The Heuristic is Dead - Long Live The Heuristic

One of the latest non-scandals to rock monolithic psychiatry and psychiatrists everywhere is David Healy's commentary on serotonin and depression (1).  Certainly nothing new there from the Healian perspective - SSRIs don't work, SSRIs don't work for melancholic depression, no evidence that SSRIs raise or lower serotonin levels, SSRIs pushed tricyclic antidepressants out of the market, and SSRIs forced the abandonment of research on biological disturbances in depression like hypercortisolemia.  The only thing I did not see was the idea that SSRIs are somehow addicting because they cause discontinuation symptoms in a subgroup of people who take them.  Feel free to call that a withdrawal syndrome, but withdrawal does not constitute an addiction.  All of these premises allow him to reject serotonin and it's role in depression on the vaguest possible grounds while stating that it is not irrelevant:

"Serotonin is not irrelevant.  Just as with noradrenaline, dopamine, and other neurotransmitters, we can expect some correlation with personality and temperament."

Indeed - but I expect those to be a very weak correlations probably not on par with the mood disorder work.  I was glad to see his reference to the late Marrku Linnoila (2) or more specifically Linnoila and Virkkunen.  Linnoila had done some of the outstanding work in this area and work on serotonin metabolites (CSF HIAA) in alcohol use disorders remains a classic.  He talks about the serotonin based research running into the sand.  I did a Medline search of serotonin and major depression and plotted the papers per year and there does not seem to be any precipitous fall off (the 2015 references are through March).  If anything I would expect the research to increase with the availability of ligands for additional receptors and the further characterization of serotonin transporter (SERT) variants.

But the main problem with Healy's argument is that he is talking about serotonin as if there is a chemical floating around in the brain and that is it.  He is basically describing his own brand of chemical imbalance theory.  So if he is saying there is no serotonin chemical imbalance theory I would of course have to wholeheartedly agree with him.  And in fact, I would tell him the same thing I told the Prozac rep back in the 1980's:  "The brain is far more than a bag of chemicals.  Unless you can say something about brain structure and physiology naming a neurotransmitter is meaningless."  There is no such thing as a chemical imbalance theory and reading through the index of any psychopharmacology text printed in the past 30 years will confirm that.

Healy can't stop himself at that level.  He goes on to describe the impact of his chemical imbalance theory on clinicians:

"This history raises a questions about the weight doctors and others put on biological and epidemiological plausibility.  Does a plausible (but mythical) account of biology and treatment let everyone put aside clinical trial data that show no evidence of lives saved or restored function?"

Things get very tenuous at that point.  As a clinician who has made a career out of treating patients with the most severe problems  I don't care at all about the "biological and epidemiological plausibility" of a theory of a medication.  I got past that in the 1990s when the elegant Nobel laureate mechanism of action of aminophylline was debunked and the former first line drug for asthma and COPD exacerbations was suddenly relegated to tertiary status.  And even then, with the people I was running up on gurneys from the emergency department while calculating the parameters of their aminophylline drip - not a patient of mine was lost.  I suppose you could say it was all an elaborate placebo response, treating all of those people with acute shortness of breath bad enough to be brought in by paramedics.  I was after all using a tertiary treatment with a disproven molecular mechanism.  But really?  And my living, breathing pulmonary patients did not seem to mind.

The only thing that matters to me is if the medication works in my hands, has few side effects, and I am using it exclusively to save lives and restore functioning.  And without keeping anyone in suspense, I do prescribe SSRIs and they do work, and I do fully acknowledge to anyone willing to listen that the mechanism of action is unknown. Not surprisingly many patients want more than that and I can discuss speculative mechanisms as well as the next psychiatrist.  I don't think that makes me a drug company stooge or an idiot, because I am the only person with any accountability in the entire scheme of things.  It really doesn't matter to me what David Healy or anybody else thinks.  I am seeing very ill people and it is my job to get them better and not cause them side effects with the medication and not have the drug interact with one of their underlying medical conditions.  When you get right down to it, I don't need a mechanism of action to use a medication - only the approval of a regulatory body like the FDA.  At some point somebody may say that  SSRIs are no better for depression than aminophylline was for asthma, but so far (apart from Healy and various sympathizers) that has not happened.  I just attended a CME conference last weekend and they were still recommended.  As far as I know the FDA has not sent out any letter to doctors telling them not to prescribe them any more.

