Teaching an Old Drug New Tricks

Chris Ballas, M.D.
Wednesday, April 02, 2008

There is some new data concerning an old drug. Mecamylamine is an old medication originally used to treat hypertension. It had numerous side effects, such as hypotension and sedation, and thus was not often used. It had a bit of a resurgence later on as an anti-smoking drug (it is a nicotine antagonist) but the overall efficacy was poor, and the side effects made it difficult to use. It was then suggested for use as an augmentation agent to traditional nicotine replacement drugs (gum, patch, etc.) It also has some off label and occasional use for autism, Tourette's, and OCD.

Recently, it has been tested for the treatment of depression. It was found to be better than placebo on the traditional rating scales for patients who had failed citalopram. While this is good, what made it particularly interesting is that the doses used were considerably less (by a factor of 10) than what had been used for hypertension—and at these low doses, mecamylamine only blocks central nervous system nicotinic receptors, not peripheral ones—resulting in much less sedation and hypotension.

It also had considerable efficacy in reducing irritability. Think what it may be like for a smoker to have a cigarette after a long plane ride.

All of this is well and good, but it brings up three questions:

First,why are we testing old medications? The answer probably has a lot to do with the current anti-Pharma climate. Antidepressants in general have already come under fire, both from researchers who have recently "discovered" they may not be very effective, as well as insurance companies, lawyers, and the media. Drug companies, even if they could, would be hard pressed to bring a novel compound for depression into an environment like this. It's easier to re-approve an existing drug. So you see repackaging of old drugs (consider Pristique), expanding the approval for medications already used in psychiatry (Abilify getting approval for adjunct use in MDD; Seroquel as monotherapy for bipolar depression), and looking through what already exists for new indications.

Second, if old drugs can be used for mood (in this case, specifically depression) then what does that say about depression itself? The norepinephrine hypothesis of depression was in vogue for some ten years, soon to be replaced by serotonin; but how do you explain how some people respond to Seroquel and others to Wellbutrin, when the two have nothing in common pharmacologically? More importantly, how do you explain it when the same person responds to both meds?

Third—and I've checked—there is no evidence so far that mecamylamine increases the suicide risk. (The same can be said of Seroquel and Abilify.) If mecamylamine does indeed get approval for depression, will it automatically inherit a black box warning for suicidality? The drug shares no chemical similarities to any existing antidepressant; but if we call it an antidepressant, does it inherit all the risks of one?

This isn't an idle question; warnings like this, attached to drugs which science has no reason to suspect—but which words indict—contribute to the environment I wrote about earlier, in which no one wants to try anything novel because it simply isn't worth it. And so we offer up the faint hope that old, barely tolerable blood pressure pills will save us.

Do Antidepressants Cause SUICIDE?

by Chris Ballas, M.D.

Monday, May 14, 2007

First, and most importantly, the answer is no. No single thing can cause a complex behavior such as suicide (or violence), and to say that a drug, or event, or illness made someone do something is simplistic and, well, wrong.

A more refined question would be whether antidepressants (or anything else) can contribute to the suicide process, move someone further along. Cocaine doesn't cause violence, but if you see a violent guy on cocaine, it's best to get out of the way.

The FDA, in 2002 and 2004, issued warnings about suicidal ideations in children who take antidepressants. Here are a couple of points for us to consider.

1. These were kids
2. The point of discussion is suicidal ideation, not suicide (death) per se.

The FDA reviewed nine, then later 24 pediatric studies and found that the risk of ideation "doubled" from two to four percent.

The authors of a recent review of 29 studies found a similar small increase in risk.

Importantly, however, no actual suicides occurred.

They also analyzed whether or not the antidepressants were actually helpful to people, and weighted that finding against the risk of suicide. Their results determined the risk/reward ratio to be about 11:1, meaning that patients have 11 times better chance of being helped than hurt by antidepressants.

I should point out that, in my opinion, while there is absolutely no compelling evidence that these drugs promote suicidality, there is also a lack of compelling evidence indicating that they reduce suicidality. Nor would I expect there to be. Again, these drugs may change how someone feels, but there are a million steps between a feeling and an action. Which has the greater impact on suicidality: medications or the availability of a gun?

