Follow the Fantasy

I just had this weirdo idea. I saw a commercial the other day for Nasacort, which is now over-the-counter. This is awesome. I have seasonal allergies, antihistamines make me groggy, sudafed makes me jumpy, so every year I have to procure some prescription flonase. And now I don't.

Here's my idea. What if SSRIs were sold OTC? What would that be like?

I poked around online to try to find out if SSRI's are sold OTC anywhere, currently. Maybe India, China, Mexico. I could not find any current information-most recent was 2009.

So I'll have to stick to the fantasy. What would that be like?

In medical school, they taught us that the best down-and-dirty way to find out if a patient in a primary care setting was depressed was to ask, "Are you depressed?" Embedded in that is the notion that people know when they're depressed.

So maybe you'd realize you were depressed, and then you'd mosey on down to your local drug store and pick up a pack of zoloft, along with a birthday card for your niece and a couple of pieces of bazooka gum.

Maybe people would take SSRIs PRN, like tylenol. Maybe this would help with PMDD (I still find it hard to believe that women who take SSRI's for PMDD don't end up with withdrawal symptoms each month, even if the PMDD effects do work via a GABA-ergic mechanism).

Maybe people who weren't depressed would take them. Maybe they'd feel sad that they're hamster died, and think, Oh, I'm bereaved and depressed, I should take prozac.

Maybe there would be more suicides. Maybe there would be fewer. Maybe there would be more work days lost due to side effects and withdrawal. Maybe there would be fewer work days lost due to depression. Maybe there would be more substance abuse. Maybe there would be less.

Maybe people would be emotionally disengaged and spend hours on Facebook and Twitter and playing League of Legends online without ever leaving the house to see their friends. Oh, right, that already happens. Maybe because SSRI's are so freely prescribed by primary care providers.

Maybe there would be fewer starving people in the world, because those taking SSRI's would stop having sex and reproducing, and the population of the planet would be contained.

Maybe people would begin to realize that pills won't fix their character pathology or their interpersonal problems. Maybe more people would make use of therapy. Maybe insurance companies would be forced not to find sneaky ways to withhold reimbursement for therapy.

Maybe the reason I have so much conjecture about what would happen if SSRI's were freely available to whoever wants them is because not much is actually known about what they do. Or more accurately, they do so many things, or are SUPPOSED to do so many things, that it's hard to tell what they are and aren't doing.

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.

No Worries, Lurasidone

This just in: In July, Lurasidone, originally approved for Schizophrenia, was approved by the FDA for treatment of Bipolar 1 depression.

You can now prescribe Latuda for your depressed, bipolar patients. I can't think of "Latuda" without hearing, "Latuda Matata".

Here's a link to the AJP in Advance abstract for Lurasidone Monotherapy in the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study. The primary outcome measure was the MADRS, and the study was sponsored by Sunovion.

"Lurasidone treatment significantly reduced mean MADRS total scores at week 6 for both the 20–60 mg/day group (−15.4; effect size=0.51) and the 80–120 mg/day group (−15.4; effect size=0.51) compared with placebo (−10.7)"

According to a Wikipedia article that may be wrong,

"An effect size calculated from data is a descriptive statistic that conveys the estimated magnitude of a relationship without making any statement about whether the apparent relationship in the data reflects a true relationship in the population. In that way, effect sizes complement inferential statistics such as p-values."

I'm not sure what it means for an effect size to be 0.51, or for the placebo score not to be recorded with an effect size.

Once again, I went to ClinicalTrials.Gov, and lo and behold, I found:

Lurasidone HCI - A 6-week Phase 3 Study of Patients With Bipolar I Depression (PREVAIL3)

Now, I don't know for sure if this is the same trial they're talking about, but since it was last verified in August 2013, it seems likely (and it was first received in January 2011).

And miracle of miracles, the results are listed.

This may be a little hard to read, but the primary outcome result for Lorasidone 20-120mg is -11.8, and for placebo, -10.4. And the p value is 0.176, which, last I checked, is larger than 0.05.

The abstract had the difference for lorasidone as -15.4, but grouped into two separate dosage groups, 20-60mg, and 80-120mg. This appears to be a subgroup analysis, where you chop up your results into smaller groups after the study is over, and which is a no-no because it can yield spuriously positive results for individual subgroups (I'll get to how this works in a later post).

So the results on clinicaltrials.gov seem to indicate that there was no significant difference.

It turns out, there was another trial listed on clinicaltrials.gov, entitled, Lurasidone - A 24-week Extension Study of Patients With Bipolar I Depression. this study was first received in March 2009, and last verified in February 2013. There were no results reported for this study on the site.

So we have a 24 week study, conducted earlier than the 6 week study, with no results reported. And we have a 6 week study with conflicting results, depending on where you look.

I could be wrong about how to interpret this data. What do you think?

HAM-D'ing It Up

Last month I published a post entitled, Lifelong Learning-A New Frontier. In it, I introduced the idea of an online journal club, and I threw down the gauntlet with a challenge-let's talk about this paper:

A Rating Scale For Depression, by Max Hamilton

So here I am, talking about it. In written form.

In case it isn't obvious, this article introduced the Ham-D, or Hamilton Rating Scale for Depression, which is still in use.

And in case you happen to think there's something new under the sun, the paper begins with, "The appearance of yet another rating scale for measuring symptoms of mental disorder may seem unnecessary, since there are already so many in existence and many of them have been extensively used."

The year is 1960.

I'm gonna go on to delineate some random thoughts and reactions to the paper, in the hope that this will encourage dialogue, as might take place in an in-person journal club.