Healy also asks the irrelevant question:  "Do clinical trial data marketed as evidence of effectiveness make it easier to adopt a mythical account of biology ?"  Or I guess the real question is do these data make it easier to accept this strawman?  I strongly encourage any psychiatrist to read and reread the FDA approved package insert on any drug they prescribe and any drug their patient happens to be taking.  I encourage reading and rereading those package inserts especially if they are updated and sent out in a mass mailing by the FDA.  These package inserts need to be studied because they are not the final word in safe prescribing.  If you are an experienced psychiatrist you will routinely be called on to decide if a medication (based on all of the available evidence) is safe to prescribe to a patient with cardiac, liver and renal disease.  You will have minimal data to go by in most cases, because people with significant medical illness are typically eliminated from clinical trials.   Any psychiatrist reading those package inserts will recognize that for some time now, the package inserts have contained clinical trials data and that data is very useful.  It's utility has nothing to do with putative biological mechanisms, it has to do with safely monitoring and prescribing the medication.  The other consideration implicit in this question is that clinical psychiatrists are unaware that clinical trials are really a primitive technology.  Given that awareness exists, why would anyone accept clinical trials data as proof of much of anything.  How in the world does a double-blind placebo controlled study with an intent to treat analysis have anything at all to do with my practice of psychiatry?  It is totally irrelevant clinically and even less relevant theoretically.  Its only use is to get a new drug in my hands that my patients and I will accept as useful or reject as too toxic or worthless.

Why are reasonable people interested in serotonin despite Healy's commentary?

The complexity of serotonin or more appropriately serotonergic signaling for one.  Absolute levels of neurotransmitters are rarely the issue in complex disorders.  In the case of serotonin any bare bones discussion needs to consider the fact that there are 14 serotonin (5-HT) receptor subtypes coded by 18 genes.  Those receptors are organized into 7 families, 6 of which are G-protein receptor linked superfamily.  The remaining family is part of the ligand-gated ion channel superfamily.  The combinatorics of these receptor types, their specific locations, and their genetic variants can lead to a dizzying number of signaling variations that can easily be found in psychiatric research (4).  As an example, this is from a 2013 review of serotonin signaling in depression and suicide by Mann (3):

".......Part of the neurobiology observed in recurrent major depression, that is present between episodes as well as during episodes, is a series of abnormalities in the serotonergic system [19]. Cerebrospinal fluid (CSF) levels of the main serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), are low in more lethal suicide attempters, and predict the risk for future suicide with an odds ratio of 4.6 [20].  Convergent evidence comes from some reports of low CSF 5-HIAA in suicide attempters with other diagnoses such as schizophrenia [21,22], bipolar disorder [23] and personality disorders, although there are fewer studies and less consensus in these other disorders [24,25]. Nevertheless, if correct, such findings suggest that less serotonin transmission, as implied by less 5-HIAA, appears to be associated with suicidal behaviour across psychiatric diagnostic boundaries, as would be expected if it were associated with the diathesis for suicidal behaviour instead a specific psychiatric disorder. A review of post-mortem brain studies of suicides has found much the same thing: most studies find suicides have lower levels of serotonin and/or 5-HIAA in the brainstem serotonin neurons compared with psychiatric-matched groups [26–28]."
   
