Psychopharmacology And The Educated Guess

Sometimes I feel like a hypocrite.

As a practicing psychiatrist, I have an obligation to understand the data supporting my use of prescription medication.  In my attempts to do so, I’ve found some examples of clinical research that, unfortunately, are possibly irrelevant or misleading.  Many other writers and bloggers have taken this field to task (far more aggressively than I have) for clinical data that, in their eyes, are incomplete, inconclusive, or downright fraudulent.

In fact, we all like to hold our clinical researchers to an exceedingly high standard, and we complain indignantly when they don’t achieve it.

At the same time, I’ll admit I don’t always do the same in my own day-to-day practice.  In other words, I demand precision in clinical trials, but several times a day I’ll use anecdotal evidence (or even a “gut feeling”) in my prescribing practices, completely violating the rigor that I expect from the companies that market their drugs to me.

Of all fields in medicine, psychopharmacology the one where this is not only common, but it’s the status quo.

“Evidence-based” practice is about making a sound diagnosis and using published clinical data to make a rational treatment decision.  Unfortunately, subjects in clinical trials of psychotropic drugs rarely—if ever—resemble “real” patients, and the real world often throws us curve balls that force us to improvise.  If an antipsychotic is only partially effective, what do we do?  If a patient doesn’t tolerate his antidepressant, then what?  What if a drug interferes with my patient’s sleep?  Or causes a nasty tremor?  There are no hard-and-fast rules for dealing with these types of situations, and the field of psychopharmacology offers wide latitude in how to handle them.

But then it gets really interesting.  Nearly all psychiatrists have encountered the occasional bizarre symptom, the unexpected physical finding, or the unexplained lab value (if labs are being checked, that is).  Psychopharmacologists like to look at these phenomena and try to concoct an explanation based on what might be happening based on their knowledge of the drugs they prescribe.  In fact, I’ve always thought that the definition of an “expert psychopharmacologist” is someone who understands the properties of drugs well enough to make a plausible (albeit potentially wrong) molecular or neurochemical explanation of a complex human phenotype, and then prescribe a drug to fix it.

The psychiatric literature is filled with case studies of interesting encounters or “clinical pearls” that illustrate this principle at work.

For example, consider this case report in the Journal of Neuropsychiatry and Clinical Neurosciences, in which the authors describe a case of worsening mania during slow upward titration of a Seroquel dose and hypothesize that an intermediate metabolite of quetiapine might be responsible for the patient’s mania.  Here’s another one, in which Remeron is suggested as an aid to benzodiazepine withdrawal, partially due to its 5-HT3 antagonist properties.  And another small study purports to explain how nizatadine (Axid), an H2 blocker, might prevent Zyprexa-induced weight gain.  And, predictably, such “hints” have even made their way into drug marketing, as in the ads for the new antipsychotic Latuda which suggest that its 5-HT7 binding properties might be associated with improved cognition.

Of course, for “clinical pearls” par excellence, one need look no further than Stephen Stahl, particularly in his book Essential Psychopharmacology: The Prescriber’s Guide.  Nearly every page is filled with tips (and cute icons!) such as these:  “Lamictal may be useful as an adjunct to atypical antipsychotics for rapid onset of action in schizophrenia,” or “amoxapine may be the preferred tricyclic/tetracyclic antidepressant to combine with an MAOI in heroic cases due to its theoretically protective 5HT2A antagonist properties.”

These “pearls” or hypotheses are interesting suggestions, and might work, but have never been proven to be true.  At best, they are educated guesses.  In all honesty, no self-respecting psychopharmacologist would say that any of these “pearls” represents the absolute truth until we’ve replicated the findings (ideally in a proper controlled clinical trial).  But that has never stopped a psychopharmacologist from “trying it anyway.”

It has been said that, “every time we prescribe a drug to a patient, we’re conducting an experiment, with n=1.”  It’s amazing how often we throw caution to the wind and, just because we think we know how a drug might work, and can visualize in our minds all the pathways and receptors that we think our drugs are affecting, we add a drug or change a dose and profess to know what it’s doing.  Unfortunately, when we enter the realm of polypharmacy (not to mention the enormous complexity of human physiology), all bets are usually off.

