The most common ingredients in energy or power drinks are caffeine or another caffeine-like substance (from the category of methylxanthines) and sugar (or, in diet versions, a sugar substitute). These are the ingredients that give these drinks their boost. The ingredient list of some energy drinks doesn’t include the word ‘caffeine,’ however, because the caffeine is contained within another ingredient, such as ‘guarana’ or ‘yerba mate.’

Guarana is a climbing plant native to the Amazon basin. As with other plants producing caffeine, the caffeine works as a defensive toxin aginst pathogens that try to eat its berries or seeds.

Yerba mate is a small tree native to other areas of South America. The drink, made from steeping its stems, contains high concentrations of caffeine as well as lower concentrations of the other xanthines, theobromine and theophylline.

Energy drinks contain many other ingredients such as added vitamins and herbs. Common ingredients are: inositol, carnitine, creatine, glucuronolactone, ginseng, and ginkgo biloba.

When used in moderation these drinks can safely increase a person’s energy and attention. Some ingredients, such as yerba mate, can have muscle relaxing properties too. These drinks, however, have become very popular among young adults, teens and even pre-teens, many of whom do not always imbibe them in moderation.

I recommend that as part of a psychiatric evaluation a patient should be assessed for the use of these energy or power drinks, especially if irritability, anxiety, insomnia, headache, or lethargy and fatigue are a complaint. Why headache, lethargy and fatigue? Because that’s what occurs during withdrawal. The ‘weekend headache’ is a well known clinical entity among people who drink coffee on weekdays to get going on a workday but avoid or use less coffee on weekends.

As an aside, in my neighborhood it is best to avoid the coffee shop (you can guess which popular chain I’m talking about) when the middle school lets out about 3pm because the store is so crowded with students buying the caffeine and calorie loaded frappucinos.

There is a related topic to discuss. There is a trend among young people going out to party to combine alcohol with an energy drink. Why? To have the energy to keep on partying long after unopposed alcohol would have led them to become too drowsy or tired to continue. This increases the risk of alcohol poisoning. Until recently, if a person wanted to indulge in this combination, they had to do it on their own. Now, thanks to clever entrepreneurship, the drink manufacturer does it for you. You can now buy alcohol combined with caffeine (plus with many of those additional ingedients).

Here’s an article about a drink called Four Loko. The article mentions that it is also known as ‘blackout in a can!’

http://www.foxnews.com/health/2010/10/15/college-students-hospitalized-downing-alcoholic-energy-drink/

Today’s Quote

“The foolish man seeks happiness in the distance. The wise man grows it under his feet.” – Percy Shelley

Thanks and take care.

Jack Krasuski, MD
877-225-8384

Buprenorphine transdermal patch (Butrans): mixed opioid agonist / antagonist formulated as a transdermal patch is now indicated for the treatment of moderate to severe chronic pain that requires continuous treatment for an extended period of time.

Vardenafil (Staxyn): a phosphodiesterase type 5 (PDE5) inhibitor is indicated for the treatment of erectile dysfunction. Staxyn joins Viagra, Levitra, and Cialis.

Trazodone (Olpetro): an extended-release form of trazodone has received an indication for treatment of major depressive disorder in adults. Trazodone is a serotonin-antagonist reuptake inhibitor (SARI). It is an antagonist at 5-HT2A and 5-HT2C and a partial agonist-antagonist at 5-HT1A.

Doxepin (Silenor): the tricyclic antidepressant with prominent H1 antagonism has a new indication for insomnia. As Dr. Attarian educated us at the Master Psychopharmacology Course last March, doxepin is more effective and has fewer side effects than using trazodone for insomnia.

