[DrMariano2]

Thank you for your post.:)

[DrMariano2]

Thank you for your post.:)

[DrMariano2]

@Jean 6742 wrote:

Thanks you for this good analysis, many publications have financial interest and have some biased answer. I like the answer of 2 scoops of milk protein powder. 🙂

I emphasize optimizing nutritional status as an important part of treatment.

The authors of the article primarily focus on specific amino acid precursors and other cofactors as part of treatment. These provide the foundation for neurotransmitter production.

They suggest using these with reuptake inhibitors such as SSRI antidepressants since they theorize the major reason these medications stop working is because of an accelerated depletion of the precursors for neurotransmitters from the use of the medication itself.

The data they provide for this theory is very weak. And I think there are numerous more important other reasons – such as non-addressed underlying causes of depression – that cause recurrence despite treatment.

But I don’t disagree with the practice of supplementing these amino acids and cofactors. The ones they suggest have independent actions themselves on improving mood and mental function – particularly at the doses used.

For years, in complementary medicine, the use of specific amino acids and cofactors have been an alternative to antidepressant and other psychiatric medical treatment.

[DrMariano2]

@compaq 6764 wrote:

When it comes to brain health and estrogens and treating your male patients with aromatase inhibitors (that need them), what sort of estradiol levels do you try to reach in the effort to balance brain and body support from estrogen vs the common side effects such as gynecomastia, edema, etc?

Something not too high and not too low. Achieving this is complicated.

Generally, when using pg/mL for estradiol and ng/dL for testosterone, there is often going to be around a 20:1 to 30:1 ratio between testosterone and estradiol in men who don’t have hypogonadism. This gives me a range where I can predict the estradiol level from a given testosterone level during treatment. When estradiol is below a 20:1 ratio to testosterone, it may be in excess.

Another technique is to simply chose absolute levels to target for estradiol during treatment.

Note that “estrogen” side effect such as gynecomastia and edema vary a lot in occurrence with men at each level of estradiol. Some have gynecomastia, nipple sensitivity, etc. at low estradiol levels. Some have no effect at high estradiol levels.

When Estradiol goes too low in a male, frequently sexual dysfunction and loss of competitive drive may occur. This is one marker for excessive dosing of an aromatase inhibitor. However, whether or not there is going to be such a negative effect depends on other signals and metabolism.

The sensitivity of each male to estradiol’s effects will vary with the levels of other hormones, signals, and metabolic-nutritional status. For example, the estrogen signal, itself, may need adequate progesterone to stimulate the production of estrogen receptors. If hypothalamic-pituitary adrenal dysregulation is present, the estrogen signal is attenuated and symptoms of low estrogen may occur at higher levels. Additionally, thyroid hormone levels increase SHBG levels. The higher the SHBG, the higher the estradiol but less is free to function. Thus the estradiol signal is reduced despite the higher level. Once the other signal and metabolic-nutritional problems are addressed and signaling optimized in the other systems, the male may not have as large a negative effect from estradiol as prior to addressing the other problems first.

Thus each male treated needs to be considered individually in regard to the targets of treatment. Even with some guidelines, being flexible in approach necessary.

[DrMariano2]

@grif 6763 wrote:

A few more short questions:

2) You said: “When body levels are high, yet TSH is also high, there may be a problem with either thyroid transport into the brain or thyroid activation by Astrocytes in the brain. The problem then becomes how to improve brain levels so that mental function can improve.” Is this something which an ordinary endocrinologist or psychiatrist should know how to deal with? Does it make sense to bring this up or will this fall through their filter?

3) I noticed that the hair on my hairline looks different. It’s shorter than the other hair and the hair also looks thinner. Do you know if Propecia or Rogaine would be an option? I read bad stuff about both of them. Or are there other safe options?

Question 2: This isn’t something an endocrinologist would think about. However, if they use TSH as the primary measure of thyroid function, then adding thyroid hormone to lower TSH is the next logical step if the person has signs of hypothyroidism. In regard to the psychiatrist, the answer is again “no”. But thyroid augmentation with a target TSH of below 0.4 is an established standard treatment for depression, particularly to improve the response to antidepressant treatment.