Asking the question simply, "do antidepressants cause suicide?" misses the meat of the argument. Cause? In whom? When, and under what circumstances? The real question is whether someone who is depressed is more likely to commit suicide off of the medicines than on them.

So while we ponder that question, let me offer a sobering statistic.

Only 30% of the people who committed suicide had seen a psychiatrist in the past year. That means 70% hadn't.

Source: JAMA. 2007;297:1683-1696.

Clinical Response and Risk for Reported Suicidal Ideation and Suicide Attempts in Pediatric Antidepressant Treatment, A Meta-analysis of Randomized Controlled Trials,Jeffrey A. Bridge et al,JAMA.2007;297:1683-1696.

Conclusions: Relative to placebo, antidepressants are efficacious for pediatric MDD, OCD, and non-OCD anxiety disorders, although the effects are strongest in non-OCD anxiety disorders, intermediate in OCD, and more modest in MDD. Benefits of antidepressants appear to be much greater than risks from suicidal ideation/suicide attempt across indications, although comparison of benefit to risk varies as a function of indication, age, chronicity, and study conditions.








__________________

Can An Antipsychotic be an Antidepressant?

November 3, 2006
The Charade is Revealed-- We Are Doomed

Here's a question: can an antipsychotic be an antidepressant? Why, or why not?

The correct answer is that the question is invalid, because there is no such thing as an "antipsychotic" or an "antidepressant." We (should) define them based on what they do, not what they are. Therefore, Wellbutrin and Effexor are both antidepressants if and only if they both treat depression-- not because of some element of their pharmacologies, which are anyway different. Strattera, on the other hand-- which has a pharmacology (in some ways) similar to Effexor-- is not an antidepressant, only because it doesn't treat depression.

Following, just because something is called an antidepressant, or antihypertensive, it doesn't necessarily take on all the other properties or side effects of the others in its "class." Not all "antidepressants" have withdrawal syndromes (only SSRIs do). Not all antihypertensives cause urination (only diuretics do.) You wouldn't dare put a "class labeling" on "antihypertensives" of "diuresis."

So you see where I'm going with this-- except you don't.

I've previously yelled about the inanity of "antipsychotic induced diabetes" or "antidepressant induced mania" when they ignore pharmacologies, doses, and, of course, actual data.

But today I saw something that I now understand to be one of the signs of the Apocalypse. It is the new package insert of Seroquel, which just got a new indication for the treatment of bipolar depression. The new PI reads:

Suicidality in children and adolescents - antidepressants increased the risk of suicidal thinking and behavior (4% vs 2% for placebo) in short-term studies of 9 antidepressant drugs in children and adolescents with major depressive disorder and other psychiatric disorders. Patients started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SEROQUEL® is not approved for use in pediatric patients. (see Boxed Warning)

Stating the obvious: in none of these 9 studies was any patient actually ever on Seroquel; Seroquel itself is not associated with a risk of suicide; it's not even been tested for major depressive disorder; and, well, this isn't very rigorous science, is it?

Just because a is now called an antidepressant, it carries the same risk as the SSRIs? (Whether even SSRIs have this risk is besides the point.) Isn't that, well, racist?

This is not really about preventing suicide. If we were worried about suicide, really, then why 24 hours before the FDA posted this warning, no one cared about Seroquel's doubling of the suicide rate? Oh, because it doesn't actually double the suicide rate? Die.

So the game is clearly not about science, it's about politics, it's about liability, it's about money.

If this was honestly about about protecting children from suicide, we'd shrug our shoulders and say, "well, they're just very, very cautious, so we'll be careful and keep going." But that's not what this is. What this is factually inaccurate, misleading, and therefore more dangerous, more harmful. In a simple example, this warning protects no one for a risk of suicide-- no potentially suicidal patient is going to look at this and say, "well, crap, I'm not taking this." But it may prevent someone from taking it when they could actually benefit. See?

This is Structuralism gone very badly awry, Saussure just bought a pick axe and he's come looking for us all.

The Last Psychiatrist, July 5, 2005

Do Antidepressants Induce Mania?

No.