Memantine extended release (Namenda XR): the NMDA receptor antagonist indicated for the treatment of moderate-severe dementia of Alzheimer type, is now available in extended form. Starting dose is 7mg qd and the target dose is 28mg qd.

rTMS: There is no new indication for rTMS (rTMS treatment using the Neurostar machine was first approved in 2008 for treatment-resistant major depressive disorder). However, an interesting article on rTMS just appeared in Scientific American. You can read it here.

http://www.scientificamerican.com/article.cfm?id=transcranial-magnetic-stimulation-rtms 

Quote of the Day

“Several years ago I came back from a poetry reading by Chase Twichell, and told my software developer husband her three rules for making art: Tell the truth. Don’t decorate. Remember death.” – Evelyn Walsh

“In the master psychopharm course, one of your slides indicates cigarette smoke induces cyp450 enzymes.  It goes on to give psychotropics with decreased concentrations- implying the cyp450 induction is causing the decrease.  The meds listed here under benzodiazapines include Lorazepam and Oxazapam – however these are supposed to skip Phase I (Out The Liver).  So why are they being affected by cyp450 induction? Thank you, Jonathan”

Jonathan, great question. Short answer is this. Smoking does indeed induce metabolism of oxazepam and lorazepam. Both of these benzodiazepines are metabolized through glucuronidation (Phase II metabolism) rather than through oxidation (Phase I metabolism. It is well known that smoking induces some of the CYP 450 enzymes involved in oxidation. It is less well known (less studied and less reported) but true that smoking induces glucuronidation too.

Here are a few more details.

1. Polycyclic aromatic hydrocarbons (PAH) in tobacco smoke are implicated in inducing cytochrome P450 CYP1A1, CYP1A2 and possibly CYP2E1 (the latter, an enzyme not found in the brain).

2. The medications that may be affected through this CYP enzyme induction include the following: theophylline, caffeine, tacrine, imipramine, haloperidol, pentazocine, propranolol, flecainide, estradiol, and heparin.

3. Oxazepam and lorazepam are 3-hydroxy benzodiazepine derivatives whose major metabolic pathway is through conjugation to glucuronic acid at the 3-position, followed by urinary excretion of the inactive glucuronide metabolite. Approximately 70-75% of the administered dose is excreted as the glucuronide conjugate in the urine. The rest is excreted unchanged.

4. Cigarette smoke has been found to induce glucuronidation.

5. The benzodiazepines that have been found to be affected by smoking (whether it is through induction of oxidation or glucuronidation) include alprazolam, lorazepam, oxazepam, diazepam and demethyl-diazepam.  Chlordiazepoxide does not appear to be affected.

6. The clinical significance of these potential pharmacokinetic effects is unknown. At least one study found that smoking did not alter the mean serum concentration of diazepam or lorazepam.

7. All this means that for clinicians dosing decisions need to be based on the patient’s clinical response and dose changes made when efficacy or adverse effects change. Keep in mind that one reason patients may do worse in the weeks following a smoke-free hospitalization is related to returning to cigarette smoking, which could lower the levels of their medications. Of course, the psychosocial stressors are usually the main culprit in decompensations, but pharmacokinetic effects may play a role also.

8. I did not address this point here, but keep in mind that pharmacodynamic interactions with nicotine may also play a role in a drug’s effectiveness and / or level of adverse effects.

References

1. Desai et al, Smoking in Patients Receiving Psychotropic Medications: A Pharmacokinetic Perspective. CNS Drugs 15:6;2001

2. Zevin and Benowitz, Drug Interactions with Tobacco Smoking: An Update. Clinical Pharmacokinetics 36:6;1999

3. Greenblatt, linical pharmacokinetics of oxazepam and lorazepam. Clin Pharmacokinet 6:2;1981

4. Kyriakopoulos et al, Clinical pharmacokinetics of lorazepam: a review. J Clin Psychiatry 39:10;1978

Today’s Song

Today, rather than sharing a quote with you, let me share a song with you – it’s summertime after all. One of my hobbies for many years has been song-writing. I keep an eye out for great songs I can both appreciate and learn from. So today, let me introduce you to the Leonard Cohen song, “Hallelujah” as sung by Jeff Buckley.  Check it out on youtube. (You may already have seen it as it’s been viewed over 15 million times.).

 http://www.youtube.com/watch?v=y8AWFf7EAc4 

See you later. I’ll be in touch at the end of this week. We have an awesome Child & Adolescent Psychiatry Master Psychopharmacology course I want to introduce to you – the speakers are great, ones you’ll surely recognize.

Jack Krasuski, MD
877-225-8384

The surveyed doctors were asked these two questions.

