Sorry for my ingorance as not a medical professional, but in what sense are the SNRIS "basically just SSRIs" at low doses? Wouldn't the effect be linear, like at half dose it has half the effect on NET as well as SERT? Is there some physiological switch / step function where it suddenly has an effect of norepinephrine?
Medications follow a logarithmic curve when it comes to receptor occupancy due to how binding kinetics work. Since each drug has unique affinities for each receptor, you can be at two very different places on each logarithmic curve. There are arguments about exactly how much blockade of the NET and SERT you need for effects, but with Venlafaxine the difference in affinity is large enough that you can definitely get a significant gap between the two at 75mg.
Thank you so much for sharing! All of the trivia was new to me! I hypothesize that my patients adhere to lithium better when I mention lithium citrate was original flavoring in 7-UP. Anyone up for running a trivia/adherence investigation?
I've been puzzled by the duration of action of benzos for as long as I've known about them -- if half-life was the limiting factor then why does vallium not last for 2days (or longer w/ active metabolites)?
More generally these basic limitations on our understanding point to the huge potential value in RCTs regarding these drugs and just collecting undirected data on the experience of patients taking them. If we only do RCTs based on theories about new treatments we never get the data we can use to find unexpected patterns and develop new theories.
I think there should be less demanding requirements for human RCT stidies (obv still informed consent) for any drug where different doctors would prescribe different drugs to a patient. Any situation in which it is ok to randomly assign patients to treatment via their choice of doctor should be one where it's easy to randomly assign patients to drugs to gain knowledge. If you don't think the RCT is moral then the existing effective RCT w/o data is even more immoral.
Basically, if you present data showing that the same patient will frequently be prescribed all drugs in some list that should be enough to get approval for an RCT between those drugs in those cases.
-Toward the end of residency and right after, I started using MAOIs a lot, but I soon discovered many pharmacies have trouble getting them and there always seems to be shortages. They probably just aren’t making enough of the medicine these days.
-re: VPA vs. lithium, I still think the side effect burden usually favors lithium if you’re a little savvy with the dosing. Especially for women VPA side effects can be so brutal, even if they’ve got the birth control dealt with.
Fascinating! Thanks so much for your post. I am a retired psychiatrist, trained in the days when we had only “typical” antipsychotics, TCAs, MAOIs, and lithium,as well as a few benzodiazepines, back in the early 1980s. I also have suffered from severe major depressive disorder since then, and have had a lot of medications, including Trazodone when it was called Desyrel and used as an antidepressant. It took a very long time to find the right combination of meds. I would encourage psych residents and others in training to be cognizant of the metabolic side effects of the antipsychotics. I have taken aripiprazole as augmentation therapy over the past 15-20 years. It was first touted as being weight neutral. Despite taking a very small dose, I ended up with an 80 pound weight gain, hyperlipidemia, and diabetes. I felt like I had to choose between being skinny and depressed, or fat and mentally healthy. Obviously I am oversimplifying my experience, but paying attention to side effects, as you point out, is important.
I am currently working on a memoir describing the various treatments I received for major depression over the past 40 years. Lots of changes in the field.
Temazepam is commonly prescribed for insomnia in Australia, I think it's considered to be less problematic than diazepam.
Any particular reason why?
I really enjoyed this read. Thank you!
Sorry for my ingorance as not a medical professional, but in what sense are the SNRIS "basically just SSRIs" at low doses? Wouldn't the effect be linear, like at half dose it has half the effect on NET as well as SERT? Is there some physiological switch / step function where it suddenly has an effect of norepinephrine?
Medications follow a logarithmic curve when it comes to receptor occupancy due to how binding kinetics work. Since each drug has unique affinities for each receptor, you can be at two very different places on each logarithmic curve. There are arguments about exactly how much blockade of the NET and SERT you need for effects, but with Venlafaxine the difference in affinity is large enough that you can definitely get a significant gap between the two at 75mg.
Ah yes logarithmic makes sense, thanks
Another comment: the mnemonic OTL: outside the liver. Unforgettable.
Though unfortunately reinforces the myth that they are not hepatically metabolized!
It’s a shame that glucouronidation does not roll of the tongue better — you got me!
Thank you so much for sharing! All of the trivia was new to me! I hypothesize that my patients adhere to lithium better when I mention lithium citrate was original flavoring in 7-UP. Anyone up for running a trivia/adherence investigation?
I've been puzzled by the duration of action of benzos for as long as I've known about them -- if half-life was the limiting factor then why does vallium not last for 2days (or longer w/ active metabolites)?
More generally these basic limitations on our understanding point to the huge potential value in RCTs regarding these drugs and just collecting undirected data on the experience of patients taking them. If we only do RCTs based on theories about new treatments we never get the data we can use to find unexpected patterns and develop new theories.
I think there should be less demanding requirements for human RCT stidies (obv still informed consent) for any drug where different doctors would prescribe different drugs to a patient. Any situation in which it is ok to randomly assign patients to treatment via their choice of doctor should be one where it's easy to randomly assign patients to drugs to gain knowledge. If you don't think the RCT is moral then the existing effective RCT w/o data is even more immoral.
Basically, if you present data showing that the same patient will frequently be prescribed all drugs in some list that should be enough to get approval for an RCT between those drugs in those cases.
For some wonderful ethnographies dispelling Great Man thinking in science see Bruno Latour’s Lab Life and The Pasteurization of France
-Toward the end of residency and right after, I started using MAOIs a lot, but I soon discovered many pharmacies have trouble getting them and there always seems to be shortages. They probably just aren’t making enough of the medicine these days.
-re: VPA vs. lithium, I still think the side effect burden usually favors lithium if you’re a little savvy with the dosing. Especially for women VPA side effects can be so brutal, even if they’ve got the birth control dealt with.
Fascinating! Thanks so much for your post. I am a retired psychiatrist, trained in the days when we had only “typical” antipsychotics, TCAs, MAOIs, and lithium,as well as a few benzodiazepines, back in the early 1980s. I also have suffered from severe major depressive disorder since then, and have had a lot of medications, including Trazodone when it was called Desyrel and used as an antidepressant. It took a very long time to find the right combination of meds. I would encourage psych residents and others in training to be cognizant of the metabolic side effects of the antipsychotics. I have taken aripiprazole as augmentation therapy over the past 15-20 years. It was first touted as being weight neutral. Despite taking a very small dose, I ended up with an 80 pound weight gain, hyperlipidemia, and diabetes. I felt like I had to choose between being skinny and depressed, or fat and mentally healthy. Obviously I am oversimplifying my experience, but paying attention to side effects, as you point out, is important.
I am currently working on a memoir describing the various treatments I received for major depression over the past 40 years. Lots of changes in the field.