Antidepressants

[marianco]

Originally Posted by Albert

Thank you marianco, you write so eloquently and express your opinion with the patients interests in mind.

May I ask what are your thoughts on, when you're prescribing drugs, do you look at the effects of the drugs verses the quality of life issues of the patient. Do you place quality of life high on the list or are you just interested in what the drug does.

The reason I ask is, some of the drugs I have been give in recent times, either make me to dopey to lead a normal life and/or total ED and etc. and my doctor is not interested in my quality of life issues.

Thanks,
Albert.

Side effects are a quality of life issue.

I usually work from a patient's perspective - what they want to achieve. Individual criteria for quality of life for the person is often high on the list of improvements and targets of treatment desired.

Sometimes some side effects, though present, are acceptable to the patient because they payoff for taking a medication is far more important to them - e.g. relieving symptoms of depression may make sexual dysfunction acceptable as a consequence, when there are no other options. Since I constantly look for options, unless I can offer a person something better, treatment is a balancing act between the risks and benefits to the patient.

If a person feels his/her doctor is not listening to them, perhaps also this issue needs to be discussed with the doctor. If a person feels his/her doctor continues to not listen to him/her, perhaps a change in doctor is an option to be considered.

Note that due to side effects, many people stop taking their medications anyway. Helping a patient adhere to treatment is an important task in medicine. Thus side effects automatically become a treatment issue.

[earthdog]

Thanks again, marianco.

[chap]

Thank you marianco, you set me straight in my thinking and I have proper perspective on the subject now. I guess there is still a stigma about brain chemistry and mental problems, and many of us kneejerk react to thinking that drug-free has to be the best way, but that might be ok for our own brains but some people truly need the help that the drugs provide.

I guess another reason I thought 'getting her off the drugs' would be an admirable quest, is in my own case I remember years ago that a doctor told me I was too high strung and anxious and asked if I would like a prescription for ativan or some kind of sedative, I can't remember exactly, I denied the prescription and was always kind of proud of myself that I did, my thinking being that I was able to stick through the over anxiety that I often experienced and did it without drugs, and that if I had taken that first prescription that I would have been on something or other for all of the rest of my life. I realize valium is not like an ssri, and maybe I am lucky to be functional without drugs where others are much worse, but I still think that that fateful decision was an avoidance of a slippery slope.

[Albert]

Thank you again marianco, I thought you would look at it from a patients perspective.

I found that doctors I have seen recently are not interested in my quality of life issues.
I am a survivor of chemotherapy and live with the side effects of that every day. Yes I am alive today because of the chemo, but some days/nights I really wonder if it was worth it.
When I try to discuss this with a doctor, all they want to do is give me another script for anti-depressants rather then help with my problems.
Yes I am looking for a new doctor, my wife came with me last visit and on the way out, she said "Looks like you'd better find another one."


Thank You,
Albert.

[Novick]

Marianco,
Was hoping you could clarify this. When you say that Wellbutrin primarily works as a norepineprhine re-uptake inhibitor, I assume you mean as to its efficacy in depression?
I realize there is research that minimizes Wellbutrin's dopaminergic activity as being relevant to depression (lack in correlation between DAT occupancy and response [human], questioning the role of dopamine in the forced swim test [rat]). However, the research does point to the idea that Wellbutrin (and its metabolites) can occupy the DAT in humans, although not to the extent of say, ritalin.
I'd also think you'd agree that Wellbutrin is qualitatively different and possibly even acutely more pleasant (not a rush, but pleasant) to take than a pure NRI like desipramine, reboxetine, tomoxetine. Obviously there are people who have the "freak out" response on Wellbutrin, as you've alluded to from hyperstimulaton. But anyway, the properties of Wellbutrin's metabolite that make it dopaminergic without the cocaine-high have been investigated by Volkow and Fowler.
My research is currently focused on investigating the role of dopamine in depressive behavior (we work with a strain of rat that goes into learned helplessness very easily yet is very responsive to drugs like desipramine, nomifensine and bupropion). From what I gather from current psychiatric practice (and marianco, please correct me here), is that drugs with dopamine activity can be very useful in depression, however "core" antidepressant response for most comes from direct modulation of 5-HT and NE pathways.

