Antidepressants

[marianco]

Originally Posted by 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).

Thank you for the information. I'll keep it in mind - particularly in interpreting response of patients. Note that I still haven't seen significant dopaminergic effects but I'll keep it in mind and not discount it.

The ultimate test of any treatment I give, however, is the response from the patients I treat. Their improvement in well-being is the measure of the effectiveness of any treatment I consider. They are the only ones I ultimately have to account to.

Wellbutrin, itself, is a great antidepressant. It is very clean - meaning has relatively few mechanisms of actions and relatively few side effects - compared to the others. Though in concept, a multi-mechanism of action medication is potentially more effective than a single mechanism medication, the main limitation is in one's ability to customize the treatment to the patient. Every one is different. One or a few sizes do not fit all. Thus, a combination of Wellbutrin and Lexapro, for example, may do better since you can then better control norepinephrine reuptake and dopamine reuptake somewhat independently for each patient.

[Novick]

Marianco,
What are the dopaminergic effects you notice in your patients recieving high dose effexor?

Obviously like you've expressed, effexor, like most antidepressants is going to have consequences on the dopaminergic system (changes in levels and receptor density). However, it's been my personal experience that wellbutrin "crosses over" much more with something like ritalin or amphetamine compared to high dose effexor (>225mg). I've noticed this in terms of motivation, concentration and sense of well being.

While I understand that clinical human respsonse is much more important than effects in rats, an interesting observation about effexor is that it's documented to increase D3 receptor density in the exact same area of the brain (islands of cajella) that we notice increased D3 expression in our HYPOdopaminergic rats. The D3 receptor is an auto-receptor that acts as a "brake" on dopamine release. When effexor is given along with a D3 agonist, rats have trouble discriminating it from cocaine. One interpretation (though far from the only one) is that the administration of the D3 agonist effectively downregulates effexor's effect on D3 receptors, preventing their sensitization, allowing for increased dopaminergic activity. Marianco, do you have any experience with priampaxole used to augment antidepressants?

[marianco]

Originally Posted by Novick

Marianco,
What are the dopaminergic effects you notice in your patients recieving high dose effexor?

Obviously like you've expressed, effexor, like most antidepressants is going to have consequences on the dopaminergic system (changes in levels and receptor density). However, it's been my personal experience that wellbutrin "crosses over" much more with something like ritalin or amphetamine compared to high dose effexor (>225mg). I've noticed this in terms of motivation, concentration and sense of well being.

While I understand that clinical human respsonse is much more important than effects in rats, an interesting observation about effexor is that it's documented to increase D3 receptor density in the exact same area of the brain (islands of cajella) that we notice increased D3 expression in our HYPOdopaminergic rats. The D3 receptor is an auto-receptor that acts as a "brake" on dopamine release. When effexor is given along with a D3 agonist, rats have trouble discriminating it from cocaine. One interpretation (though far from the only one) is that the administration of the D3 agonist effectively downregulates effexor's effect on D3 receptors, preventing their sensitization, allowing for increased dopaminergic activity. Marianco, do you have any experience with priampaxole used to augment antidepressants?

At high doses of Effexor, I would expect dopamine effects to take place - including improved attention, organization on tasks, reduced depressive symptoms, reduced blood pressure (negating the expected higher blood pressure from increasing norepinephrine).

Unfortunately, almost none of my patients have been able tolerate Effexor at high doses for long. The one that did tolerate it (with no side effects) had inadequate reponse - continuing to be depressed despite treatment at about 575 mg a day. Akathisia - from excessive serotonine activity - is the primary limiting factor. But for the patients I treat, Effexor has not been very tolerable. I keep it in mind, however, since some do respond to Effexor, particularly at doses up to 225 mg a day.

Each clinician may have a different experience than I, since everyone's patient population is different and may have different responses to medications. As the saying goes, "your mileage may vary".