Question 3: Since depression has a large component consisting of excessive pro-inflammatory cytokine signaling, adding Propecia without first addressing the causes of depression is risky since it prevents the brain from responding adequately to counteract inflammatory signaling. This could lead to negative metabolic changes, impaired functioning, and the possibility of structural damage (e.g. brain cell death).

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COMPLEX ILLNESSES:

When faced with a complex illness such as depression – which generally has multiple simultaneous underlying causes, it is important to first discover what those underlying causes are then address each one in treatment. This would then maximize the chances of a positive outcome while minimizing the negative effects of treatment.

One way of organizing the causes is to organize them at four levels of organization:

1. STRUCTURAL PATHOPHYSIOLOGY: this includes infections, allergies, obesity, brain injury, gastrointestinal illness, cardiovascular illness, respiratory system illness, autoimmune illnesses, genetic predisposition for illness, etc.
2. SIGNALING PATHOPHYSIOLOGY: this includes excessive or suboptimal levels of various signals – hormones, cytokines, neurotransmitters, etc. Lab testing can be done for most of them.
3. METABOLIC AND NUTRITIONAL PATHOPHYSIOLOGY: this includes the ability to maintain adequate body temperature (thermogenesis), dyslipidemia, blood sugar production, nutritional excesses or deficiencies. Many can be lab tested.
4. PSYCHOSOCIAL AND ENVIRONMENTAL PATHOLOGY.

Each system in the body is evaluated in the history, physical, and through lab tests to help determine each of the underlying causes of a mental illness. The causes are organized as above. Then each is address the best that we can with treatment.

Another way to help improve understanding of ones illness is to list every symptom one is experiencing. Once done, they can then be organized in groups that are related – e.g. symptoms related to depression, symptoms related to other health problem.

Often, many illnesses have common underlying causes. For example, diabetes, heart disease, obesity, hypertension, mental illness, fibromyalgia, migraine, etc. have many commonalities. Thus addressing each of the identified underlying causes may not only improve mental function but physical health problems also.

[DrMariano2]

@akiravp82 6760 wrote:

Dr.mariano can one using 5htp eventually build tolerance to it and its effects stop working ?

5-HTP use can develop tolerance. Practically any treatment can lead to the development of tolerance. The reduction in effectiveness with continued use may result from the loss of receptors for the signal enhanced or downstream changes in signaling which may then change the response to the originally enhanced signal.

A sign of tolerance is a withdrawal syndrome if the treatment was suddenly stopped. With 5-HTP, this may be expressed as serotonin-withdrawal syndrome.

Generally, if a treatment’s effects stop, the question I have is What changed in that person to prevent the treatment from working? Other unaddressed problems in a person’s health may occur or worsen over time, negating the benefits of the original treatment, such as 5-HTP.

[DrMariano2]

Neuroscientists agree that new brain cells are made as we age. We cannot completely regenerate the brain. But new glial cells and neurons can be regenerated.

The general subject is Neuroplasticity. A book on this topic is “The Brain That Changes Itself” by Norman Doidge.

Certain substances can help the growth of new brain cells. This include Lithium, Estrogens, and Atypical antipsychotics, antidepressants, thyroid hormone, among others. There are studies which one can look up on MedLine. Substances that increase brain growth factors may help the growth of new brain cells. Certainly setting the stage by optimizing nutrition, hormonal status, immune system status, exercise, and mental exercise through education and other means, also can help the growth of new brain cells. Outside of any physiologic intervention, brain cell growth depends on the demand placed on brain function. If the brain isn’t used then there is no reason for new cells to grow.

[DrMariano2]

@trollo 6754 wrote:

Also, i think, urinary disturbs and infections are among the duloxetine side effects… am i right?

Rarely. I would look for other causes that are more common and rule them out first. A urinary infection requires a bacterial source for infection and an explanation of how it can go up the urinary tract – especially in a male.

[DrMariano2]

Meditation can increase dopamine signaling. It does more than that since it also affects norepinephrine, serotonin, proinflammatory signaling, etc.