Apart from all of the disputed technical details, what is the importance of the Healy commentary?  It follows the political tradition of other commentaries mentioned on this blog by prominent psychiatrists.  People have sent me e-mails and asked me: "What do you mean by political?"  In the simplest analysis it is taking one end of a polarized position and running with it and bringing everything that you can to support that position.  That is the classic way that politicians work.  They are fueled by ideology.  On the surface, it seems that science operates like that as well, but ongoing scientific arguments don't include comments about marketing or words like "neurobabble".  They don't make assumptions about how clinicians think or whether they are confusing science and hypothesis testing with clinical work.  The best science encompasses complexity and contradictory data and we are past the point where neuroscience can be watered down for the masses in a 2 minute sound bite.

Neurobabble happens when a neuroscience discussion is reduced to a sound bite and debated the way that Democrats and Republicans discuss just about anything.  That is what happens when we are all polled "Serotonin - yes or no?"

If you really want to get your opinion out in the press that way that is one thing.  Let's not pretend that psychiatrists really think this way or that psychiatrists are just flunkies for Big Pharma talking about some crazy chemical imbalance theory or that we based our clinical practice on heuristics or for that matter marketing.

Psychiatrists are really bright people, time to stop pretending that we are not.


 George Dawson, MD, DFAPA



References:

1: Healy D. Serotonin and depression. BMJ. 2015 Apr 21;350:h1771. doi: 10.1136/bmj.h1771. PubMed PMID: 25900074.

2:  View my collection, "Marku Linnoila" from NCBI

3: Mann JJ. The serotonergic system in mood disorders and suicidal behaviour. Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368(1615):20120537. doi: 10.1098/rstb.2012.0537. Print 2013. Review. PubMed PMID: 23440471

4:  KEGG.  The Serotonergic synapse.

5: Albert PR, Benkelfat C. The neurobiology of depression--revisiting the serotonin hypothesis. II. Genetic, epigenetic and clinical studies. Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368(1615):20120535. doi: 10.1098/rstb.2012.0535. Print 2013. PubMed PMID: 23440469

6: Albert PR, Benkelfat C, Descarries L. The neurobiology of depression--revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philos Trans R Soc Lond B Biol Sci. 2012 Sep 5;367(1601):2378-81. doi: 10.1098/rstb.2012.0190. PubMed PMID: 22826338

Serotonin Syndrome at The Tipping Point

I spend a lot of my time trying to prevent Serotonin Syndrome (SSyn) and in recognizing it early enough prevent major complications.  I think that I have a fairly good record of doing this, but the statement is qualified by the fact that the likely incidence of SSyn is very low.  What is even more amazing is that if you look at the graphic, a large number of very common medications are implicated in serotonin (5-HT) turnover, signaling, and metabolism.  It is very common for me to see combinations of an SSRI or SNRI antidepressant and trazodone.  Some patients are also taking serotonergic migraine medications like sumatriptan, rizatriptan, zolmitriptan, frovatriptan, naratriptan, and almotriptan.  These migraine drugs are all 5-HT1 receptor agonists with varying affinities for subtypes of this receptor.  They are commonly encountered in clinical psychiatry in patients with chronic depression, chronic headaches and poorly controlled migraines.  In some cases these patients are also on valproate for migraine prophylaxis.  Any computerized drug interaction search will frequently flag 3 or 4 medication combinations that increase the risk for SSyn.  Reading the literature and practicing psychiatry results in a broad appreciation of SSyn including the broad range of precipitants and presentations.  The syndrome can be triggered by as little as a single dose of an SSRI type antidepressant.  On the other hand millions if not tens of millions of people tolerate combinations of serotonergic medications as suggested in the above diagram and in fact some of these combinations are recommended by experts for treating depression.