This myth is the result of imprecise use of language. Many2 3 4 5 6 have detected a temporal association between the use of tricyclic antidepressants and episodes of mania in patients with bipolar disorder, though no plausible mechanism has been suggested, much less found. It has been assumed that this association could be extended to all antidepressants despite their substantial chemical and pharmacological heterogeneity. However, such an association between mania and selective serotonin reuptake inhibitors has not been found. In fact, the studies 7 8 9 which have been done strongly indicate that the rate of mania with SSRIs is no different than the normal switch rate of bipolar disorder. A recent study10 11 of venlafaxine, sertraline and bupropion found a 13% 10 week switch rate into mania or hypomania (excludes symptoms lasting less than 7 days), and an 18% one year switch rate, but this study was confounded by the concomitant use of mood stabilizers of dubious efficacy (lamotrigine, gabapentin, topiramate) in 22% of the patients, and the lack of a placebo arm to establish the baseline switch rate. Because of the significant phenomenological heterogeneity of the patients with “bipolar disorder” in clinical trials, a placebo arm is vital in order to compare results in different studies.

It must be reiterated that these are studies of temporal associations between mania and antidepressants, and no causal link can be inferred. Despite this, many continue to discuss the question in terms of the induction of mania by antidepressants. This betrays a bias that is supported neither by data nor logic. For example, studies of novel antidepressants cite rates of “induced” mania, while studies of antiepileptics discuss “breakthrough” manias, automatically presupposing a difference in the mechanism of mania. Similarly, it is popularly assumed that bupropion is less likely to induce mania than SSRIs. This assumption is formalized in the Expert Consensus Guidelines 200012, where bupropion “was clearly rated as the antidepressant least likely to precipitate an episode of mania.” It is not immediately obvious why this was so clear, as there is virtually no evidence indicating this. One single study13 (N=19) found bupropion to be less likely to induce a switch than desipramine. The final results of Post, above, are still pending, but it appears evident that if one has decided to accept the myth that antidepressants induce mania, there is no reason to believe bupropion is any less likely to do this.

The accumulated data in the field strongly suggest that the real risk in the treatment of bipolar depression is ineffectiveness, not mania.

-------------
2 Prien RF. Klett CJ. Caffey EM Jr. Lithium carbonate and imipramine in prevention of affective episodes. A comparison in recurrent affective illness. Arch Gen Psych 29(3):420-5, 1973 Sep.

3 Prien RF. Kupfer DJ. Mansky PA. Small JG. Tuason VB. Voss CB. Johnson WE. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psych 41(11):1096-104, 1984 Nov.

4 Boerlin HL. Gitlin MJ. Zoellner LA. Hammen CL. Bipolar depression and antidepressant-induced mania: a naturalistic study. J Clinical Psychiatry. 59(7):374-9, 1998 Jul.

5 Wehr TA. Goodwin FK. Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry. 36(5):555-9, 1979 May.

6 Jann MW. Bitar AH. Rao A. Lithium prophylaxis of tricyclic-antidepressant-induced mania in bipolar patients. Am J Psychiatry. 139(5):683-4, 1982 May.

7 Amsterdam JD. Garcia-Espana F. Fawcett J. Quitkin FM. Reimherr FW. Rosenbaum JF. Schweizer E. Beasley C. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. Journal of Clinical Psychopharmacology. 18(6):435-40, 1998 Dec.

8 Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. British J Psychiatry. 164(4):549-50, 1994 Apr.

9 Nemeroff CB, Evans DL, Gyulai L, Sachs GS, Bowden CL, Gergel IP et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001; 158:906-12.

10 Post RM. Altshuler LL. Frye MA. Suppes T. Rush AJ. Keck PE Jr. McElroy SL. Denicoff KD. Leverich GS. Kupka R. Nolen WA. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. [Clinical Trial. Journal Article. Randomized Controlled Trial] Bipolar Disorders. 3(5):259-65, 2001 Oct.

11 Post RM. Leverich GS. Altshuler LL. Frye MA. Suppes TM. Keck PE Jr. McElroy SL. Kupka R. Nolen WA. Grunze H. Walden J. An overview of recent findings of the Stanley Foundation Bipolar Network (Part I). [Journal Article. Review. Review, Tutorial] Bipolar Disorders. 5(5):310-9, 2003 Oct.