[marianco]

Originally Posted by Novick

When you say that Wellbutrin primarily works as a norepineprhine re-uptake inhibitor, I assume you mean as to its efficacy in depression?
I realize there is research that minimizes Wellbutrin's dopaminergic activity as being relevant to depression (lack in correlation between DAT occupancy and response [human], questioning the role of dopamine in the forced swim test [rat]). However, the research does point to the idea that Wellbutrin (and its metabolites) can occupy the DAT in humans, although not to the extent of say, ritalin.
I'd also think you'd agree that Wellbutrin is qualitatively different and possibly even acutely more pleasant (not a rush, but pleasant) to take than a pure NRI like desipramine, reboxetine, tomoxetine. Obviously there are people who have the "freak out" response on Wellbutrin, as you've alluded to from hyperstimulaton. But anyway, the properties of Wellbutrin's metabolite that make it dopaminergic without the cocaine-high have been investigated by Volkow and Fowler.
My research is currently focused on investigating the role of dopamine in depressive behavior (we work with a strain of rat that goes into learned helplessness very easily yet is very responsive to drugs like desipramine, nomifensine and bupropion). From what I gather from current psychiatric practice (and marianco, please correct me here), is that drugs with dopamine activity can be very useful in depression, however "core" antidepressant response for most comes from direct modulation of 5-HT and NE pathways.

As far as I know, Wellbutrin primarily works as a norepinephrine reuptake inhibitor in humans - in regard to any of its uses - depression, attention deficit/hyperactivity disorder, sexual dysfunction, etc. In asking the manufacturer for a literature search and one of its pharmacologist to write me a report about its mechanism of action - the literature bears this out. Clinically, I also have not seen a dopamine-related mechanism of action and effect on patients. If it, for example, can increase dopamine levels significantly, it should be able to treat restless legs syndrome, treat dystonia, treat Parkinson-like symptoms, etc. Wellbutrin in rats can block dopamine reuptake significantly - thus the disconnect between human and rat effects. Wellbutrin’s other mechanisms of action are not clear. I think there should be more to the story since Wellbutrin is a relatively weak norepinephrine reuptake inhibitor. Some of Wellbutrin’s side effects resemble anticholinergic side effects (blurred vision, dry mouth, constipation) but Wellbutrin isn’t known to significantly block acetylcholine receptors. Thus remains the mystery, after all these years, of how Wellbutrin works.

The response to Wellbutrin that I see is different for each person, as is the response to other “relatively selective” norepinephrine reuptake inhibitors (NRIs). It is abusable to a mild extent - upon learning about how some prison inmates would crush their Wellbutrin pills and inhale the powder. Some prison inmates, however, will try to abuse anything to feel better - given the position they are in. Whether or not Wellbutrin is more pleasant in effect than other NRIs depends on the person’s individual genetically-influenced response. Some patients get sharp knife-like headaches or nightmares on Wellbutrin, for example. Overall, Wellbutrin tends to have fewer side effects in clinical use than other antidepressants in most people. This makes it useful as a first line antidepressant when one wants to primarily increase norepinephrine.

I have not yet seen a “pure” NRI (or "pure" anything for that matter). A problem I encounter is that the manufacturer or textbook author will often minimize the other mechanisms of action of a medication (e.g. using words such as “not significantly”) when such a mechanism of action is clinically relevant - often contributing to adverse effects that are seen in real-life or other positive uses for the medication. Simplifying the list of mechanisms of action makes the major actions of a medication more understandable. But it leaves out the finer points which a good physician can put to great use in helping understand what is happening to a person who receives a medication.

Desipramine (the active metabolite of Imipramine) is a tricyclic antidepressant which primarily blocks norepinephrine reuptake. However, it also blocks serotonin reuptake, blocks muscarinic acetylcholine receptors, blocks histamine H1 receptors, and blocks norepinephrine alpha-1 receptors.

Reboxetine (which was declined by the U.S. FDA) is primarily a norepinephrine reuptake inhibitor. However, it also blocks serotonin reuptake; blocks cytochrome P450 enzyme 1A2, 2C9/19, 2D6, and 3A4; and blocks muscarinic acetylcholine receptors.

Tomoxetine (Strattera) is primariliy a norepinephrine reuptake inhibitor. However, it also blocks serotonin reuptake and blocks dopamine reuptake, among its mechanisms of action. These are not insignificant mechanisms since they may account for side effects from Strattera such as nausea, and why Strattera may not work with some people - given how serotonin reuptake if strong enough for that person may reduce dopamine production.

The primary lesson is to learn as much about what mechanisms of action a substance may have. The words “not significantly” means someone is arbitrarily setting the definition of significant - which may not be borne out by experience.

