What You Should Know About Prozac and Other Antidepressant Meds, Part 2, SNRI's

We had talked about SSRIs with brand names such as Prozac, Lexapro, Celexa, Zoloft, Paxil and Luvox.  

In this post, we talk about another common class of antidepressants, SNRI's with popular brands such as  Effexor, Effexor XR, Cymbalta and Pristiq. 

SNRI's are Serotonin Norepinephrine Reuptake Inhibitors so they work on two neurotransmiters--serotonin or norepinephrine (also called noradrenaline) instead of just one as it is with SSRI's.

SNRI's did not score "highly" compared to other SSRI's for depression based on a meta-analysis published in Lancet (which rated Lexapro and Zoloft highly).  BUT--SNRI's are particularly useful when it comes to anxiety and panic disorder.  SNRI's also often work faster than SSRI's (which can take weeks) and they can relieve depression symptoms within a week for many.  Effexor in particular can start to work within 3-4 days.

Con's:
1. Like SSRI's, most SNRI's can decrease libido and make it more difficult to achieve orgasm. This side effect tends to show up when the dose of the antidepressant goes up; also, over time, this side effect may decrease. If this side effect is unacceptable, one strategy would be to switch to another antidepressant which is known to have much less libido/orgasm side effect, such as Wellbutrin.   Sometimes, it's also possible to decrease the dose of the SNRI and add a small dose of Wellbutrin so that someone can still get relief from depression with less side effects.

Unfortunately, SNRI's like SSRI's can also cause weight gain in some. The most notorious "weight gainer" is Paxil but it can also happen in varying degrees with other antidepressants. Not everyone who starts an antidepressant gains weight.

2. Many SNRI's can have more withdrawal symptoms versus SSRI's when someone is deciding to discontinue their medication for whatever reason.  The most notorious is Effexor (second is probably Cymbalta) and some of the withdrawal symptoms include nausea, dizziness, anxiety, feeling an "electric shock,"  feeling "zaps," and other odd sensations.

There are several ways to address this: The first

What You Should Know About Prozac and Other Antidepressant Meds, Part I SSRI's

Most of my patients come to see me for non-pharmacologic or no-medicine treatments for depression and anxiety. However, I also discuss antidepressant medications with my patients and there are several reasons for this:

1. I think it is ethical and part of informed consent that patients also learn about anti-depressants so that they can make better informed decisions. I try to provide an unbiased, balanced and evidence-based point of view as much as I can and discuss both the benefits and side effect profiles of each medication. One major limitation of this approach is that many of the studies we base our knowledge of these antidepressants were short term studies, usually about 8 weeks. But in reality, many patients take this for longer periods of time. Therefore, I even though the patient may decide to start with antidepressants, I would encourage doing other non-pharmacologic treatments, which I have found very helpful and effective in my practice, to make their recovery from depression more sustainable and healthier in the long run.

2. For practical purposes, many of my patients are already on anti-depressants (this is one of the most prescribed medications in the United States) and they come to see me so that they can get off them, usually because they don't like the side effects or because they want a more sustainable treatment. Because of this, I discuss the pharmacology of the anti-depressants with patients to explain why certain drugs take a longer time to wean off than others.  For example, drugs with shorter half life's should be weaned off more slowly and carefully to reduce withdrawal side effects.  We also discuss pharmacology so that the patient understands the pro's and con's of discontinuing medication.

So here is the general overview I present to my patients in the office:

1. Anti-depressants classification may be broken down as:

(a) SSRI's or Specific Serotonin Reuptake Inhibits (also called Selective Serotonin Reuptake Inhibitors)--common brands are Prozac, Lexapro, Celexa, Zoloft, Paxil, Luvox);

(b) SNRI's or Serotonin and Norepinephrine Reuptake Inhibitors--Efexor, Effexor SR, Cymbalta, Pristiq;  (More information on SNRI's on this post)

The Wise Use of Thyroid Hormone T3 in Treating Depression

Cytomel or the T3 form of thyroid hormone has a long use in psychiatry for the treatment of depression.

In fact, while many endocrinologists and family doctors today prefer to use T4 aka Synthroid monotherapy only for the treatment of hypothyroidism, psychiatrists are one of the specialties who are actually familiar with the value of adding Cytomel/T3 in the treatment of depression, specially in the types of depression where treatment with anti-depressants alone is insufficient.