What’s most disturbing is how often our assumptions are wrong—and how little we admit it.  For every published case study like the ones mentioned above, there are dozens—if not hundreds—of failed “experiments.”  (Heck, the same could be said even when we’re using something appropriately “evidence-based,” like using a second-generation antipsychotic for schizophrenia.)  In psychopharmacology, we like to take pride in our successes (“I added a touch of cyproterone, and his compulsive masturbation ceased entirely!”)  but conveniently excuse our failures (“She didn’t respond to my addition of low-dose N-acetylcysteine because of flashbacks from her childhood trauma”).  In that way, we can always be right.

Psychopharmacology is a potentially dangerous playground.  It’s important that we follow some well-established rules—like demanding rigorous clinical trials—and if we’re going to veer from this path, it’s important that we exercise the right safeguards in doing so.  At the same time, we should exercise some humility, because sometimes we have to admit we just don’t know what we’re doing.

35 Responses to Psychopharmacology And The Educated Guess

  1. leejcaroll says:

    As a non medical person my first thought was thhat, in psychiatry, in particular, it is harder to have hard and fast rules as diagnostic criterion. Not all who are depressed lose their appetites, cannot get enough energy to get out of bed, etc. It is my understanding many psych disorders with the same diagnosis have different ways of presenting. How then can you have a standardized clinical trial for these meds when the symptoms and behaviors of one disorder may mimic that of another or just not fit in at all with the ‘normal’ diagnostic criteria?
    ( ))

  2. stevebMD says:

    Precisely, Carol.

    I’m not “dissing” psychopharmacology per se, because (for the reasons you point out) this is how we must practice. It’s part of what drew me to the field, in fact.

    What does surprise me, however, is how often our educated guesses are wrong, and how often we fail (a) to admit (or even recognize) it, and (b) to reconsider our hypotheses.

    • Carol Levy says:

      I have to say this is not just relegated to the psychiatric profession. I have seen this same behavior when in comes to treating those with chronic intractable pain. “You are not responding, then it is you” Ironically that is often when the psych referral comes in.

  3. Gary says:

    “In fact, I’ve always thought that the definition of an “expert psychopharmacologist” is someone who understands the properties of drugs well enough to make a plausible (albeit potentially wrong) molecular or neurochemical explanation of a complex human phenotype, and then prescribe a drug to fix it.”

    We’ve moved from Freud’s made-up mythology, to this type of “scientific” narrative.

    A plausible molecular explanation equals story-telling. The basis of the decision is whether it “sounds” right.

  4. Jackie says:

    Another great topic for discussion, Dr. Steve!

    My now-adult son has been on many meds over the last 8 years or so, for recurring major depression/some form of bipolar depression (like every other patient, he doesn’t fit the DSM-IV box). Things have been better for him the last year or so, but he still has major hypersomnia issues.

    Two things I’ve noticed on going through literature trying to help him:

    1. Reverse vegetative symptoms are not even measured in most clinical trials for depression treatment, as they tend to use the HAMD – 17 which talks about insomnia, not hypersomnia. I think it was “The Last Psychiatrist” who said that a sleeping pill and a couple of Krispy Kreme donuts would lower your score on the HAMD-17 as/more effectively than any AD. He’s probably right!

    2. Some drug side effects are under-played. It was only when I found some Lilly papers from the early 90s, that I learned how sedating fluoxetine can be (for some people). And some more digging revealed that my son’s “non-drowsy” allergy meds are sedating, too, for some people.

    Your job is a most difficult one. You have to rely in part on clinical trials that exclude a large part of the patient population that you are trying to help. However, the fact that you consider pathways and receptors, drug-drug interactions, etc., instead of just prescribing something because “we haven’t tried this one yet” means that you most likely will have more hits than misses, and that your patients are in good hands.

    Thanks for sharing your knowledge and enthusiasm with us.

  5. medskep says:

    Wow, I give you a long lasting standing applause for this essay. It’s said the beginning of wisdom is understanding and honestly admitting what one does not know.

    If I ever know anyone in your area that needs help, I’ll not hesitate to send them your way.

    Thank you.

  6. Tom says:

    Of course we, as psychiatrists, are ALWAYS right. We are a profession filled with bloated egos. When our patients get better, it is because WE came up with a magical drug cocktail that only a genius could brew. But when, as is all too often, patients do not respond to our brilliance, we have a solution: We blame the patient. And we have even coined professionally-accepted terminology to cover our collective assess: “The PATIENT is TREATMENT-RESISTANT!” That’s right folks: The fault is not with our medication or our brilliance; it is the patient’s problem. Or another favorite way to dismiss the patient: “It’s Axis II.” Yeah. I love that one too.