The presentation of SSyn will vary on who you ask.  If you are asking acute care internists or hospitalists, they are likely to say that it is an acute mental status change - usually delirium accompanying a toxic reaction to a drug.  If you ask movement disorder experts (1, 2), they may describe it as confusion, myoclonus, rigidity, and restlessness and list it in the differential diagnosis of those movement disorders and ataxia.  Psychiatrists should have the lowest threshold since we are prescribing more serotonergic medications, using augmentation strategies, and generally follow patients more closely.  I have seen it develop very gradually with onset of muscle pain secondary to hypertonia.  At that point the patient describes clear cut muscle pain and may have difficulty walking or with balance.  In consult settings, I have seen people with acute delirium completely unresponsive with ataxic breathing to the point I had to suggest an ICU setting and mechanical ventilation.

Harvey Sternbach is credited with coming up with the first diagnostic criteria for SSyn (3).  At the time his article was published in 1991, there were many descriptions of syndromes that were thought to be due to serotonergic hyperstimulation, both in humans and animals.  He analyzed 12 case reports covering 38 patients.  In the majority of these patients, the manifestations lasted for a period of 6 hours to 4 days.  There was one fatality in this case series,  where the patient developed seizures, hypotension, and disseminated intravascular coagulation.  Sternbach also discusses a second death from the literature where the patient presented with probably SSyn that was mistaken for Neuroleptic Malignant Syndrome (NMS).  As the patient was treated for NMS she developed disseminated intravascular coagulation, renal failure, hepatic failure and died.  In both of those cases, the patients were taking monoamine oxidase inhibitors with tryptophan and fluoxetine or lithium.  This was about the time that tryptophan was removed as a supplement from the American market and the author comments that this might reduce future risk.  Sternbach laid out his Suggested Diagnostic Criteria for Serotonin Syndrome based on that analysis:  

"A. Coincident with the addition of or increase in a known serotonergic agent to an established medication regimen, at least three of the following clinical features are present: 1) mental status changes (confusion, hypomania) 2) agitation 3) myoclonus 4) hyperreflexia 5) diaphoresis 6) shivering 7) tremor 8) diarrhea 9) incoordination 10) fever 
B. Other etiologies (e.g., infectious, metabolic, substance abuse or withdrawal) have been ruled out. C. A neuroleptic had not been started or increased in dosage prior to the onset of the signs and symptoms listed" (from reference 3, p. 713)

SSyn appears to be a major omission in DSM-5 (6).  The manual contains a cursory description of NMS in the section Medication-Induced Movement Disorders and Other Adverse Effects of Medication (pp. 709-714) but the only reference is in the differential diagnosis of NMS:

"Neuroleptic malignant syndrome also must be distinguished from similar syndromes resulting from the use of other substances or medications, such as serotonin syndrome; parkinsonian hyperthermia syndrome following abrupt discontinuation of dopamine agonists; alcohol or sedative withdrawal; malignant hyperthermia occurring during anesthesia; hyperthermia associated with abuse of stimulants and hallucinogens; and atropine poisoning from anticholinergics." (p. 711).

A syndrome this important needs at least equal time in the DSM-5.  In average clinical practice serotonergic medications and the flagged side effects in electronic databases probably far exceeds the concerns about medications for Parkinson's Disease and antipsychotic medications causing NMS.  The role of antidepressants in movement disorders especially myoclonus and akathisia should not be underestimated.

The most recent approach to diagnosis of SSyn has been the application of the Hunter Criteria (4).  In their original paper the authors point out that the diagnosis was typically made on the basis of recognizing 3/10 of Sternbach's criteria, but those features had low specificity and were present in other toxidromes.  The Hunter Criteria were developed by a toxicology service observing people with overdoses of serotonergic agents and were therefore more specific.  A single feature like spontaneous clonus or combinations of features like tremor and hyperreflexia or inducible clonus and diaphoresis leads to a diagnosis of serotonin toxicity (see the paper for all of the variations).