The first thing old Max H does is describe the purpose and appropriate usage of this particular rating scale. Or more accurately, what it's purpose isn't:

1. It's not devised for normal subjects
2. It's not self-rating
3. It's not about social adjustment/behavior
4. It's not broad range

Rather, it focuses on the measurement of symptoms in individuals already diagnosed with depression.

The present scale has been devised for use only on patients already diagnosed as suffering from affective disorder of depressive type. It is used for quantifying the results of an interview, and its value depends entirely on the skill of the interviewer in eliciting the necessary information… It has been found to be of great practical value in assessing results of treatment.

One question I have is, who makes the diagnosis? And based on what diagnostic system? The DSM-II was published in 1968, which means the HAM-D was developed to assess depression in people who may or may not have met the DSM-V criteria for Major Depression, were they being assessed today. So is it still appropriate to use the scale?

The scale includes 17 variables related to depression, plus 4 additional variables, diurnal variation, derealization, paranoid symptoms, and obsessional symptoms, that are either related to type rather than severity or intensity of depression (diurnal variation), or are seen only rarely in the context of depression (the other three). Each variable is rated on either a 5 point (0-4) or a 3 point (0-2) scale, with the latter in use when quantification is difficult, e.g. insomnia and agitation. It's interesting to note that on the modern HAM-D form, agitation is measured on a five point scale, which Hamilton found "impracticable".

The scale was written with the intention of having a given patient rated by two different raters. Where only one rater is available, the score should be doubled.

Some caveats for the raters:

1. No distinction is made between intensity and frequency of a symptom-the rating is at the discretion of the rater, who is expected to take both into account.
2. Depressive Triad: depressive mood, guilt, suicidal tendencies-the rater needs to avoid a  halo effect, e.g. giving guilt and depressive mood the same rating because they're closely related.

Table 1 is the correlation matrix.

It's how well each individual symptom correlated with each of the other individual symptoms. So, for example, Depression has a 1.0, since it correlates 100% with Depression. Guilt correlates with depression 49.1% of the time, and 100% with Guilt, etc.

This is followed by the extraction of some data, summarized into 4 factors-not sure how these are obtained.
As I understand it (poorly), factor analysis is a way to take your data and look at it as fewer variables than you started with. I briefly perused the Wiki Article, which seemed to involve some Linear Algebra. And since it's been many a year since I was intimate with eigenvectors, I'm gonna leave it at that. In other words, it's magic.

But, for example, Factor 1 has high correlations with depressed mood, guilt, suicide, delayed insomnia, work and interests, retardation, genital, and insight; And low correlation with agitation and anxiety, so they call it a "retarded depression"
This, so the article claims, corresponds well with the classical description of depression.

Which one? Melancholia? Seems like.

Finally, the end of the paper includes several case descriptions, not just scores. This is in stark contrast to today's style. I suppose this is knowable, but I don't know it-were most papers written with case descriptions then?

Please comment so we can get a discussion going. It's a short paper. Check it out.

DSM-5 in Action

Last week, I saw a new patient who was referred to me by her therapist for evaluation for med management, specifically, for depression.

The therapist wasn't certain the patient needed meds. And the patient wasn't sure she needed, or wanted meds.

She was suffering-that was the only certain thing.

I'm a decent psychopharmacologist, despite the fact that I mostly do therapy and analysis. The reason I'm good with meds is not because I'm an expert on the Cytochrome p450 system, or I'm the first shrink on the block to prescribe a brand new med. I believe it's because I listen to my patients, so important feelings/experiences/symptoms don't get overlooked, or boxed into neat little 15-minute med check categories that don't really fit.

So I listened to this patient, and while I was listening, I started thinking about everything I've learned regarding DSM-5. Like, maybe Major Depression, as defined by the DSM, doesn't really exist. (Note: I am NOT saying I don't believe depression exists. I'm just referring to the DSM definition of depression). And even if it does exist in DSM form, if I run through the checklist, and the patient meets five of the nine criteria, does that imply that she'll benefit from medication? And if she doesn't meet 5/9, does that mean she won't?

And what about the meds? What exactly am I treating? And how? A world-outlook? A traumatic childhood loss? If I can't be sure there's a disease process going on, and I can't be sure which aspect of the disease, if such it is, I'm treating, and no one even knows how the meds work, then why would I medicate?

I thought about how easy it would be to say to her, "You meet criteria for MDD, here's a pill, take it and you'll feel better." But I just couldn't bring myself to do that. I didn't believe it would help.

This is not the first patient I've sent home prescription-less. But it's the first time I've thought about it this way. In the past, I might've said to myself, the patient doesn't meet criteria, and therefore doesn't have the disorder in question, and consequently won't benefit from medication for this condition.

But now I'm reminded of the joke about the philosophy exam question, asking students to describe the physical characteristics of the chair at the front of the room. One student's response: What chair?

What disorder?

I came up with the following analogy: Suppose I decide that people who have more than 5 bad hair days per month carry a diagnosis of BHDD (Bad Hair Day Disorder). Am I describing an entity? Yes, people who have too many bad hair days. Does that make it a disorder, or disease?

I'm not sure the analogy is valid. At least some of the DSM diagnoses have a basis in clinical experience.

The truth is, and I realized this while I was writing, that I do find the DSM criteria for MDD useful, as a line of questioning.
This patient did not fit into any nice little DSM category. And I didn't try to make her fit. My thinking was, let's explore what she's been experiencing, using DSM criteria as a starting point. And that was useful.

I haven't purchased a copy of DSM-5. I don't want to. And I resent that, despite all the protests to the contrary, it remains the "bible" of psychiatry, and decisions are made based on its contents-reimbursement decisions, legal decisions.

But I do wish it could be what it professes to be: a guideline. Then it could sit on my book shelf with all the other books I use as references and guidelines, not with pride of place, and not with shame, either.