The primary mechanisms of action used to treat depression are to increase serotonin, norepinephrine, and dopamine. All the antidepressants to a certain extent do all three but in different proportions, some more selective for one than others. Effexor has variable effect on serotonin, norepinephrine and dopamine depending on the dose used (with dopamine reuptake inhibition becoming usually clinically relevant at the higher doses).

Interestingly, cocaine - which is primarily thought of in textbooks as a dopamine reuptake inhibitor - is not. It fairly equally and strongly blocks reuptake of dopamine, serotonin, and norepinephrine reuptake. It is not, however, an effective antidepressant, causing more problems than not.

Another complicating factor in antidepressant treatment: Localization in the brain of receptors. In general, serotonin reuptake inhibition causes a simultaneous reduction in dopamine production - possibly (as far as I recall) by inhibiting tyrosine hydroxylase, the primarily limiting enzyme in dopamine production. However, in some parts of the brain, the dopamine reuptake transporter and the serotonin reuptake transporter lie very close together on the neuron cell membrane. Serotonin, it turns out, can also be transported by the dopamine reuptake transporter. Thus in these areas of the brain, the higher serotonin levels from reuptake inhibition causes a competition for the dopamine reuptake transporter between serotonin and dopamine. This effectively increases dopamine levels in that part of the brain. Interesting, huh?

Increasing dopamine is highly useful in treating depression - being one of the big three mechanisms. However, a limit to this mechanism is that with medications (other than pure dopamine) it is often tied to other mechanisms of action - e.g. blocking acetylcholine receptors (which can cause confusion and other adverse effects). Further, it is important to localize the effect on the brain. Increasing dopamine in some areas, for example, can cause psychotic symptoms (e.g. hallucinations, paranoia). Dopamine activity in the brain is further dependent on so many other neurotransmitters (e.g. serotonin) that teasing it apart from other mechanisms is very difficult. With Effexor, for example, you have to accept serotonin and norepinephrine reuptake when you only want to increase dopamine.

Despite the “dirtiness” of present medications, however, while keeping an eye out for adverse effects, the medications are still highly useful in treating patients with depression. There is a lot of "art" to the treatment since there are many unknowns and we cannot specifically control one mechanism action nor easily localize its effects to the desired parts of the brain.

[Albert]

Wow, thank you.

Brilliant information.

Later,
Albert.

[androjello]

I know huh? This guy is incredible! I can sit and read his writings/posts all day. Will be interesting when I attend Med school next year after reading all the insights of Dr. Marinaco.

[Novick]

Thanks Marianco for your reply. I agree that your insights are invaluable. I can definitely appreciate the confounding issues of individual variance, receptor localization, and neurotransmitter-neurotransmitter interactions when trying to tease out antidepressant mechanism. I also agree that after all these years, wellbutrin in particular is a bit mysterious.

I also applaud your willingness to accept the effects of psychotropics that most deem "non significant", such as the receptor and CYP interactions that you've pointed out for various drugs.

And I suppose that's why I'm going to attempt to convince you further of the dopaminergic effects of wellbutrin. While therapeutic use of wellbutrin does not inhibit the DAT to the >50% level that is seen with something like methylphenidate or cocaine, the literature clearly does indicate that it blocks the DAT in humans (not just rats). The value in the following studies usually shows values around 20% inhibition in the striatum for bupropion treatment. One of the most interesting looked at just bupropion's main metabolite (called radafaxine in the study), and also took into account its pharmacokinetics. While this value might be "low" and very different from the action of other DAT blockers (long lasting), it does seem to be a consistent effect of wellbutrin treatment, something that isn't documented in humans with any other antidepressant (to my knowledge), including zoloft and effexor (although the people at wyeth seem to be pretty protective of letting any information out that would indict effexor as being habit forming).

Also, regarding your statement that a drug that raises dopamine substantially should have efficacy in restless leg, dystonia, and parkinson's. From what I know of these disorders and from the literature, drugs that increase dopamine via DAT blockade can provide "adjunct" therapy at best, and sometimes make things worse. Other dopaminergic mechanisms such as direct dopamine agonism with l-dopa or other receptor agonist are usually preferred. Thus, wellbutrin's inefficacy in treating these symtpoms does not seem to rule out its dopaminergic activity.