Note that dopamine activity regulates norepinephrine output in the brain through a tract from the dopamine nuclei to the locus ceruleus, possibly contributing to some of dopamine's somewhat paradoxical effects: increased calmness, sedation, and lowered blood pressure.

Pramipexole (Mirapex) is an interesting medication which has its use in psychiatry to treat depression (besides its neurological use to treat Parkinson's Disease and Restless Legs Syndrome; and its use in Fibromyalgia). As far as I know, it is a dopamine agonist on D2, D3 receptors, Alpha-2 Norepineprhine receptors (similar to clonidine); it increases Nurr 1 gene expression (needed for survival of dopaminergic neurons); and is a potent anti-oxidant. Other effects include reducing norepinephrine output (as described above), reduced thyroid stimulating hormone (and thus reduce thyroid hormone levels), and increased growth hormone level. As can be seen, the Mirapex story is not that simple.

As a dopamine agonist, it can potentially improve mood. As far as I know, it is primarily useful as adjunctive treatment - alone, not strong enough for long-term treatment of depression. Reducing norepinephrine activity and thyroid hormone levels, if significant enough in an individual, can also increase depressive symptoms.

I have experience with it. Unfortunately, in the patient population I treat, no one has been able to tolerate Mirapex. The most common reasons patients stop using it is anxiety, dizziness/faintness, fatigue, oversedation and reduced alertness.

Some clinicians have more luck with it than I. It depends on the population of patients a physician has (most of my patients, in general, are under constant, unrelenting, extreme stress and have very severe, treatment, resistant illnesses - they are not the usual middle class worried well). Thus, I keep it in mind as an option because it is a relatively clean dopamine agonist, and may work in some patients where other medications don't.

Other effects to keep in mind: sudden unexpected, uncontrollable attacks of sleep can occur (this increases the risk of patients getting into car accidents and of dying by accident - thus one has to be very careful in informing patients about the risks). A patient can also develop hallucinations and paranoid delusions (limiting its use in patients with psychosis), pupil dilatation (not good when the patient is stopped by the police), increased heart rate.

[snipe]

This is one of the best (and most important) threads I've ever seen. The amount of information is phenomenal! Many thanks to Dr.M for his time.


I'm currently on: Depo-Test, 80mgs/week - Avodart, 0.5mg ED - Arimidex, 0.25mg. 3x/week - Paxil, 30mgs.
I began the Depo and Paxil concomitantly about 3 years ago during a period of depression marked by extreme anxiety which necessitated my taking 0.5mg Xanax 3 to 4 times per day. After Approx. 4 weeks I was able to eliminate the Xanax. Still emotional issues remain at the fore. (This, all under the care of a holistic/life extension/ nutritionally oriented physician.)



Marianco- Two questions.

What is your feeling about the use of HCG or lack thereof with TRT? Even though TRT usually has positive emotional impact, do you feel the suppression induced by exogenous testosterone (in strictly replacement doses) may, at some point, begin to have a negative effect on mood? Might this be alleviated by use of HCG? (I've wanted to use HCG as an adjunct to my TRT but my doctor has no experience with HCG and is not comfortable writing for it.)

Some mention has been made regarding supplements as an alternative or addition to the standard anti-D's. My doctor has recently become a proponent of a product called NeuroReplete. (A combo of Tyrosine, 5-HTP and Lysine, with vitamin C, B6, Folate and Calcium as co-factors.) It is also suggested to take CysReplete (Cysteine, Folate, Selenium) to prevent sulfur amino acid depletion when using NeuroReplete. She suggested I try this as an adjunct to the 30mgs of Paxil that I've been on.
(Note: She sells this out of her office along with many other supplements. I feel this is inherently unethical.)
I decided not to use this supplement but, have added 50mgs of 5-HTP, taken at bedtime. (Purchased at a local store.)
What are your thoughts regarding the efficacy and safety of supplements like this or the use amino acids as neuro-hormone precursors

[Novick]

"At high doses of Effexor, I would expect dopamine effects to take place - including improved attention, organization on tasks, reduced depressive symptoms, reduced blood pressure (negating the expected higher blood pressure from increasing norepinephrine)."