•  ”Do physicians order more tests and procedures than patients need to protect themselves from malpractice suits?”
• “Are protections against unwarranted malpractice lawsuits needed to decrease the unnecessary use of diagnostic tests?”

Overall, 91 percent of doctors surveyed agreed with both statements.

There were no statistically significant differences among the different specialties. The only difference was between male and female physicians, with 94% of male doctors agreeing with the statements whereas only 86% of female doctors did so. A significant difference – yes – but doesn’t appear substantive to me.

What effect does this fear of malpractice lawsuits have on US physicians? The cost in physician stress is difficult to quantify, but in my judgment it is substantial. So many doctors I’ve talked to live with a low level chronic feeling of uncertainty and insecurity. And recall, I get to speak with psychiatrists, neurologists, surgeons, and internists. Doctors from every specialty have concerns.

On the other hand, the cost in dollars of defensive medicine to our economy has been quantified. In 2008 a healthcare research institute (PriceWaterHouseCooper) reviewed 35 studies of wasteful spending in healthcare.They found that approximately $1.2 trillion was wasteful out of total health care expenditures of $2.2 trillion! More specifically, they report that defensive medicine practices, such as ordering inappropriate or unnnecessary tests, accounted for a large share of the healthcare expenditure, approximately $210 billion annually, or about 10% of total spending. This defensiveness is not ill-founded. One of the common categories that result in medical malpractice lawsuits relate to wrong or missed diagnosis. So physicians are order more tests than clinically justified in order not to miss some occult medical condition, no matter how unlikely it is to occur.

There is one more unfortunate downside to this type of defensiveness (in addition to the increased costs.) It has to do with a statistical concept called positive predictive value. If a test is ordered on a patient when the pretest likelihood of the medical condition that the test is meant to identify is low, then a positive result (indicating presence of that medical condition) is more likely to be a false positive rather than a true positive. Then, once a patient has a positive result that often leads to more tests and even treatments provided for a condition that does not exist. Think “iatrogenic complications.”

In the next post I will have more specific information for psychiatrists regarding this troublesome area.

Today’s Quote

“Without self-expression, life lacks spontaneity and joy. Without service to others, it lacks meaning and purpose…. Conceiving of ourselves as artists in whatever work we do gives us a metaphor for a life of integrity, service, enjoyment, and excellence.”- Laurence G. Boldt

Take care and please stay in touch.

Jack Krasuski, MD
Executive Director
877-225-8384

    .

Tramadol Suicide Warning

Tramadol (Ultram) is a centrally acting synthetic opioid analgesic indicated for the management of moderate to moderately severe chronic pain. On May 25, 2010 the FDA directed its manufacturer to add to its package insert a warning of increased suicide risk. The FDA announcement states that “the strengthened Warnings information emphasizes the risk of suicide for patients who are addiction-prone, taking tranquilizers or antidepressant drugs and also warns of the risk of overdosage.”

Tramadol has a dual mechanism of action. It is a mu opioid receptor agonist. Both the parent compound of tramadol as well as its M1 metabolite have these agonist properties, with the M1 metabolite a more power analgesic than the parent compound. The second mechanism of action of tramadol is its norepinephrine and serotonin reuptake inhibition. So in effect tramadol is a SNRI. This property may add to its analgesic effect (recall that duloxetine also decreases the pain experience) as well as lead to its suicide increasing potential, an effect seen among antidepressents when used by young people. It is also this SNRI effect that can lead to development of a Serotonin Syndrome when tramadol is used in conjunction with an SSRI, SNRI or MAOI.

Note that tramadol is sold under the brand name of Ultram and Ultracet (tramadol with acetominophen).

New Symbyax Indication

Symbyax’s (olanzapine / fluoxetine combination) previous indication was for the treatment of Bipolar Depression. Its new indication is for treatment of treatment-resistant depression. The package insert states that it is indicated for patients who have failed 2 separate trials of different antidepressants taken at adequate doses for an adequate time. The recommended starting dose for this new indication is 6mg / 25 mg (olanzapine / fluoxetine) taken qpm. Highest recommended dose is 18mg / 75 mg.