As a practicing and teaching clinical psychiatrist who has worked across a number of settings, it is critical that all psychiatrists known about SSyn and familiarize themselves with the diagnosis and acute treatment.  I have listed some of my preferred strategies in the table below on prevention and early recognition.  It is safe to say that the earlier the recognition, the better the outcome.  That is another reason why I don't suggest to anyone that they need to "get used to" a medication or even take an antidepressant if they tell me that they can't tolerate one.  It is also why the toxicity of the medications needs to be carefully explained to anyone taking them, and as a physician I have to believe that either that person or their representative will call me if there are problems.  There also needs to be a high level of vigilance for new agents that can potentially precipitate SSyn.  I recently investigated Suboxone and found a case report that when it was added to tricyclic antidepressants it precipitated the syndrome (5).
 

George Dawson, MD, DFAPA



1:  Stanley Fahn,  Joseph Jancovic.  Principles and Practice of Movement Disorders.  Churchill Livingstone Elsevier.  Philadelphia, PA, 2007.

2:  Mark Forrest Gordon,  Adena Leder.  Serotonin Syndrome.  in Movement Disorder Emergencies; Steven J Frucht, Stanley Fahn (eds).  Humana Press, Inc; Totawa, New Jersey 2005: pp 175-193.

3:  Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991 Jun;148(6):705-13. Review. PubMed PMID: 2035713.

4:  Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust. 2007 Sep 17;187(6):361-5. Review. PubMed PMID: 17874986.

5:  Isenberg D, Wong SC, Curtis JA. Serotonin syndrome triggered by a single dose of suboxone. Am J Emerg Med. 2008 Sep;26(7):840.e3-5. doi: 10.1016/j.ajem.2008.01.039. PubMed PMID: 18774063.

6:  American Psychiatric Association.  DSM-5  Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.  Arlington, VA, American Psychiatric Association, 2013.


Supplementary 1:

For an additional graphic of Serotonin Syndrome with a glossary of the abbreviations take a look at this link.

Vortioxetine

I have been hearing about the new antidepressant vortioxetine (marketed under the brand name Brintellix).  I decided to post something about it because there have been numerous searches that resulted in hits on this blog looking for information on this medication.  As a consultant, I am probably not in the best position to start prescribing this medication.  The majority of the people I see are already on at least one antidepressant and they have typically tried many.  The  common mistakes of ten years ago like inadequate dosing are not as prevalent.  Augmentation strategies like the addition of bupropion, aripiprazole, and buspirone are common. In primary care settings nobody uses lithium or T3 anymore.  Apart from mood disorder specialists, nobody uses monoamine oxidase inhibitors.  I am just getting to the point where I am seeing people who have responded to vilazodone when nothing else seemed to work.  Even then the numbers are very low.  

What if anything is unique about vortioxetine?

Looking at the package insert, it is approved for the treatment of major depressive disorder and nothing else.  The date of approval was 9/30/2013.  It has the standard contraindications, black box warning and warnings of most antidepressants.  It is a substrate of CYP2D6 and therefore the dose needs to be decreased with inhibitors and increased with inducers of this enzyme.  Other cytochromes CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6 also play minor roles in the metabolism.  The metabolite is inactive.   Discontinuation symptoms are also mentioned in the package insert citing headaches and muscle tension following abrupt discontinuation.  The manufacturer states that in anyone taking 15 or 20 mg/day that the dose should be decreased to 10 mg/day for a week before discontinuation is done.  Vortioxetine has a 66 hour half-life.

There is generally more detailed pharmaceutical and pharmacodynamic information in recent FDA approved package inserts and vortioxetine is no exception.  As noted in the graphic below it is a potent inhibitor of serotonin reuptake by 5-HTT (SERT) on the same order of magnitude as escitalopram.  The pharmacology of serotonin receptors (right column) is complex.  I have highlighted the serotonin receptors that vortioxetine binds to with Kis of < 100 nM.  The drug is also an antagonist at 5-HT3, 5-HT1D, 5-HT7, a 5-HT1B partial agonist, and a 5-HT1A receptor agonist. (all values in package insert).