Why Use Thyroid Hormone to Treat Depression?
Thyroid hormone is a hormone that affects almost every tissue in the body, but moreso the brain. We already know that thyroid hormone is essential during fetal development in pregnancy. A deficiency of thyroid hormone during pregnancy can cause mental development retardation. This is why pregnant women with hypothyroidism are more closely monitored and given more thyroid medication during pregnancy.  Thyroid hormone is so important that the brain uses a different set of genes to convert T4 into T3. Recall, T4 is the more abundant but less active form of thyroid hormone in the body, while T3 is the more active but less available form of hormone produced by the thyroid gland.

Many of the symptoms associated with hypothyroidism or low thyroid hormones levels are similar to the symptoms of depression. They include fatigue, slow thinking, low moods.

It is also worthwhile to note that a significant percent of persons with major depression have hypothyroidism or subclinical hypothyroidism.

You can now see that there is a big overlap between hypothyroidism and depression.


What is the evidence for using Cytomel to treat depression?
A summary of the literature and evidence is discussed in the journal Current Psychiatry. Here's an overview of some of the evidence:

• A meta-analysis has found that adding Cytomel to tricyclic antidepressants can speed up or accelerate the time it takes for depression symptoms to lift. One study found a reduction in depression symptoms (using Hamilton scale) of 50% by an average of 11 days with T3 augmentation vs. an average of 22 days with tricyclic anti-depressants alone.  Another study also showed that women seemed to respond more favorably with Cytomel augmentation with response evident by day 3 for some. 

• Another study found similar results-that Cytomel augmentation with SSRI's is also effective. SSRIs are the most commonly prescribed antidepressants these days with brand names such as Prozac, Lexapro, Zoloft, Paxil. 

• Another impressive study called STAR-D showed that Cytomel augmentation was effective in treating depression among patients who've already tried two other anti-depressants that didn't work on their own. Another point to consider is that the other medication they tried, lithium, was also shown to improve depression among persons who did not improve on other anti-depressants but that Cytomel showed fewer side effects than Lithium, making Cytomel the more rational/safer option. 

How can this be useful for me?

There are a few important take-aways here:

• Do not take a diagnosis of depression at face value. Always ask your doctor if they can also test if you are hypothyroid.  This is a good differential to make. If your TSH is perfect (what "perfect" is partly a matter of opinion, for me, it means it should be at least 2.5 or lower.)  If your thyroid labs are normal but between 2.5 and 4.5, then thyroid hormones should be considered if "conventional" treatments for depression such as medication, counseling, psychotherapy, cognitive behavioral therapy do not work or do not work well enough. 

• Cytomel aka T3 aka the more active form of thyroid hormone seems to be the specific type of thyroid hormone to take to treat depression symptoms. Synthroid does not seem to have the same efficacy.  Armour or Nature-Throid have both forms of T3 and T3, so they are better than Synthroid alone. However, because Armour and Nature-Throid are derived from natural sources, there may be a higher variation in their T3 content, so consider  Cytomel. 

• There are nuances in using Cytomel to augment the treatment of depression. In my practice, most patients will improve with a low dose addition of Cytomel in the morning. However, I have found that some patients will need a compounded time-release version of Cytomel to get the optimum results. 

Optimum Thyroid Labs--the New Normal

Is there such thing as an optimal lab number within the normal range for thyroid labs? Absolutely, yes.

Although there are small variations, most labs these days report the following as the normal range for thyroid labs:

• TSH: 0.5 – 4.5 uiu/mL
• free T4: 0.8 – 2.8 ng/dL
• free T3: 2.3 – 4.2 pg/mL

But is there are an optimal range within the these normal ranges? The answer is yes. Consider the following:

• A few years ago, TSH as high as 10 was considered normal. But today, a TSH above 4.5 would fit into the diagnosis of hypothyroidism or low thyroid function. Therefore, for many years, people with TSH between 4.5 – 10 were told that their thyroid function was “normal” even though by today’s standards, they would be hypothyroid. All those missed diagnoses and years of symptoms for undiagnosed and untreated patients. The trend over time has been the lowering of TSH in terms of what is considered “normal” and some labs now report that TSH above 3 or 3.5 is consistent with hypothyroidism. 

