Feeling Like a Fish Out of Water

Fish out of waterThis weekend I was feeling like a fish out of water, mainly because I was on call for different duties than usual at the hospital. And that got me thinking about some doctors who may feel the same way nowadays when it comes to prescribing certain psychotropic medications like lithium, the monoamine oxidase inhibitors, and clozapine.

As a psychiatric consultant, I sometimes get called to help my colleagues in medicine and surgery figure out whether or not a patient is experiencing toxicity from one of these older and infrequently prescribed drugs. That says something eye-opening just by itself. These drugs are known for their toxicity and now that we have other medications that are better tolerated, have fewer drug interactions, and are much easier to titrate–we’re unlikely to go back.

However, as I was clicking through back issues of Current Psychiatry, I found one article about clozapine indicating that it might actually lower mortality. The first paragraph reads:

Researchers in Finland surprised psychiatrists this year by announcing that clozapine “seems to be associated with a substantially lower mortality than any other antipsychotic.” This finding also surprised the researchers, who expected their 11-year study to link long-term use of second-generation (“atypical”) antipsychotics with increased mortality in patients with schizophrenia. Instead they found longer lives in patients who used antipsychotics (and particularly clozapine), compared with no antipsychotic use.


This article was published in 2009 and the guidelines for administering clozapine are out of date, of course, now that we have that slick new operation, the Clozapine REMS Program. Oh, now you got me started.

Anyway, here is a table of the new clozapine monitoring guidelines. Box 1 in the article is passe, but the remainder of the paper is serviceable. The enthusiasm for clozapine as something you should think of as more than a second or third line drug is dampened considerably by the difficulty of titration and the rather long list of dangerous side effects. Many clinicians shy away from offering it for those very reasons.

Now even more might avoid it because of the unsuccessful rollout of the FDA Clozapine Risk Evaluation and Mitigation System (REMS) Program starting October 12, 2015. This is extremely unfortunate because of the documented advantages of clozapine, including reduced suicidality and aggression. The possibility of renewed aversion to starting clozapine for patients with treatment-resistant schizophrenia is ironic, given the idea that centralizing the monitoring by creating the REMS program was thought by some experts to be the answer to reducing “…the administrative burden associated with clozapine registration and monitoring…”


No, I have still not been able to certify in the Clozapine REMS Program as of October 25, 2015, which makes 14 days.

Lithium is another agent which few trainees graduating these days know much about in terms of prescribing, monitoring, and managing toxicity. Dr. James Jefferson’s article on lithium in a 2002 issue of Current Psychiatry has a title indicative of the cobwebs developing around this very effect agent for bipolar disorder: “Rediscovering the art of lithium therapy.”


Lithium is another drug that is known to reduce suicidality, yet few trainees nowadays use it as first line. Dr. Jefferson’s observation is telling:

As a mood stabilizer for patients with bipolar disorder, lithium was the darling of U.S. psychiatry from the 1970s to well into the 1990s. It then began an ill-deserved, gradual fall from grace and today could be considered a pharmaceutical endangered species. But why?

Did lithium lose effectiveness? Is it too toxic? Is its side effect burden too heavy? Does it interact adversely with too many medicines? Is it too cumbersome to use? Was it just a fad whose time came and went—a psychiatric pet rock? Did it fall prey to the marketing might behind patent-protected drugs? Was it replaced by more effective and safer drugs?

You are partially correct if you checked “all of the above,” because all contain a kernel of truth. At the same time, each is an exaggeration that does grave injustice to a remarkable medication. In addition, psychiatry appears to pay only lip service to convincing evidence that lithium is the only mood stabilizer that reduces the risk of suicide during long-term treatment.

The sad part of this story is that, as a psychiatric consultant in the general hospital I’m sometimes called to assess the neurotoxicity of lithium in patients who are often misdiagnosed with bipolar disorder–and did not have an indication for it in the first place.

Last but not least, the monoamine oxidase inhibitors (MAOIs) are a third line treatment for depression and I can remember a time when psychiatrists recommended it for treatment-resistant depression. It’s another one which will probably not be used by trainees after they graduate. Again, I found article in Current Psychiatry which bemoans this state of affairs regarding the MAOIs.


The authors’ remark about the lack of use of this effective antidepressant is important:

MAOIs have been used for >6 decades, and published studies continue to document their efficacy and safety when patients are monitored appropriately. However, based on our observations we suspect MAOIs are underutilized in clinical practice today. We are concerned that such practices can trickle down into residency training programs. Psychiatric residents typically do not receive adequate training in prescribing MAOIs, largely because many training faculty are not prescribing MAOIs themselves. Despite MAOIs’ limitations, concerns about an increased risk of suicide in patients with TRD and the high likelihood of a poor outcome associated with persistent nonresponse to prior treatments must be weighed against the relatively low risk of a hypertensive event with MAOIs.

Hello! The trickle down effect happened a long time ago.

The three articles here are unlikely to turn the tide of prescribing back toward the older agents. Any doctor who does would likely feel like a fish out of water given the many choices that don’t involve the toxicities, the monitoring–and the extra time educating patients and families, extra time that doctors do not have, especially in the days of the electronic health record, which has yielded little in the way of interoperability which doesn’t streamline communication between hospitals and practitioners (essential if we’re going to use these drugs), but has led to a lot of extra empty verbiage and data which does not improve patient care or the patient-doctor relationship.


The clinician who uses these drugs nowadays is probably flopping around a lot–like a fish out of water.

Fish out of water

2 thoughts on “Feeling Like a Fish Out of Water

  1. I’ve always wanted to make it to at least one of those updates in Madison. We lived there, oh so briefly. That’s close to Verona–where the Epic monster lives, breathing fire.

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  2. Jim,

    I just got back form the 3rd Annual Update in psychiatry in Madison. Jefferson and Greist were there – along with a number of excellent lecturers. In response to your post, lithium, MAOIs, and even T3 were all alive and well at this conference. Scant mention of newer antidepressants – just to say that they are no better than the old ones. I actually think that there is no such thing as treatment resistant depression. Just the heterogeneous syndrome that can be hard to treat.

    I think that lithium was killed off in the 1990s by the fact that Depakote was heavily promoted for bipolar disorder – at least until people realized that it did not do anything for bipolar depression.


    George Dawson, MD, DFAPA

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