Serotonin pharmacology is complex.  One review (2) written by PharmDs with no financial conflicts of interest described the vortioxetine as a "novel multimodal antidepressant agent with a complex mechanism of action".  They suggest that the pharmacodynamic profile "results in increased levels of serotonin, norepinephrine, dopamine, acetylcholine, and histamine."  Interestingly, there has been no comment that it has a greater binding affinity (113) for the norepinephrine transporter (NET) than SNRI venlaxine (385) but not the SNRI duloxetine (70). (see table below).

Also contained in this package insert is information about serotonin receptor occupancy based on imaging studies.  Two clinical Positron Emission Tomography (PET) studies using 5-HTT ligands showed 50%, 65%, and 80% occupancy at doses of 5, 10, and 20 mg/day respectively.

 

Clinical trials results were also described in the package insert.  There w ere 6-8 week double blind placebo controlled studies using the HAM-D and MADRS as outcome measures.  Six studies are plotted on a mean change from baseline plot and all were better than placebo at week 6 or 8 but in 2/11 measurement the error bar touched or went past the no difference from placebo line.   The results of a maintenance study were also described that looked at the results of  randomizing 396 patients in remission to continuation treatment of vortioxetine 10 mg/day or placebo.  The survival analysis showed significantly longer remission of depression in the vortioxetine group.  Using an effect estimation approach the Number Needed To Treat/Harm (NNT/NNH) was 7 (NNT) for response, 11 (NNT) for remission, and 36 (NNH).  In the review article the authors describe a total of 10 short term clinical trials and 6 with an active comparator.  In 5/6 the active comparator ws duloxetine 60 mg/day and in the other it was venlafaxine extended release 225 mg/day.  All 6 of the comparator trials were run against placebo.

Like other serotonergic agents nausea and diarrhea were the most common reasons for discontinuation and the likelihood was dose dependent at significant rates (21-36% vs 9% on placebo).  Sexual dysfunction was measured in 7 of the clinical trials using the Arizona Sexual experiences Scale (ASEX) after baseline rates were established by other clinical means.  The initial rates were 3-5% for men and 1-2% in women.  Using the ASEX, the rates ranged from 22-34% in women versus 20% placebo and 16-29% in men versus 14% placebo.  The most interesting side effect for me was headaches.  There are seven references to head in the package insert and all of them are in discussions of discontinuation symptoms or as a sign of hyponatremia.  I could not find it listed as a side effect.  In looking at the review (2) this may be an artifact of the high rate of headache (7.6-24.8%) in the placebo group.  Overall rates of discontinuation from the clinical trials compared to placebo were low.

At this point vortioxetine is described as a moderately effective antidepressant with a purported novel mechanism of action.  There has been relatively limited exposure of 2616 people in clinical trials.  I expect the pricing to reflect the usual high price of a novel antidepressant medication and in most managed care and pharmacy systems it will require prior authorization and documentation that other medication trials have failed.  From the clinicians perspective, I will be cautious when using it with other medications that have potential pharmacodynamic and pharmacokinetic effects.  The disclaimer that vortioxetine had an effect of cardiac repolarization that was "below 10 ms the threshold for regulatory concern" will not deter me from doing the necessary evaluation in patients who are taking combinations of medications that affect cardiac conduction or present with new cardiac symptoms.  I will also try to provide some discussion of the unknowns to people who are looking for the next medication that might be effective for chronic depression.  In doing that I am going to renew my membership in the ACS for access to a more detailed discussion of the medicinal chemistry involved (reference 3).

George Dawson, MD, DFAPA

1.  Brintellix (vortioxetine) FDA approved package insert.

2. Pearce EF, Murphy JA. Vortioxetine for the treatment of depression. AnnPharmacother. 2014 Jun;48(6):758-65. doi: 10.1177/1060028014528305. Epub 2014 Mar 27. PubMed PMID: 24676550.

3. Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG,Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011 May 12;54(9):3206-21. doi: 10.1021/jm101459g. Epub 2011 Apr 12. PubMed PMID: 21486038.