Category Archives: Uncategorized

How Stimulants Control Hyperactivity


I recently stumbled on this article that talks about stimulant medications and how they reduce hyperactivity — a phenomenon which seems at first glance to be quite paradoxical. The dopamine receptors called DRD4 located in the basal ganglia and neighboring brain regions are responsible for this effect; in rat studies, DRD4 knockout rats (rats genetically modified so they have fewer to no DRD4 receptors in these areas) exhibited greatly increased motor activity (i.e. the fidgeting and bouncing off the walls I’m sure so many of you are familiar with!). When these rats were treated with amphetamine, their excess motor activity (hyperactivity) disappeared. There’s more to it, naturally, but that’s the crash course.

This intrigued me for two reasons:

One, because this means that hyperactivity is probably inherited genetically, for the most part, and perhaps is somewhat independent from other aspects of ADHD (inattention, impulsivity, etc). This could lead to more refined subcategories of ADHD, and hopefully to more individualized pharmacotherapy if Big Pharma ever gets around to updating their hopelessly antiquated stimulant formulations (this shit’s been around since 1937, we’re ready for version 2.0).

Two, because this suggests that ADHD arises from dysfunctional DRD4 receptors in SUBcortical areas (lizard brain areas) rather than in the prefrontal cortex (associated with planning, working memory, impulse control, sustained attention, etc). Non-stimulant medications such as Strattera and Intuniv primarily target the prefrontal cortex and exhibit little to no effects in the subcortical areas, whereas stimulants target both the PFC and aforementioned “lizard brain parts” — and as we all know, stimulant medications are far more effective than any other available treatment.

Moral of the story: the ADHD kid’s lizard brain is tragically messed up, and apparently we all need a properly functioning lizard in our brains in order to sit still and be boring. Damn lizards.

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Trash day?


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Oh you know, just… half my college career’s worth of garbage.. no big deal.

Ketamine: the new Prozac?


Though my pharmaceuticals of choice are certainly not in the same class as the SSRIs, I was nonetheless intrigued by this article  about NMDA-receptor antagonists producing virtually instantaneous relief from depressive symptoms. Ketamine, an anesthetic and sometimes horse tranquilizer, may provide new insights into the way we treat depression.

But let’s start with our current standard: fluoxetine. Also known as Prozac, it is perhaps one of the most well known pharmaceuticals on the market, and is currently the most prescribed medication in the US. It’s prescribed for a variety of conditions, including Generalized Anxiety Disorder and Major Depressive Disorder (or, Clinical Depression). What is less widely known, however, is that neither doctor nor pharmacological engineer truly understands how or why it works – and doesn’t work – and, in fact, a large body of evidence indicates that it is no more effective than placebo. This isn’t a vendetta against Prozac, mind you — most of the newer antidepressants, particularly those in the class of drugs to which Prozac belongs — Selective Seretonin Reuptake Inhibitors, or SSRIs — have been proven no more effective than placebo time and again in various clinical trials. Clinical trials that produce unfavorable results or that are inconclusive often go unpublished, while one or two trials with positive results ensure Big Pharma turns a profit on their (multi-billion dollar) investment. It all sounds a bit suspect, but considering the astronomical risks they’re taking… I can almost look past it.

In any case, Prozac and other antidepressants are used primarily to treat Major Depressive Disorder (MDD), a psychiatric illness afflicting millions of Americans. MDD is characterized by: a loss of interest or pleasure in activities that used to be enjoyable, insomnia and/or sleeping excessive amounts, fatigue, lethargy, feelings of worthlessness or inappropriate guilt, poor concentration or difficulty making decisions, and thoughts of suicide or death. These symptoms must persist for at least 2 weeks in order to be diagnosed as MDD.