Dopamine, by itself, tends to reduce agitation, makes one sleepy, causes fatigue, lowers blood pressure, etc.

Any behavioral change is the sum of many signals and metabolic changes occurring in an individual.

[DrMariano2]

@compaq 6748 wrote:

Wow I never came across that on the bottle or heard of any substantial warning regarding liver and SJW.

Is this increased liver activity a cause for health concern in your opinion? Is there anything to do to mitigate it?

Thanks again Dr Mariano.

Like any other medication, one needs to take into account interactions with other treatments to avoid problems. Some anticonvulsants, like Carbamazepine, increase liver enzyme activity like St Johns Wort.

The potential for interactions with other medications doesn’t rule out the use of such medications since interactions are common with nearly every treatment.

When combining such a medication with others, like birth control pills or cardiac medications, one has to make dose adjustments or other interventions to take the interactions into account to avoid unknowingly weakening the other treatment. In the case of some heart medication, the risk of not adjusting for the interaction may be potentially dangerous. For birth control pills, not making an adjustment may result in an unplanned pregnancy with the further risk of birth defects.

[DrMariano2]

@compaq 6712 wrote:

And, would we expect liver enzymes to be raised from long term St Johns Wort intake?

The activity of Liver Enzymes Cytochrome P450 enzyme 3A4 and 2C9 will always be elevated so long as St. Johns Wort is taken.

[DrMariano2]

5-HTP is a supplement I sometimes prescribe to patients.

I consider 5-HTP a medicinal supplement since it is generally not present in the diet, unlike L-Tryptophan.

5-HTP is the direct product of L-Tryptophan. It is the precursor for Serotonin and Melatonin. It can enter the brain easily without requiring a transporter (unlike L-Tryptophan which requires a transporter). When ingested, about 70% is absorbed. The rest is converted into serotonin in the gut, which then increases body serotonin level. Unlike L-Tryptophan, 5-HTP can’t be used to form niacin or to be used in protein production.

It has usefulness for treating:

• depression
• anxiety
• insomnia
• fibromyalgia
• headache (migraine, tension-type)
• obesity (to reduce food cravings)
• premenstrual dysphoric disorder
• tetrahydrobiopterine deficiency (very rare illness)
• etc.

Like any medication, the effectiveness varies from person to person.

It may be used in conjunction with Serotonin Reuptake Inhibitors to improve mood, particularly in those patients more likely to be deficient in dietary L-Tryptophan. Interactions with medications, however, need to be assessed and the risks considered. With a serotonin reuptake inhibitor, there may be a small risk of developing serotonin syndrome.

The dose varies depending on use. The usual range is 33 to 300 mg a day in divided doses with meals or single dose, depending on the use.

Adverse effects (such as may occur when one already has adequate amounts) include:
anorexia

• diarrhea
• flatulence
• heartburn
• nausea/vomiting
• stomach pain
• increased risk for ulcers
• increased risk for osteoporosis
• increased risk for diabetes
• edema
• eosinophilia-myalgia syndrome
• sexual dysfunction, daytime sedation
• seizures (particularly in patients with Down’s Syndrome)
• etc.

[DrMariano2]

@Jean 6743 wrote:

It’s an example:
If you have optimal hormonal and immune pathways with optimal diet and exercise level and you become to be old, what the best way to improve/protect brain dopamine pathway ? Each decade you lose dopamine level, I don’t known why ?

I think that a good dopamine pathway, particulary in the prefrontal cortex, is very important to preserve/improve with aging.

I known that exercise, good diet, brain training is the key. But with aging, do you think that some medication like selegiline (IMAOb), modafinil, low dose of valproic acid, metformin, low dose of dexedrine or ritalin, some nicotine gum or pacth have some value or not ?

Scharzenenerger and Eastwood smoke sometime a good cigar, maybe there are some value for the hormesis effect.

I wouldn’t recommend smoking a cigar. It accelerates cellular aging. Schwarzenegger looks old for 65 and already has had heart surgery.