New Zyprexa & Symbyax Warnings

In January 2010 the FDA added the warning to Zyprexa and Symbyax (olanzapine / fluoxetine combination) of the risk of increased prolactin levels. A change from normal to elevated prolactin levels was seen in 28% of adults treated with Symbyax and in 30% of adults treated with Zyprexa. These rates were significantly higher than among the placebo groups (5% and 10.5% respectively).

Clozaril & Obsessive Compulsive Risk

In February 2010 one of the package insert changes approved by the FDA is the risk of developing obsessive compulsive symptoms during use of clozapine. I’m glad to see this addition because in my years of prescribing clozapine I had a about 10% of my patients develop new-onset OCD during clozapine use. The OC symptoms ranges from mild to severe. Among these patients, I had to switch meds, decrease dose, or add fluoxetine as a result. I’d certainly recommend warning patients of this possibility when starting clozapine. Other 2010 changes to Clozaril’s warnings are: 1. increased risk of diabetes mellitus, 2. increased risk of fatal pneumonia, 3. drug interaction with tobacco smoke which can lower clozapine levels, and 4. increased risk of cerebrovascular events in dementia patients.

Jack Krasuski, MD

877-225-8384

Here are some that I use for various purposes.

For Patient Handouts

The FDA has a webpage that includes patient handouts for most of the psychotropic agents we prescribe. These are the informational handouts that the drug companies provide the FDA. Their strength is that they are rather complete. They also provide you safety by virtue of being submitted to and approved by the FDA. One downside is that some of them really drill heavily into the risk in a way that may scare patients. Take a look – this page may be a good resource.

http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm

For New Medications

The FDA approves new medications and new indications. But try finding out this information on the FDA website – it’s not easy. So I go to a webpage that has all FDA approvals by year. I look at this page every couple of months when I’m updating the Med Quik Guide.

http://www.centerwatch.com/drug-information/fda-approvals/

For Package Insert Information

If you don’t have epocrates or a PDR handy you can go to either of these websites for drug information.

http://www.rxlist.com

http://www.drugs.com

I use both of these sites and choose based on which site loads more quickly. Note that on drugs.com when reviewing a medication, switch to the “for health professionals” view. That will give you the prescribing information. When in the “for patients” view, the information is quite good and can be recommended to patients for review.

For Drug Interactions

Many drug interaction websites are not very effective because they provide you with too much pharmacodynamic drug-drug interactions, such as warning you from giving for example paroxetine with clonazepam due to the CNS depressant effects, or with amphetamine due to increased CNS stimulatory effects. This is important, of course, but is information we know. We are usually looking for more specific drug-drug interactional effects, especially pharmacokinetic ones that affect metabolism.

One that may be useful to you is the drug checker on medscape. You enter in the drugs your patient is taking and provides you with the interactions. I like it because it also provides references, a helpful feature when I’m writing lectures. (If you have trouble accessing it means you may need to become a medscape member. Go to the home page. )

http://www.medscape.com/druginfo/druginterchecker

Write me of your favorites and I’ll include in a follow up post. Thanks much.

Jack Krasuski, MD

877-225-8384

Today I’d like to share with you a mental picture I developed that helped me be a more effective clinician that at the same time also took much of my stress away. Here it is.

 I would imagine the patient I was face-to-face with as a person being dragged down underwater and drowning. Being underwater represented their mental illness with all its associated desperate thoughts, dysphoric emotions and frightening psychotic symptoms. Being above water represented mental health and it was my job to help them get their heads back above water.

Further, I imagined the reason they were underwater was because there were many, many bricks tied by ropes to different parts of their bodies. The bricks represented all of the contributors to their mental illness, both the vulnerability factors and the acute triggers. It was my job to one by one cut the ropes to free the patient from the things that were weighing them down and leading to them ‘drowning.’

This picture worked for me and still does is because it incorporates the following concepts.

1. I see the patient as naturally bouyant just as they are naturally self-protective and self-healing. Patients, like all people, have access to many, many internal and external resources to help them survive and even thrive in life. It is the presence of an overwhelming level of negative stresses and problems, that keeps patients from making greater use of their positive resources. So I saw my job not so much as ‘fixing’ patients as much as giving thier natural self-healing qualities and resources an opportunity to work. I did that by finding ways of decreasing the burden of the contributors to their mental illness. I saw my job as one-by-one cutting the ropes that would release their ‘bricks’ and allow them to ‘float to the top.’