• Many endocrinologists today would treat a patient to a target TSH–usually between 0.5 and 2.5. For example, if a patient is diagnosed with hypothyroidism with a TSH of 6, the endocrinologist might start with a dose of thyroid medication at 0.05mg. If the follow-up labs show that TSH is now lowered to 4, the doctor might increase the dose to 0.07mg, and so on until the “target” TSH is achieved. A wise doctor would of course correlate the “target” TSH with the patient’s signs and symptoms. It is not always necessarily better to go for the lowest TSH. But if a patient has TSH of 3.0 but is still symptomatic, I personally would still dose up the patient to see if improvements can still be made. This approach may be called “treat to target.”

• For hypothyroid women who are preparing for pregnancy, the guidelines now indicate that the goal is to have a TSH of 2.5 or lower.  Many fertility doctors also now try to get TSH below 2.5 if they are helping sub-fertile women get pregnant. Therefore, many subspecialties such as obstetrics/gynecology and fertility medicine now recognize that TSH below 2.5 is the more optimal target, and not just a number “within the normal range.”

• Like TSH, there are also optimal numbers for free T4 and free T3 within the normal range. The ranges indicated in the chart above are based on some studies and clinical experience. I will admit that there is not a lot of comprehensive and solid evidence yet that we should always “treat to target” in terms of free T4 and T3. But evidence is emerging and this will get clarified over the years. HOWEVER, I want to point out that the concept of an optimal target is still very helpful clinically when it comes to free T4 and free T3. One example I can give is when you see a patient with normal/optimal TSH, but their free T4 or free T3, while within the normal range is on the cusp of becoming abnormally low. In these cases, you have to consider if maybe there is an issue with absorption with the medication, if the thyroid medication may be interacting with the other medication that the patient uses, or perhaps the patient because of genetics or some other factor, is not very good at converting the more inactive form of thyroid hormone to the active form. There are fixes to each of these scenarios (for example, adding T3-Cytomel if free T3 is abnormally low) and a good doctor who treats each patient patiently and individually will try to tailor-fit a treatment plan that will help address the patient’s signs and symptoms more adequately.

Take home messages:

• Within the normal range of common thyroid lab values, there is an optimal range.
• If a patient gets treatment for hypothyroidism, is within the normal range AND feels fine–then that’s wonder–continue the treatment and monitor regularly as we would with any patient who has a diagnosis.
• If a patient gets treatment for hypothyroidism, is within the normal range but outside the optimal range AND does NOT feel fine–my opinion is that there is a good argument that medication levels and/or the type and combination of medications (levothyroxine, cytomel. armour thyroid, compounded medication) should be adjusted to reach the optimal range.
• Do not let your doctors dismiss your questions about possibly adjusting thyroid medications if you are still feeling symptoms of hypothyroidism just because your labs are within the normal range….”so it must be something else.”  If the labs are not optimal, effort should be made to try to reach the optimal range.
• If the optimal range is reached, and you still feel symptoms…this is when I would say other possible causes of fatigue should be considered and addressed.

Widely Used Heartburn OTC's and Meds Interfere with Thyroid Hormones

Some of the most common and most widely used heartburn and indigestion medication (both prescription and over-the-counter) have been shown to interact with thyroid meds–with the effect of decreasing the absorption of thyroid meds and possibly worsening sign and symptoms of hypothyroidism.

Here are some of them:

• Aluminum containing antacids–Popular brands includeGaviscon, Maalox and Mylanta. These heartburn medications work by neutralizing stomach acids. They are effective and are widely used. However, the aluminum salts in these medications also bind to thyroid medication. In one prospective study, the TSH of the subjects worsened from 2.6 to 7.2 (from normal TSH to abnormally high TSH, which indicates insufficiently managed hypothyroidism).

• PPI–Proton pump inhibitors are commonly used to suppress or stop acid production in the stomach. There are not many studies regarding the interaction of thyroid medication with PPI’s (in this case, lansoprazole, branded as Prevacid). In one study involving 55 subjects, there was a slight increase in TSH by 0.69–not very much compared to the study referred to above for aluminum containing antacids.

• Calcium carbonate antacids–Popular brands includes Tums and Rolaids. Calcium has also been shown to bind to thyroid hormone/thyroid medication. One study showed that TSH worsened from 1.7 to 2.7 when thyroid medication as taken with a calcium supplement.