One of the current thoughts in neuroscience is that if a person doesn’t have a specific disease that causes neuronal death, then most, if not all, of the neurons remain healthy until you die. The thought is that age-related changes are primarily from functional changes in the neurons.

Of course, this assumes a lot. And I think it is inaccurate since most people end up having illnesses or health problems which can cause neuronal death. And the functional changes – if they are the primary cause of brain aging – indicate that those neurons are not healthy at all even if they survive.

By the time you reach 85 years old, 45% of people have Alzheimer’s disease. When you include other dementias, then up to 60+% of people over 85 years old have dementia. These are not reversible dementias.

When you look at top athletes, for example, the older 30+ year old athlete is slower mentally than when they were 20 years old. They are certainly more experienced and have better unconscious processing that occurs with many more years of practice. But the reaction times are slower despite excellent or optimal health.

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Note that there is heavy emphasis on neurons in the literature. I also pay attention to the glial cells. These cells outnumber neurons 10 to 1 in the brain. They are particularly sensitive to metabolic and signaling problems and physical illness. And when they die, the neurons they support may die. Alzheimer’s disease may be thought of as a glial disease since they are the first to die.

Since glial cells contribute to information processing, support the neurons, control the production and activity of neuronal synapses, speed neuronal information processing up to 200 times, determine timing of circuits in the brain, protect the brain from infection and damage, etc. etc. they are particularly important to keep healthy as we age.

Notably, it is the number of glial cells we have that determines our intelligence. On an MRI, one way to determine a person’s intelligence is to determine the amount of white matter there is in the brain, not grey matter. White matter primarily consists of glial cells and neuron axons.

Nerves are often drawn with axons covered by myelin sheaths. What isn’t stated is that the myelin sheath is actually part of a glial cell – the oligodendrocyte – and is not part of the neuron. Neuroscientists often forget the other half of the brain – the glial cells.

The loss of glial cells may contribute a lot to the 10 to 20 % brain mass loss we experience as we age.

Physiologic treatments which improve brain cell growth often mostly increase glial cell growth. With behavioral demand is necessary to also stimulate neuron growth.

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We are born with only 50,000 dopamine neurons. Over time, we may loses these neurons gradually, particularly in the motor circuits where they are heavily used. One idea is that we loses some of these neurons because with heavy use, the neuron is unable to keep up with the oxidative stress of producing dopamine. This results in neuronal damage if not neuronal death. Keeping up dopamine function is necessary for numerous purposes.

Optimizing nutrition, hormonal status, addressing immune system problems, physical illnesses, exercise, and life-long learning are important in maintaining brain health and help prevent neuron degeneration. Exercise and learning may promote neuronal and glial growth.

Specific nervous system treatment may also be needed as we age to improve function depending on the condition and situation and to address specific nervous system problems.

If targetting dopamine neuron preservation, anti-oxidant and anti-inflammatory treatments (there are too many to list) may be particularly useful to reduce the risk of dopamine neuron damage. Low dose selegiline, lithium, progesterone, etc. may be useful for their neuroprotective effects. Nicotine may improve dopamine signaling but doesn’t prevent dopamine neuronal degeneration. Stimulants (such as methylphenidate, modafanil) help improve dopamine signaling but don’t prevent dopamine neuronal degeneration. One has to separate the treatments into those which are neuroprotective and those which improve signaling but are not neuroprotective.

[DrMariano2]

Generally, meditation has positive effects.

However, in a complex illness, where there are multiple underlying causes of the illness, meditation may only address part of these problems, leaving the other ones untreated. This may then result in a negative effect from either the interaction with medication and these untreated factors or a negative effect from medication uncovering these untreated factors.

As an analogy, when a person is treated with an antidepressant for depression, sometimes the antidepressant may trigger a manic episode when interacting with remaining untreated causes of the illness or when uncovering the remaining problems of the illness.

Manic symptoms may include excessive energy, agitation, insomnia or loss of the need for sleep, impulsiveness, hypersexuality, excessive goal-directed activity that can lead to harm (e.g. excessive spending or gambling), etc.