Here are the studies that I'm referring to:

Volkow ND, Wang GJ, Fowler JS, Learned-Coughlin S, Yang J, Logan J, Schlyer D, Gatley JS, Wong C, Zhu W, Pappas N, Schueller M, Jayne M, Carter P, Warner D, Ding YS, Shea C, Xu Y. The slow and long-lasting blockade of dopamine transporters in human brain induced by the new antidepressant drug radafaxine predict poor reinforcing effects. Biol Psychiatry. 2005 Mar 15;57(6):640-6.


Argyelan M, Szabo Z, Kanyo B, Tanacs A, Kovacs Z, Janka Z, Pavics L. Dopamine transporter availability in medication free and in bupropion treated depression: a 99mTc-TRODAT-1 SPECT study. J Affect Disord. 2005 Dec;89(1-3):115-23.

Szabo Z, Argyelan M, Kanyo B, Pavics L, Janka Z. [Change of dopamine transporter activity (DAT) during the action of bupropion (in depression)] Neuropsychopharmacol Hung. 2004 Jun;6(2):79-81.

Meyer JH, Goulding VS, Wilson AA, Hussey D, Christensen BK, Houle S. Bupropion occupancy of the dopamine transporter is low during clinical treatment. Psychopharmacology (Berl). 2002 Aug;163(1):102-5.

Learned-Coughlin SM, Bergstrom M, Savitcheva I, Ascher J, Schmith VD, Langstrom B. In vivo activity of bupropion at the human dopamine transporter as measured by positron emission tomography. Biol Psychiatry. 2003 Oct 15;54(8):800-5.

[marianco]

Originally Posted by androjello

I know huh? This guy is incredible! I can sit and read his writings/posts all day. Will be interesting when I attend Med school next year after reading all the insights of Dr. Marinaco.

Thank you.

Medical school for me is a distant but great memory. I was lucky enough to go to a medical school which had no grades - just a pass/fail system. This incredibly improved the enjoyment of medical school compared to schools which had grades. No grades means you have a class of 120 friends (as opposed to the tension and the 120 potential enemies who may backstab you or not share information as in schools which have grades). We worked as a team - the entire class - in school. We shared old tests. We had several intermural sports teams such as in basketball and ultimate frisbee. Most physicians hated their medical school experience. I had a blast. It was a second childhood. Elementary school all over again.

One of the things I did was to "decelerate". This meant to take a year off from studies to do whatever you want - while still being listed as a medica student. I took this time to self-study computer science - after realizing classes were too slow - and helped start a medical software company. And I traveled. The decelerated time is about the only time in one's life when anyone can completely take off a year to do anything he or she wanted - while still being under the umbrella of medical school. You can still live off student loans during this time. It was a great time to "smell the roses". I helped convince a large number of classmates to do the same. About a fourth of the class did so. Some went to other countries to study medicine. One went into the desert to meditate. Some wanted to get to know their wives before disappearing into residency (where you may not be home at all almost all the time). If this is an option in your medical school, I would strongly look into it. The best time is after the second year - prior to the 3rd year clinical rotations.

The most important skill to learn in medical school is to learn how to teach yourself. "To learn how to learn" is the motto my residency program professors wanted to have. I shot them down on that point - after which they chose a different nondescript motto. I told them a physician should have learned that by medical school. By residency, physicians should be independent thinkers and learners.

I do not believe you will get the information I write about in medical school. Medical school is intense - the equivalent of a complete 4 unit 10-week course taught in one week. But medical school is very basic. It has to be. To use an analogy: if medical school is analogous to elementary school, and residency is analogous to high school, then what I do is at the Ph.D level. Sadly, hardly any psychiatrist I meet, including residency professors, study molecular pharmacology to the extent I do. And fewer still study neuroendocrinology.

Medicine itself is incredibly complex and data filled. And you forget 99 percent of what you learn in medical school. What you hope to retain and develop is a saavy or street smarts about how things work. This is the ability to understand something in a conceptual manner rather than a rote memorized manner. This allows you do a lot with the material you retain. Its similar to physics. If you conceptually understand college physics, for the medical school admission test, all you would need to do well is to memorize a 3x5 inch card of basic equations. From them you can derive all the others.

Most of the learning you will have about medicine is after your residency, when you truly have to think for yourself. Its fun to watch how most young doctors mature. Coming out of residency, the thought patterns reflect primarily book learning, has a rigidity to it. Over time, they start exploring new things, add to their repertoire - forced to by the demands of real-life patients. They learn to play jazz - so to speak - as they mature. They learn how to improvise to form solutions (at least the good ones do). (A good jazz player has good solid understanding of standard music as a base, from which they can improvise.)