Iron Supplements Can Interact with Thyroid Meds

Many daily multivitamins and pre-natal vitamins contain iron and calcium. But did you know that these common minerals can interfere with your thyroid meds if taken at the same time?

Why do doctors recommend taking thyroid medication, usually at the same time every morning, away from food and other medication/supplements?  There are two reasons: (1) because thyroid medication is trying to replace a hormone that our body naturally produces, it makes sense to take it at the same time everyday to keep levels steady; (2) because thyroid hormone is one of those medications that have a lot of interactions with other supplements, other medications and even food.

Here are a few common supplements to avoid taking with your thyroid meds:

• Calcium supplements-several studies have shown that calcium supplements (in the studies they used calcium carbonate, citrate and acetate) lowers the absorption of levothyroxine or T4 (e.g. Synthroid). This is because calcium binds to T4.  In fact, taking T4 with calcium can lower the former’s absorption by at least 20%.  Not only that, TSH values of people who took T4 with calcium actually went up (meaning, their hypothyroidism was less controlled) from 2.7 vs 1.7 when they did not take T4 with calcium.

• Iron supplements–the binding of iron with thyroid medication seems pretty significant. In one study, when patients did not take iron with T4, their TSH was well controlled at 1.6. However, when they took ferrous sulfate (a common form of iron supplement), their TSH skyrocketed to 5.4 on average, one patient’s TSH went even as high as 29.  These are significant because a TSH above 4.5 is already considered abnormally high (for most labs). Like calcium, the mechanism is that thyroid hormone binds to iron.

Note, the take-home message is not to discontinue these supplements if there is a good reason to take them. For example, iron supplements may be important for persons with anemia and calcium supplements may be helpful for persons who are at risk for osteoporosis. Rather, the take home message is to take these supplements away from your thyroid medication.

Hypothyroidism During Pregnancy: Different Standard of Care

Pregnancy is a special time for mother and child that requires closer and more involved management of hypothyroidism.

Thyroid hormone is specially important for the fetus, as it is required for proper brain and nervous system development.

Note that the target or normal values for TSH are different during pregnancy.  The American Thyroid Association has released the following recommendations and here are some highlights:

TSH normal ranges are different for every trimester

• 0.1 – 2.5mIU/L for the first trimester
• 0.2 – 3.0mIU/L for the second trimester
• 0.3 – 3.0mIU/L for the third trimester

These lab values are overall lower than the normal ranges for non-pregnant persons. Therefore, if a woman with hypothyroidism is planning to get pregnant, it might be wise to discuss this with her doctor to see if she might need to increase her thyroid medication dose to get her TSH levels lower in preparation for pregnancy.

A common question at this time is the usefulness of measuring T4. While it is still useful to be measure, be prepared to know that T4 levels using the most common type of test (called the immunoassay test) is less accurate during pregnancy. This is because there are now other molecules/proteins, such as thyroid binding globulin, in a pregnant woman’s blood that alter the accuracy of the test. These molecules/proteins include increasing levels of thyroid binding globulin (TBG), increases in non-esterified fatty acid levels and decreasing levels of albumin. Newer tests such as liquid-chromatography-tandem mass spectrometry (LC/MS/MS) testing is seen to be more accurate than the more commonly available immunoassay test, and it is a good option for more accurately measuring T4 if this test is available in a community or laboratory.

The testing schedule and follow-up is more involved

In a non-pregnant person, follow-up for thyroid labs and adjustments to thyroid medication may happen only twice to once a year, especially if the hypothyroidism seems steady and “well-managed.” However, during pregnancy, the follow-ups tend to be more frequent–partly because of the many and rapid changes that happen day-to-day/week-to-week/month-to-month during pregnancy, and partly because the importance of thyroid hormone to the developing fetus is much higher.

A rough outline of a recommended schedule includes:

• Lab assessment of TSH and T4 levels every 4 weeks during the first half of pregnancy to ensure that target levels are reached
• Regular reassessment of TSH and T4 levels during the second half of pregnancy, the frequency decided between the patient and doctor depending on how stable the pregnancy, labs, signs & symptoms are

Finally, it is now also recommend that for women who are already taking thyroid hormone, that extra doses of thyroid hormone be taken once the pregnancy is confirmed.  The recommendation is two extra doses per week (one dose taken several days apart x 2) of the current dosage level may be started once a pregnancy is confirmed.