Sometimes the diagnosis is changed, under circumstances like this, from depression to bipolar disorder, if warranted, to help understand the condition better and its subsequent evaluation and treatment.

The solution is to continue to look for as many of these underlying factors as possible, then to address each one, to achieve a more effective treatment.

Generally, I prefer keeping an effective behavioral intervention, such as meditation or exercise or emotional regulation skills since the benefits may significantly outweigh the negatives in the long run. If there is a negative effect, then the causes needs to be found and addressed before restarting the behavioral intervention. Just like hypertension or asthma may need to be addressed prior to engaging in exercise, the other factors contributing to a mood disorder that results in a negative interaction with the behavioral intervention need to be addressed first.

[DrMariano2]

Here is a good review article:

T3 augmentation in major depressive disorder: safety considerations.
Rosenthal LJ, Goldner WS, O’Reardon JP. Am J Psychiatry. 2011 Oct;168(10):1035-40.
PMID: 21969047

http://www.ncbi.nlm.nih.gov/pubmed/21969047
http://ajp.psychiatryonline.org/article.aspx?articleid=178261

Excerpts from the article:

Augmentation of antidepressants with T3 is one of the oldest evidence-based treatments for major depressive disorder.

In 1969, Prange et al. conducted a pivotal study (8) demonstrating that administration of liothyronine en- hanced response to tricyclic antidepressants in patients was monitored, but methods available at that time were not sensitive or specific. … Many subsequent studies have confirmed the Prange et al. study’s finding of efficacy, but few have formally assessed the HPT axis during treatment.

Joffe and Singer (4) evaluated T3 versus T4 in a randomized trial and found significant changes after 3 weeks in T3, T4, free T4, TSH, and T3 resin uptake in both groups, but these changes were not positive predictors of response; the main finding was that T3 was more effective than T4 as an augmenter.

Two studies of T3 in combination with SSRIs included baseline and follow-up thyroid testing. In the first, Cooper- Kazaz et al. (21) compared sertraline (50–100 mg) combined with either T3 (25–35 μg) or placebo in an 8-week study and found that the sertraline-T3 combination produced superior response and remission rates. After 8 weeks of T3 supplementation, the mean TSH level fell significantly from 1.70 μIU/ml at baseline to 0.28 μIU/ml in responders, whereas nonresponders had mean pre- and posttreatment levels of 1.88 μIU/ml and 0.76 μIU/ml, respectively; responsiveness to treatment was significantly correlated (p=0.01) with the change in TSH level, suggesting that the therapeutic benefit could have been due to changes in the thyroid axis in this population. In a post hoc analysis, baseline T3 levels in patients who responded to T3 augmentation were significantly lower than in those who did not respond (107.60 ng/dl compared with 137.4 ng/dl, p=0.002).

Recommended Safety Guidelines for T3 Augmentation of Antidepressant Medication include:
1. Obtain baseline TSH, free T4, and free T3 levels prior to augmentation.

2. Recheck thyroid indices at 3 months and then every 6 months, or at minimum annually. The goal is for the TSH level to be at least at the lower limit of the normal range (around 0.4 μIU/ml) or below in the absence of hyperthyroid symptoms. Free T3 level can be maintained at the upper limit of the normal range based on the severity of depressive symptoms and response to T3.

3. In the longer term, if the patient has a history of multiple episodes or significant treatment resistance, maintenance on T3 is reasonable as an open-ended treatment option. If there are no symptoms of hyperthyroidism and no known cardiac disease, consider maintenance T3 supplementation even if the TSH level is below the normal reference range, depending on clinical efficacy.

Note that the dose used in studies is 25 mcg of T3. T3 is superior to T4 for treatment of depression.

The goal is a TSH at or below 0.4 uIU/mL – without showing signs of hyperthyroidism.

In patients with depression, it is very common to see suboptimal thyroid signaling – either the TSH is excessively high or body levels are suboptimal. Depression often has strong proinflammatory and nutritional deficiency components. These will impair thyroid signaling. The addition of T3 to restore thyroid signaling is thus a logical intervention.

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