Now, although Prozac is often helpful, it carries quite a side effect profile with it. Compare the symptoms of depression to the adverse effects associated with Prozac:

aggressiveness, impulsiveness, irritability, restlessness, or inability to sit still; severe or persistent anxiety, trouble sleeping, or weakness; suicidal thoughts or attempts; tremor; unusual or severe mental or mood changes; unusual weakness; and worsening of depression (among others

Interestingly, the side effects of Prozac seem to coincide for the most part with the symptoms of MDD itself. Though it is unlikely that a patient would experience even a small proportion of the potential side effects, it is nonetheless a peculiar similarity. Although Prozac may often prove effective, most studies indicate it’s no more effective than placebo — and its side effect profile suggests we have no idea how it’s producing the positive outcomes that we do see.

All right – it’s starting to sound like I’m on a soapbox, so I’ll step down from my unintentional tirade. I won’t deny that SSRIs DO help a lot of people, even if we don’t know why, even if we have to deal with a number (WITH A SHITTON) of unpleasant side effects. The plot really started to thicken for me when (flashback to the beginning of the post — remember the link to that article about ketamine? Here I come, making a point at last) I read a new study which examined the antidepressant effects of a SINGLE dose of ketamine — administered intravenously – effects which caused total remission of symptoms in a majority of cases and which lasted a full seven days post administration. Additionally, these antidepressant effects were determined to be independent of any euphoria or intoxication related to the ketamine state. Again, ketamine is an NMDA-receptor antagonist, and it produces dissociative effects much like PCP or dangerously high doses of cough syrup (Robo-trippin!). It’s used as an anesthetic and a horse tranquillizer, and apparently it cures even the bluest of blues (at least until the clock strikes twelve and Depressed Dave turns back into a pumpkin, er, I mean a psychiatric patient).

WHAT. THE. HELL. I don’t know about you, but that blows my mind.

There are numerous advantages to a basically instantaneous reversal of depressive symptoms. Most importantly, this eliminates the risk of suicidal ideation and self-harm that many patients experience when their depression does not improve or worsens; furthermore, SSRIs carry a risk of actually inducing suicidal thoughts or actions — a side effect clinicians must watch out for. Ketamine, on the other hand, produces instant results with no risk of treatment-induced suicidal tendencies. What’s more, the patient won’t have to wait the typical 6-8 weeks for treatment to begin improving their quality of life. They’ll feel better before the doctor sends them home, even. Granted, the relief is short-lived, and ketamine is known to have addiction potential. But the mechanisms at work here, as well as the warp-speed recovery, are the keys to newer, more effective drugs and better treatment outcomes (happier patients! happier golden retrievers from those Cymbalta commercials! … who does depression hurt? …EVERYONE).

But unfortunately, we’re stuck with Prozac for the time being. All in all, it’s clear that we know very little about how these compounds produce the results they do, and even less about what causes the imbalances causing depression in the first place. Though I am certainly not one to discourage the use of pharmaceuticals, I do think it’s time we exercise more caution in clinical practice, as these drugs – which are prescribed more and more every day – may permanently alter your brain in ways we don’t yet understand. While it may still be a worthwhile option in the more severe cases (though not the mild to moderate cases of depression — read more here), a Lexapro a day won’t keep the weepies away for long for Joe Six-Pack and his Hockey Mom wife suffering from a touch of Seasonal Affective Disorder (or worse – suburban psychosis).

Parting words: depression is very real, and it’s not something you wear on your sleeve. If you think you’re depressed, talk to someone; and, if need be, talk to your doctor about medication. It’s still the best shot we have — just don’t make the decision to commit to pharmacotherapy lightly.

And for the FINAL parting words, a little dark humor (or at least, it’s humorous for me): I never could take those Zoloft commercials from like 2004 seriously. I’m pretty sure the Zoloft lump is a character out of a Shel Silverstein book… The Missing Piece Meets the Big O, I think? Come on, Pfizer. Don’t exploit my childhood like that.

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ADD


ADD/ADHD is (loosely) the theme of this blog. Follow @RitalinSpin on twitter for attentionally dysfunctional ruminations and commentary.

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