    • stevebMD says:

      Tom, I share your frustration with the Axis II issue. People with axis II conditions do indeed suffer greatly and deserve (and often want) help. I think the reason many clinicians “dismiss” patients as axis II is because conventional psychiatry offers– with few exceptions– few reliable and effective interventions for these patients, so the label provides a safe excuse when our efforts are unsuccessful. Moreover, there are no medications for axis II complaints or symptoms (which I consider a good thing– perhaps I’ll write more on this later), so the modern psychiatrist feels justified in saying “there’s nothing I can do.”

  7. moviedoc says:

    The expert psychopharmacotherapist finds the effective cocktail earlier than the hack, hopefully subjecting the patient to fewer failures along the way. This is no different than other branches of medicine, and the same applies to psychotherapy: When the patient doesn’t get better we just call that particular “made up mythology” as Gary aptly labels it, “long term,” which really just means it hasn’t worked. (Yet)

  8. duanesherry says:

    Maybe it’s time to stop playing such “dangerous” games with the human brain…

    Maybe it’s time to admit that psychiatry OFTEN causes more harm than good, and in many cases grave harm…

    Maybe it’s time for a system transformation –

    Duane Sherry, M.S.

  9. Jackie says:

    @Duane Sherry: Scientologist?

  10. duanesherry says:

    Roman Catholic.


  11. duanesherry says:


    How offensive, that you would ask.
    It’s so easy to write off people once you label them, isn’t it?

    Read this, Jackie –

    And read some more.
    Lots more, in fact.

    I’ve put about 8,000 hours into the study of psychiatry, to include alternatives to the paradigm of care currently on the market.

    All I can say, is that it’s high-time we tried some new things, wouldn’t you agree?

    Duane Sherry, M.S.

    • duanesherry says:


      If you’re awfully busy, and just don’t seem to have the time… at least read this –

      Or if you really want to learn what’s taking place, read Robert Whitaker’s book, ‘Anatomy of an Epidemic’, and see if you reach any conclusions.

      By the way, what religion are you, Jackie?

      Duane Sherry, M.S.

    • duanesherry says:


      Why the 8,000 hours of study?
      To save my son’s life… He was given paxil for irritable bowel syndrome, which set off a “manic episode”… He was subsequently diagnosed with “bipolar disorder” (which happens quite frequently from Paxil, by the way)…

      His story from Bloomberg is imbedded in this post from Ed Silverman’s Pharmalot –

      Our son, Brian has been symptom-free for five years.
      Not because of psychiatry, but because I made sure we avoided psychiatry – like the plague!

      Read, Jackie.
      Read some more.
      Read some more.

      And stop with the ‘scientology’ question to those of us who are tired of the injury and death we see, and are searching for ways to help others find integrative approaches that work… such as the Open Dialogue approach in Lapland, Finland… a non-drug approach with an 85% recovery rate for psychosis –

      More here –

      Duane Sherry, M.S.

  12. leejcaroll says:

    Duane, I think all here have indicated their concerns over the over medication as well as questions about psychopharma. That being said. I am sorry for what your son went through, and glad he is doing so kuch better but an anecdote is not science or evidence of anything other than that one person had the response they had.
    My face was paralyzed from medical malpractice during a neurosurgical procedure. I tell people that, in my experience, you have to be very careful in considering whether to have it done but I can only speak for my experience and not damn the procedure in general.
    I think the same has to be said about your family’s experience with psych meds treatment,

  13. duanesherry says:


    Psychiatry is unlike any other form of medicine… In that, we are dealing with thoughts, feelings, behavior.

    Also, there is fraudulent research throughout medicine, but psychiatry is riddent with fraud! And it claims to be “evidence-based”… It simply is not!

    I was injured by non-psychiatric medicine myself… underwent six major intestinal/colon surgies, due to picking up an infection while in the hospital… Which is one of the reasons why I had the time to do research on psychiatry… So, you’re preaching to the choir.

    Again, psychiatry is unique… No other form of medicine uses such force… No other form of medicine claims to know the brain… the human mind. At the end of the day, none of us know much about the brain, and we know squat about the human mind… I have a master’s degree in counseling, but I think it’s fair to say, that if I pursued a Ph.D., I would do so humbly.. with the knowledge, up-front that the human mind will forever remain a mystery…

    I look forward to the day when psychiatrists help people get off mind-altering, brain-damaging, body-injurying, spirit-numbiing drugs… But the field will have to reach a higher level of sanity in order to do so… It will need to come-clean, and openly admit it’s abysmal failures, and offer people hope.

