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Welcome to my blog, a place to explore and learn about the experience of running a psychiatric practice. I post about things that I find useful to know or think about. So, enjoy, and let me know what you think.


Friday, November 1, 2013

By The Wayside

I've started to read up on tricyclics, since I did my residency in the age of SSRI's, and I rarely used a tricyclic in training, although I knew all about them for boards (except how to comfortably prescribe them). And in fact, I've never prescribed an MAO-I, which is also something I knew about for boards.

So I started to look back at the early articles on imipramine, and I found:

THE TREATMENT OF DEPRESSIVE STATES WITH G 22355 (IMIPRAMINE HYDROCHLORIDE)

Now, as far as I'm concerned, the AJP people are being jerks about this, because the article was published in 1958, and they still only allow access to the abstract, without a subscription. A historian friend, who is also the head of library archives at the oldest psychoanalytic institute in the US, told me that if it's more than 50 years old, it's basically open source (that's not how she phrased it, so don't hold her to my misunderstandings).

But I gleaned some interesting things from the abstract. Here it is:

Over a three-year period, more than 500 psychiatric patients of various diagnostic categories were treated with imipramine hydrochloride. It was demonstrated that the compound has potent antidepressant action. Best responses were obtained in cases of endogenous depression showing the typical symptoms of mental and motor retardation, fatigue, feeling of heaviness, hopelessness, guilt, and despair. The condition is furthermore characterized by the aggravation of symptoms in the morning with a tendency to improvement during the day. Treatment with imipramine hydrochloride resulted in full or social recovery in a high percentage of the patients. As a rule, the initial response was evident within 2 to 3 days, while in some cases 1 to 4 weeks of therapy were required. In view of the symptomatic nature of the action of imipramine hydrochloride, therapy must be maintained as long as the illness lasts. The side effects noted were relatively slight, and with the exception of one case of severe allergic exanthema necessitating discontinuance of treatment, no serious complications were encountered. In some cases of depression, particularly those associated with organic brain damage or schizophrenic psychosis, transitory states of agitation or exacerbation of the psychotic features were noted. These observations suggest the importance of a proper selection of the patients as to type and etiology of depression. While in a number of instances, neurotic, schizophrenic or other depressions were also benefited by the drug, particularly when used in combination with chlorpromazine, electroshock or psychotherapy, it is concluded that imipramine hydrochloride is primarily indicated and effective in the treatment of endogenous depression.

First of all, consider how the presentation style has changed over the years. There are no, Intro, Method, Results, Conclusions sections. No demographics, No HAM-D (1960, if you recall from my post). No MADRS. No p-value. No percentage changes. Nada. Just:

"It was demonstrated that the compound has potent antidepressant action", and, "...a high percentage of patients."

Now look at the disease description:

"...endogenous depression showing the typical symptoms of mental and motor retardation, fatigue, feeling of heaviness, hopelessness, guilt, and despair. The condition is furthermore characterized by the aggravation of symptoms in the morning with a tendency to improvement during the day."

Typical symptoms of endogenous depression are:

~mental and motor retardation
~fatigue
~feeling of heaviness
~hopelessness
~guilt
~despair
~aggravation of symptoms in the morning

None of the, "Most days for two weeks" stuff, or "Not better explained by another condition".

To my thinking, it's a pretty good way of describing a serious depression.


And then there's how they understand the response:

"Best responses were obtained in cases of endogenous depression..."

"...full or social recovery in a high percentage of the patients. As a rule, the initial response was evident within 2 to 3 days, while in some cases 1 to 4 weeks of therapy were required."

I'm curious about the precise meaning of "social recovery", and how it differs from "full" recovery, and how they can tell.


There's the acknowledgment that it isn't for everyone, together with suggestions about who may benefit more, and less:

"...a proper selection of the patients as to type and etiology of depression. While in a number of instances, neurotic, schizophrenic or other depressions were also benefited by the drug, particularly when used in combination with chlorpromazine, electroshock or psychotherapy, it is concluded that imipramine hydrochloride is primarily indicated and effective in the treatment of endogenous depression."

Notice the diversity of the complementary treatments: Chlorpromazine, electroshock, psychotherapy. 


There's a description of side effects that doesn't try to pretend that it's not a problem for anyone:

"The side effects noted were relatively slight, and with the exception of one case of severe allergic exanthema necessitating discontinuance of treatment, no serious complications were encountered. In some cases of depression, particularly those associated with organic brain damage or schizophrenic psychosis, transitory states of agitation or exacerbation of the psychotic features were noted."

No muss, no fuss, no defensiveness, just, "Yeah, some patients got agitated or psychotic". 
In other words, the people we think it's good for tolerated it well. And the people who tolerated it poorly, well, that's partially why it's not good for them. But it's also not as good for them as for the people with endogenous depression, and we know this because they needed additional treatment modalities for beneficial effects.


And finally, it's not a cure. It treats the symptoms of endogenous depression, and should be used while the endogenous depression lasts. There's no claim that these patients will need to stay on the drug forever. 

"In view of the symptomatic nature of the action of imipramine hydrochloride, therapy must be maintained as long as the illness lasts."


It just seems so straightforward. I don't find myself wondering what they're really trying to say, and what they're hiding. A lot has changed along the way.


2 comments:

  1. I think the complication along the way was that it was determined that there was no way to determine what was an endogenous versus a so-called neurotic reactive depression (shades of the bereavement exclusion). The dimension that also unfortunately slipped away was depression severity. I think it was possible to show that people with HAM-D scores of greater than 30 were probably more likely to have biological markers than people with HAM-D scores of just over 20. The problem of course is where you choose to set the line.

    I was squarely at the end of the TCS period during my training and Prozac did not become available until several years after I was out in practice. My drug of choice in those early days for depression was nortriptyline. It was and still is easy to prescribe. It generally requires the lowest dose of any TCA and has the most well defined therapeutic range. The other interesting aspect is that contrary to all of the hype about better side effect profile of SSRIs - in practice I think it is a wash. When you start practicing and realize that your job is to manage side effects more than pick a medication, you generally adapt strategies that will result in lower side effects and complications. I don't find any difference between TCAs and SSRIs and noted an article in the British Journal of Psychiatry (several years ago but still modern times) that TCAs were at that time the #1 prescribed antidepressants in the world.

    MAOIs are quite another story. I think that it is very difficult to prescribe antidepressant doses of these drugs and not have a patient who has significant side effects. The other practical issue is how many augmentation or replacements trials will severely depressed patients tolerate before you recommend ECT?

    I think the current approaches are definitely preferable. The more information the better. It speaks to biological variability and study design more than anything and it is still useful to interpret it to the patient. I don't think that finding a drug where 10% of the people have weight loss and 15% have weight gain is very useful information to consider if you are worried about weight gain. I would put the FDA warning about citalopram and QTC in the same category.

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  2. Nortryptiline is the TCA I've had the most experience with. Probably for the reasons you've mentioned. I always worry about overdose, though. And while I'm certainly a proponent of ECT, and have recommended and implemented it for some suitable patients, I do wonder if an MAO-I, even with all the restrictions, wouldn't be easier. Outpatient ECT is a logistic mess, and the memory problems are no picnic. And inpatient ECT is, well, inpatient.

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