So are you saying you don't see these effects with wellbutrin? I guess I'm still a little unclear about how you're measuring the clinical effects of dopaminergic activity.

[marianco]

Originally Posted by Novick

"At high doses of Effexor, I would expect dopamine effects to take place - including improved attention, organization on tasks, reduced depressive symptoms, reduced blood pressure (negating the expected higher blood pressure from increasing norepinephrine)."

So are you saying you don't see these effects with wellbutrin? I guess I'm still a little unclear about how you're measuring the clinical effects of dopaminergic activity.

Measuring the clinical effects of dopaminergic activity is very difficult without doing a lumbar puncture or an imaging study that can specifically pick out dopamine activity in the brain. Dopamine itself can be measured via urine testing as can other neurotransmitters. But I haven't found it to correlate well with how a person is doing.

Measuring the clinical effects of dopaminergic activity is primarily done from clinical observation and history from the patient - and monitoring for effects expected from increasing dopamine or reducing dopamine activity.

Other dopamine effects I would expect: the ability to give a person a sense of wellness and contentment, the ability to reduce symptoms of Parkinsonism (tremor, stiffness, slowed movement), the ability to increase testosterone levels, the ability to reduce norepinephrine output, the ability to treat symptoms of akathisia or restless legs syndrome, the ability to reduce anxiety and perceived stress, the ability to improve sleep, the ability to improve memory, the ability to treat hyperprolactinemia.

No. I have not seen the clinical effects of increasing dopamine with Wellbutrin. I have seen primarily its effect on increasing norepinephrine levels - including improving attention, reducing depressive symptoms - but not clearly what is a dopamine effect. Wellbutrin clearly raises blood pressure, not lower it. Higher doses of Wellbutrin increase stress levels greatly - since norepinephrine is a signal for stress through the sympathetic nervous system - not reduce stress as would be expected of a dopamine-increasing substance. Adrenal insufficiency can occur from excessive doses of Wellbutrin. Adrenal insufficiency is much less likely to occur if there was a significant increase of dopamine with Wellbutrin - dopamine being protective at the brain level of adrenal function by reducing stress levels. Thus, Wellbutrin is not a clinically useful way to increase dopamine in humans - so far in my experience, and in the experience and research done by a neuroendocrinologist colleague I work with, who has used Wellbutrin years before I did. I would say the that if it does raise dopamine levels, it does it insignificantly - not enough to be a useful mechanism of action in the day-to-day treatment of patients.

Perhaps the metabolites of Wellbutrin may have a more significant action on dopamine. Maybe one day these will be used as antidepressants. We shall see.

Wellbutrin, despite its limitations on regard to dopamine, is still one of my favorite medications for increasing norepinephrine levels relatively cleanly.

[Random987]

marianco,

Have you ever used deprenyl in your practice?

[pmgamer18]

The more I read about this the better it sounds here is a link.
http://www.selegiline.com/

[marianco]

Originally Posted by Random987

marianco,

Have you ever used deprenyl in your practice?

I have used deprenyl/selegiline often in my practice, though less often recently. I am reexamining its use - particularly when the selegiline patch comes out. The patch will bypass intestinal monoamine oxidase, and thus reduce the risk of food and medication interactions that limit monoamine oxidase inhibitors use.

Deprenyl/selegiline is a monoamine oxidase (MAO) inhibitor that is "specific" at "low" doses (generally 10 mg/day or less) to the MAO-B type enzyme. This allows it to avoid blocking MAO-A in the intestines which cause problems of excessive hypertension (and stroke, etc.) in interactions with certain foods and medications (e.g. stimulants, decongestants, etc.).