    The natural recovery rate for “schizophrenia” is over fifty percent –

    With orthomolecular medicine (early onset) is goes up to 90 percent… The work of Abram Hoffer, M.D., Ph.D. – with 5,000 patients over the course of sixty years, documented in the Journals of Orthomolecular Medicine, and freely given to the Canadian government before his death.

    Neurofeedback, Psychiatric Service Dogs, Peer-Run Respites, Meditation, Hyperbaric Oxygen Therapy… There are many others that have phenomenal succes… We don’t use them!

    No, I disagree.

    The story of our son is not anectdotal… It is actually the norm, for those who use proven, non-drug methods… Sometimes, in combination…

    I would like to close by asking you to look at your fingertip.
    There is not another like it in the world.
    It is unique, because you are unique.

    Can you imagine how unique our brains are?

    We can do better than the current paradigm has to offer –

    We have to!


    Duane Sherry, M.S.

  14. Jackie says:

    Mr. Sherry, there were several reasons why the links in your posts reminded me of Scientology. Here are a few of them:

    1. The mention of Nazi Germany

    2. The formulations of new laws that would get between patients, parents (in the case of minors), and psychiatrists (but not other kinds of doctors)

    3. The imagery of psychiatrists somehow forcing treatments on people, especially children

    4. The reference to “human rights”

    I am vigilant of any attempts made by others to limit my choices in medicine, under the guise of protecting me. One such attempt in my state a few years ago, a proposed law drafted by Scientologists — would have criminalized the prescription of medication by psychiatrists.

    Nothing to do with religion.

    • duanesherry says:


      “Human rights” is far too vague a term, in my opinion…
      Constitutional rights being upheld…
      That’s what I’m for.

      The facts are that psychiatric drugs are forced on people.
      In fact, it’s very common place.
      So is ECT.
      So is incarceration.
      Mental health courts do not provide for an attorney to represent the person whose very freedom is at stake. They are represented, far-too-often by social workers, who have been trained in a medical model, and often feel that it is in the “best interest” of the patient to be locked up.

      Children need our protection, and I am not opposed to the state intervening to protect them, especially considering the fraud that is so prevalent in the field of Psychiatyry and Pharma. It has been with enormous political pressure that psychiatric drugs (some of them) have been FDA-approved for children. Medicaid fraud is rampant in the field of psychiatry –

      In my opinion, psychiatry is more political science than medical science.

      If you follow some of the links I provided, you’ll begin to understand where I draw that conclusion.

      I enjoy healthy debate, and tend to be able to see the other side… at least respectfully disagree, but it’s tough psychiatry…. You mention, for instance, Nazi Germany… It is rare that I compare anything in life to the Holocaust…. But a thorough study of psychiatry (a fearless one), produces some very unpleasant realities, as Psychiatrist, Peter Breggin, MD. explain… Keep in mind, he is a former teaching fellow from Harvard, and consultant to the National Institutes of Mental Health (NIMH)… hardly a scientologist (or a guy working in a basement in Idaho) –

      Psychiatry is what it is.
      And in my opinion, we can do a lot better.
      A lot better!

      Duane Sherry, M.S.

  15. duanesherry says:


    You asked me whether I was a scientologist, and I responded that I am Roman Catholic.

    As a Catholic, I was moved when I read about Pope John Paul’s visit to a hospital for children that uses integrative medicine… and his call to the Church (and the world) to begin to look at “nutritional deficiencies, and “immunological reactions to food and the environment” –

    More here –


    Duane Sherry, M.S.

  16. leejcaroll says:

    Duane, It would be better if your citations were not slanted to those people who agree with your position. Peter Breggin has had an anti-psychiatry bias since I first heard of him when I was in college in the 70’s. Orthomolecular is holistic, the bias is inate

  17. duanesherry says:


    and of course, you have no bias


  18. duanesherry says:


    i’m done with this particular back-and-forth
    i’ve provided you with some good links

    you can read them, and learn something new
    or you can put your head in the sand

    it’s your choice
    unfortunately, it’s not always informed choice for psychiatric patients


  19. Jackie says:

    Re. “educated guess”

    Today’s WSJ health blog has an article about a pilot study that Medco is doing to see if a genetic test can help physicians select the best psychiatric drug/s for individual patients.

    The test seems mostly about CYP450 metabolism.

