The proposed mechanism for atomoxetine was that it would increase the concentrations of norepinephrine and dopamine in the brain.

One of the current theories of ADHD is that there is a deficiency in dopamine. However, it can’t be that simple. Why? Look at atomoxetine. It increases dopamine selectively in the prefrontal cortex (the area of the brain some people think is the area that ADHD affects). Atomoxetine does not work well at all for ADHD. So what if we supplement with dopamine directly? You can’t take dopamine as it is because it doesn’t cross the blood-brain barrier, so you have to give L-DOPA (the precursor that gets converted to dopamine in the brain). That also doesn’t treat ADHD at all.

Let’s move on to the stimulants. There are 2 forms of amphetamine (dextroamphetamine and levoamphetamine) and 4 kinds of methylphenidate (MPH) (dextro-threo-MPH, levo-threo-MPH, dextro-erythro-MPH, and levo-erythro-MPH). Of those 6, only dextroamphetamine and dextro-erythro-MPH treat ADHD effectively. What makes those special? We don’t know. If you look at any package insert for any stimulant that is used for ADHD, you’ll see the language “the exact mode of therapeutic action in ADHD is unknown.” Anybody who says they know how stimulants treat ADHD is either lying or misinformed. We know how stimulants act as stimulants, but we don’t know how they treat ADHD. And it has to be something other than stimulation, otherwise all the forms of amphetamine and methylphenidate, plus cocaine, caffeine, MDMA, phentermine, etc. would be useful in treating ADHD. But they’re not. And think about what happens when somebody with ADHD takes a stimulant medication at a therapeutic dose : they SLOW DOWN. For some people, stimulant medications help them SLEEP (!). I have my own theories about how stimulant meds work for ADHD but this post is too long already.

So to answer your question: Strattera doesn’t work as well as stimulants likely because its design was based on a faulty interpretation of how ADHD works. We don’t know why some stimulants work, but we know that they do. Much of the pathophysiology of ADHD is still being uncovered, but be wary if anybody ever says “oh, we just need more dopamine.” It’s almost certainly not that simple.