2. My picture reminded me that patients usually have a lot (a lot!) of contributors to their illness. It almost always included bio, psycho, and social contributors. I didn’t worry about the contributors that were not possible to change. As you know, there are demographic factors (age, gender, race) that are associated with certain mental illnesses. But I couldn’t change those. There are also vulnerabilities factors such as parental loss at a young age or a history of childhood abuse or neglect. But I couldn’t go back in time to change those. On the other hand there were Oh so many contributors I could change. It was my job to address each as best I could. Each time I cut a brick off one of my patients, it increased their chances of being able to overcome the weight of the remaining contributors to their pathology.

3. My picture further reminded me that I didn’t have to be perfect. I didn’t have to rid patients of every problem confronting them. I would just proceed (with expressed calm and confidence) to address the contributors one by one. And each time I lessened to a smaller or greater extent the burden of the contributors that maintained their illness. I couldn’t know and and the patients couldn’t know at what point their natural self-healing (their natural bouyancy) would be able to overcome the remaining burden of stressors.

Let me give you an example of all the ‘bricks’ one of my patients carried around with her. She was a woman in her early fifties, who worked as an HR manager at a large manufacturing company. She developed a severe and treatment resistant depresssion. (After many, many medication regimens she eventually responded to a regimen of mirtazapine, lorazepam, T3, and lithium. Either it was just the right regimen for her or perhaps the passage of time was the curative factor!)

This patient felt overwhelmed on a daily basis. She had to care for her elderly mother with early dementia; she had a unsupportive husband with whom she was frequently in conflict; and she was spending ridiculously long hours at her job because everyone at her plant would use her not only as the HR resource that she was, but also as a couples counselor, immigration attorney, parole officer, addiction specialist, and so forth. She could never say no and was often way behind on her own work. She was also overweight, didn’t exercise, had lost touch with her friends, and didn’t have any time for herself.

Now think about this (incomplete) picture of this patient. Imagine all the different bricks you can cut away from her. I never had a shortage of interventions that I could incorporate into her treatment that could lead to a lessening of her burden and a strengthen of her internal and external resources. I was never at a loss and thus, never overwhelmed or stressed out – although I empathized with her pain. I could help her even in a med mgt session by conveying in a matter of 2-5 minutes a helpful intervention. I kept my calm and positive attitude, which is what she needed, as I also went about trying different med regimens.

These are just some of the ‘bricks’ I focused on trying to cut away.

• I helped her (through role playing) to find a way to ask her sister to help out caring for their disabled mother.
• I met with her and her husband and explained depression, its contributors and consequences, so that the husband could be little bit more supportive.
• I recommended couples therapy and gave examples of how they were causing each other distress with their unexamined and unmet expectations of each other. I also explained how they could each get more of what each wanted wanted through better communication and negotiation skills.
• I engaged her in examining and challenging some of her cognitions surrounding her inability to set reasonable boundaries at work. 
• I gave her ‘doctor’s orders’ to go out with friends for a regular ‘girls-night-out.’
• I had her start MVIs, gave her tips on how she could eat healthier lunches, and forced her to incorporate moderate exercise into her day.
• I helped her see (through reframing) that she could be an even greater force for good in the world, which was part of her self-identity, by ensuring that her own needs were met. The concept of taking care of her needs always had caused her pangs of guilt- it was the way she was brought up. 

So there you have it, my mental picture. Try it out. If it doesn’t work, develop your own picture or idea. Whatever the specifics of the image or idea you develop is less important than the fact that you have one. It can help you avoid burnout, and feelings of helplessness and lack of control.

If you have your own image / thought, please share it with me and I’ll share with our colleagues.

Today’s Quote

“Understand that the right to choose your own path is a sacred privilege. Use it. Dwell in possibility.”- Oprah Winfrey

Take care,

Jack Krasuski, MD
877-225-8384

Dr. Carlat is the founder and chief editor of The Carlat Psychiatry Report. This monthly newsletter has thousands of subscribers. In fact, 10% of all the psychiatrists in the USA are his readers.