MAO inhibitors are great antidepressants. Low blood pressure is one of the most common side effects, not high blood pressure. I think they tend to be more effective than the other antidepressants. The problem is that they have so many interactions with other medications and have so many limits in what foods a person can eat (e.g. no pizza), that many people do not want the lifestyle changes and many doctors are afraid of it and of others using it. Hopefully, the MAO patch will at least reduce the intestinal food/medication interaction risks and improve safety.

Deprenyl/selegiline is relatively safe at low doses. I say "relatively" because it depends on an individual's susceptibility to side effects. Many people still have significant MAO-A inhibition no matter how small a dose of Deprenyl is used - thus running the risk of death, etc.

Even at low doses, Deprenyl/selegiline, in general, cannot be used with another serotonergic medication because of the risk of death from serotonin syndrome (excessive serotonin activity). Unfortunately, since Deprenyl/selegiline is classified as a Antiparkinson medication, many clinicians do not realize this and may inadvertently add a serotonergic medication thinking it is safe - though it is not. I've seen this mistake happen and it was not pretty. If it was classified as an MAO inhibitor, automatically this would be known. Adding Deprenyl/selegiline even at 10 mg or less a day to Prozac or other serotonin reuptake inhibitor is very risky. It can be done but one must be careful. Many medications increase serotonin and this has to be taken into account. For example, the pain medication Tramadol/Ultram works as a serotonin reuptake inhibitor, as one of its mechanisms.

The primary problem of oral Deprenyl/selegiline is that the doses needed to keep specificity for MAO-B is too low for it to be effective in most cases as an antidepressant. At higher doses, a person is just as well off using other MAOs with lower cost, such as Nardil. It is still worthwhile considering as an alternative in treatment resistant cases.

MAO Inhibitors primarily increase serotonin levels as their main effect, though they also significantly increase dopamine and norepinephrine. Given the risks of the use of MAO inhibitors, and the primary mechanism of increasing serotonin levels, the serotonin reuptake inhibitors largely replaced them in general use.

Deprenyl/Selegiline can be looked at as a "smart drug" or "nootropic" - and is used by some practitioners as such. By its stimulant properties and antioxidant properties, it may improve one's thinking capacity. Perhaps. I think your mileage may vary as with anything else. One still has to be very careful about the potential for significant interactions and risks.

One using any MAO Inhibitor should carry a medical tag informing others of this so that in emergencies, the paramedic, ER doctor, etc. does not accidentlly harm the patient by giving the wrong medication. Simple things such as the over-the-counter decongestant, pseudoephedrine are off-limits.

[T Man]

In your opinion what medications/substances can safely raise Dopamine levels? I want to talk to my Doctors about this option. I am on Remeron 7.5mg nightly and Klonopin as needed as I mentioned before (.25 or .5mg twice a week usually). I think I am getting symptoms of Akastitia when we try to raise my Testosterone levels. I am not certain of this, but the symptoms seem to be as you described. Anxiety, ants in the pants, burning or tingling skin feeling. Maybe it is estrogen related as someone mentioned in another thread. Also I do get restless legs for a short time after taking the Remeron. It goes away within an hour or so and doesn't affect my sleep.

I also have a low sense of well being or contentment. I always felt content when on testosterone replacement therapy in the past. I know that I must raise my Testosterone levels back up to high normal again to feel good. I just can't seem to get this through my Doctors head. I have been on TRT since 1989.

Once again my problem is that I can't seem to tolerate Testosterone levels above 400 ng/dl. I never had this problem before I went moronic and did a few cycles of high Testosterone (400-500mg weekly for 10 weeks) and a few other Anabloic/androgenic agents. I am tired of this anxiety and depression that comes and goes. Could higher levels of Dopamine possibly help with my situation. The Doctors at a very good reasearch University don't seem to know what to do or what medications I should take. They suggested Buspar or Nardil. Or just stay on the Remeron and take Klonopin. Any suggestions?