  20. duanesherry says:


    This is a different subject than the back-and-forth we were involved in earlier, so I’d like to respond.

    In 2008 (if memory serves), Wolfgang Saddee of Ohio State University discussed genetics and pre-screening to find the “right antipsychotic” for patients….

    What was telling… involved a comment he made, “by the time we determine efficacy, irreputable harm has been done.”

    That particular comment spoke volumes to yours truly. In other words, a conventional psychiatrist openly admitted that the “educated guess” was causing “irreputable harm.”

    Americans bought into the 2nd-generation antipsychotic myth… hook-line-and-sinker.

    I shutter to think of the damage that will come from the 3rd-generation.

    IMO, we will not find a miracle drug.. and we will cause further injury in the effort to do so. The answers lie in getting the body/brain strong… through deep relaxation/meditation/neurofeedback… addressing trauma (not always with “talk therapy”… some people are all talked-out, and tend to continue to talk about the same issues, although it has its place for many)… There are other methods, in fact hyperbaric oxygen therapy goes a long way with trauma… The bottom line on the physical-side is to get nutrients and nutrients to a brain that is starved for both…

    Get the body strong, the mind often follows.
    Get the mind to learn how to deeply relax, and find the present (through a host of options)… this can help overcome past trauma.

    The answer has not been drugs.
    It will likely never be drugs.
    And we are foolish to unleash a 3rd-generation onto the public, with a wing-and-a-prayer that they MIGHT work!

    Duane Sherry, M.S.

    • duanesherry says:


      nutrients and oxygen to the brain –
      hbot works for trauma, to include war-related trauma –


    • leejcaroll says:

      I was not going to respond more but I feel I need to. “What was telling… involved a comment he made, “by the time we determine efficacy, irreputable harm has been done.” You give no citation and it appears that this is not the full comment. Without context it is somewhat meaningless. And, by the way, my bias is objectivity.

      • duanesherry says:


        It’s been several years since I read the article, but I was able to find it –

        I used the term “irreputable harm”… He, in fact used the term “irreparable harm.” My apolgies for the misquote.

        As far as your bias being “objectivity”.
        I have no idea how to respond.

        I thought we were talking about thoughts, feelings, behavior, moods, hopes, dreams, aspirations, the human experience…
        the brain, the mind.

        I hope I never see these things in soley “objective” terms.
        I think I would rather die first.

        Duane Sherry

      • duanesherry says:

        scroll down to the ninth paragraph


  21. leejcaroll says:

    I refer to objectivity by researchers, bias as known to be the arena of some of the folks you cite. Op-ed and commentary are more the bailiwick of some of these folk.

    Identifying these predictive markers is important because antipsychotic drugs are effective in only a portion of patients upon first treatment, and it takes a month or more to establish their efficacy,” says Sadee, who is also a professor of psychiatry and chair of the department of pharmacology.

    “During this time, irreparable damage can result if the wrong antipsychotic is given to a patient”

    Your quote omitted important words, i.e. “… involved a comment he made, “by the time we determine efficacy, irreputable harm has been done.”

    Context is absent without the words “the right antipsychotic”

    He did not “openly admitted that the “educated guess” was causing “irreputable harm.”

    A cogent discussion requires full quotations. To change them to merge with your bias makes it a soliloquoy, not a conversation.

    • duanesherry says:

      Oh Carol,

      He said it takes “a month or more to determine efficacy”…
      He followed by saying, “during that time irreparable damage can result.”

      It’s been 3 and a half years since I read the piece… I think my memory of what I read was in context with what he said… Many not perfect, but accurate.

      If we all just be as “objective” as you…
      My, what a wonderful world we would have, huh?

      Actually, I think it would be a much better world if we got rid of some of the drugs that are prescribed by “guesswork”…. and replace the current mental health system with more “sanity”.

      How sane is this stuff, huh? –

      Duane Sherry

      • duanesherry says:

        Intersting, that you left this out of my comment –

        In 2008 (if memory serves), Wolfgang Saddee of Ohio State University discussed genetics and pre-screening to find the “right antipsychotic” for patients….

        Oh, if I could just learn how to be more “objective”…
        Psychiatrists like you would begin to appreciate my PASSION!

        No thanks.

        You be you.
        I’ll be me.

        Duane Sherry, M.S.

  22. duanesherry says:


    A lecture from a board-certified neurologist on the subject of “objectivity”… 150 dollars.

    The same lecture from a conventional psychiatrist…

    Duane Sherry, M.S.

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