Dr. Carlat is also known for his stance against the undue influence of the pharmaceutical industry in medical education and training. He garnered much attention when an article of his experiences and his viewpoint was published in the New York Times Magazine in 2007. It is called “Dr. Drug Rep” and the link is below.

http://www.nytimes.com/2007/11/25/magazine/25memoir-t.html 

In addition, he has contributed several op-ed pieces to the New York Times. Here’s one called Diagnosis: Conflict of Interest.

http://www.nytimes.com/2007/06/13/opinion/13carlat.html  

So, learning from and meeting Dr. Carlat is yet another good reason to join us at the MPP March 12-14, 2010.

Take care and see many of your there.

Jack Krasuski, MD

877-225-8384

                                 .

Pharmacokinetics & Pharmacodynamics

First, DDIs can be split into those due to Pharmacokinetic Mechanisms and those due to Pharmacodynamic Mechanisms. Don’t be intimidated by these multisyllabic terms. I will first describe the terms pharmacokinetics and pharmacodynamics and then I will explain how DDIs occur by the different pharmacokinetic and pharmacodynamic mechanisms.

Pharmacokinetics refers to the movement (kinesis) of a drug (pharmaco). So just think about how a drug moves through the body, from beginning to end, and you will know what pharmacokinetics focuses on. It is traditionally divided into these four aspects: Absorption, Distribution, Metabolism, and Elimination. For the sake of completeness, we will break out Protein Binding as a separate mechanism. You can have DDIs occur at any of these five pharmacokinetic points.

Now, let’s turn our attention to pharmacodynamics. Pharmacodynamics focuses on the modes of action of a drug on the organism. When dealing with psychotropics, the drugs’ intended site of action is the neuron. So pharmacokinetics are all the ways the body deals with the drug up to the point of the drug’s site of action. And pharmacodynamics is how the drug affects the body at the drug’s site of action, which is again, in the case of psychotropics, the neuron.

Now, these are some (not all) of the main pharmacodynamic points at which one drug can affect the actions of another drug: the release of neurotransmitter, at the transporter, and at the post-synaptic receptor.

OK. Now let me give you examples of each.

Pharmacokinetic Mechanisms of Drug-Drug Interactions

DDIs Related to Absorption   

One drug can effect the rate of absorption or the extent of absorption of a second drug. For example, the proton-pump inhibitors, that make the gastric environment less acidic, can increase the bioavailability of acid-labile drugs like penicillin.

DDIs Related to Distribution

One drug can indirectly change the volume of distribution of another drug. For example, diuretics that cause diuresis of body water that can lead to decreases in the volume of distribution of water-soluble drugs like lithium, leading to increased levels in plasma and tissues. (Diuretics additional affect lithium levels by increasing renal reabsorption of lithium, still another DDI mechanism).

DDIs Related to Proteim Binding

Drugs in blood exists in one of two forms, protein-bound and free drug. Only the free drug can reach its site of action to produce an effect on the body. So a DDI can occur if one drug displaces another drug from its plasma protein-binding site, increasing levels of free drug. For example, warfarin is approximately 99% bound to plasma albumin. Certain antibiotics can displace warfarin and lead to much increased concentrations of unbound drug.

DDIs Related to Metabolism

This is a multi-faceted mechanism and the cause of many DDIs. I will discuss drug metabolism in more detail in a later post. For now note that drugs can affect the metabolism of other drugs through inducing or inhibiting the enzymes that metabolize drugs. The enzymes involved include the CYP 450 series of isoenzymes. For example, carbamazepine can induce its own metabolism and that of other drugs such as oral contraceptives. On the other hand, other drugs such as erythromycin can inhibit the metabolism of carbamazepine. (I chose erythromycin because its inibitory effect on CYP 3A4 was the focus of a recent psychiatry board exam question.)

DDIs Related to Elimination

Several of the NSAIDS act to decrease the elimination of lithium, thus potentially increasing lithium concentrations to toxic levels.

Pharmacodynamic Mechanisms of Drug-Drug Interactions

When it comes to Pharmacodynamic DDIs, they can occur even when drugs have different mechanisms and sites of action. The DDIs can occur when the drugs’ effects on a particular neurotransmitter system are additive or subtractive, even if they occur at different points of neurotransmission. Below are the main sites of action of drugs and an explanation of how these interactions can occur.

DDIs Related to Neurotransmitter Release

A drug’s mechanism of action can be its direct release of a neurotransmitter. DDI’s can occur if this drug is combined with another drug that has synergistic effects on the same neurotransmitter system. For example, one of the mechanisms of action of amphetamine is the release of dopamine and norepinephrine. If you combine it with a drug that inhibits the Dopamine and Norepinephrine Reuptake Transporters, such as Bupropion, you can theoretically trigger a noradrenergic (hypertensive) crisis.

DDI’s Related to Transporter Inhibition

The most frequently prescribed antidepressants are the SSRIs, the Specific Serotonin Reuptake Inhibitors. And how are these medications inhibiting reuptake of serotonin? By interfering with the function of the Serotonin Reuptake Transporter (SERT). This has the effect of extending the duration that serotonin, once released, is allowed to interact with the post-synaptic receptors. If you combine two SSRIs/SNRIs they may inhibit the SERT more strongly, possibly leading to serotonin syndrome. But you can also precipitate a serotonin syndrome by combining an SSRI/SNRI with a medication that does not inhibit the SERT. A good example is an MAOI. MAOIs are not SERT inhibitors. Rather they act by inhibiting the enzyme that breaks down the monoamines (i.e., serotonin, norepinephrine, epinephrine, dopamine). So if you combine a SSRI/SNRI, a drug that inhibits the reuptake of serotonin with an MAOI, a drug that inhibits its breakdown, you also can precipitate a serotonin syndrome.

DDI’s Related to Receptor Activation

Notice that both the SSRI/SNRIs and the MAOIs are not acting on the post-synaptic serotonin receptors. Rather they are, in their own ways, making the brain’s own serotonin more available to do its work. Some drugs, however, do have as their mechanism of action a mimicking of the brain’s own neurotransmitters, and are interacting directly with receptors. For example, the triptans, the medications used to treat migraines, are 5HT1b agonists. They mimic real serotonin, at least when it comes to activating this specific subgroup of post-synaptic serotonin receptors. Here again you can have a DDI by combining a triptan with an SSRI/SNRI or with an MAOI, even though these three classes of meds have different mechanisms of action. Their effects on the serotonin neurotransmitter system are additive. Combining a triptan with one of these antidepressants has led to life-threatening cases of serotonin-syndrome.

OK, if this wasn’t bad enough, many drugs affect each other through both pharmacokinetic and pharmacodynamic mechanisms. There are a mind boggling number of possible interactions, and nothing we can hope to keep in mind.  I do hope this essay has clarified things at least conceptually.

I do want to ask you a favor. I have been disappointed with so many aspects of my own psychiatric training. I have made it one of my career goals to present psychiatrically-relevant information and skill-building guidance to you, my colleague, that is simpler to understand, that will give you a conceptual clarity that you may not have had previously. I would like to know if what I presented here is something that has clarified things for you. Or perhaps not. I can’t know if I’m on the right track without your advice. So please leave me a comment. Tell me what you think and what I can improve. Your email does not show up on the comment, so it can be anonymous.

Thanks and take care.

Jack Krasuski

877-225-8384

Axona (caprylidene): A Medical Food for the treatment of Alzheimer’s disease, Approved March 2009 (Company Accera)

Edluar (zolpidem tartrate): For the treatment of insomnia, Approved March 2009 (Company Orexo)

Fanapt (iloperidone): For the treatment of schizophrenia, Approved May of 2009 (Company Vanda)

Intuniv (guanfacine extended-release): For the treatment of ADHD in children and adolescents, Approved September 2009 (Company Shire)

Paliperidone Palmitate Depot Injectable: For the treatment of schizophrenia. Approved November 2009 (Company Janssen)

Saphris (asenapine): For the treatment of schizophrenia and manic or mixed bipolar 1 episodes, Approved August of 2009 (Company Schering-Plough)