12 Sachs GS. Printz DJ. Kahn DA. Carpenter D. Docherty JP. The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. Postgraduate Medicine. Spec No:1-104, 2000 Apr.

13 Sachs GS. Lafer B. Stoll AL. Banov M. Thibault AB. Tohen M. Rosenbaum JF. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psych 55(9):391-3, 1994 Sep.

See also: Bipolar Controversoies

Suicide and Antidepressants

From The Last Psychiatrist - December 19, 2007

Deus Ex Homonymia

Answer the following questions, and don't look at the next until you answer the previous:

1. Does depression in kids raise their risk of violence?
2. If a kid is violent, is it more or less likely they are depressed?
3. If someone is depressed and violent, is it likely they are a kid?
4. Can you define any of the nouns in the preceding questions?

In a study called Perceived Dangerousness of Children With Mental Health Problems and Support for Coerced Treatment the perceptions of 1100 members of the public were evaluated, finding:

Children... with major depression were perceived (by 81% of the sample) as somewhat likely or very likely to be dangerous to themselves or others, compared with children with asthma (15%) or those with "daily troubles" (13%).

and, later:

...compared with the child with "daily troubles," the vignette child with depression was more than twice as likely to be assessed as dangerous toward others and ten times as likely to be assessed as dangerous toward himself or herself.

Now, you lose no money assuming the public at large merely guess at probabilities. So what they think may be right, wrong, both-- who knows. But whatever they think, it's probably important to quote them correctly:

"The issue that was highlighted by this study that was really concerning to us was that Americans have linked depression in youth and violence, particularly violence towards others," said Dr. Pescosolido ["distinguished professor of sociology, Indiana University."] [emphasis mine, but, face it, really theirs.]

Well, no, that's not what the public thinks, at least according to your study. They think that depression leads to violence against themselves, and maybe towards others. Only 9% thought violence towards others was very likely. The majority thought violence towards others was not likely. Right?

Also, please note the subtle cut against "Americans," those barbarous, judgmental, yellow ribbon tying NRA members, i.e. "Texans." (I know, sociology professor...)

"It's really, really horrible. Many people who are not in the field perceive these youths as dangerous-- and yet we have no evidence that these kids are any more dangerous than youth randomly picked..." said Dr. Kelleher, professor of pediatrics at Ohio State.

Wow. I had thought the entire infrastructure of psychiatry rested on the very foundational idea that psychiatric disorders, especially depression, are responsible for increased risk of violence to the self. And these quotes are even more weird given that they come from Ohio and Indiana-- the two states responsible for over half the increase in female youth suicides in the whole country. You know, the increase that everyone is blaming on antidepressants.

But words are lies, and you can use loose language like "violence" and "dangerous" and "youth" and "kids"-- bending its meaning to whatever you need it to mean at that moment-- to make any point you want. The actual arguments for this position can be be flipped when necessary (e.g. Nasrallah saying a school shooting isn't "evil" but "medical illness.") You can do this if you manipulate words, e.g. conflating school shooting and suicide to "violence," and then making "violence" mean what you need it to mean at that moment.

So what is her point? I'm sure she doesn't want to be saying that depressed kids aren't prone to self harm. So?

So nothing. She, they, don't have a point, they want to convey a feeling, a political position, something like, "no one is bad just because they are sick; but if they were bad, then it was because they were sick."

It's a good position, given that it is entirely empty, and can be made into whatever you want. Right or wrong is precisely besides the point.

So what do these authors tackle next? Forced psychiatric treatment, of course.

Next...

STAR*D

From The Last Psychiatrist - July 7, 2006

Star-D Study Participants: What's Wrong With These People?

I don't even know what to make of this:

4041 patients show up and consent to be in a massive antidepressant trial, and almost 25% can't even score a HAM-D of 14? (7=complete cure.) Who are these people? What were they thinking?

And then of the ones who actually stay to participate (N=2876), their average HAM-D is 21? For two years?

And Celexa cures a third of these patients? Half of them in less than 6 weeks? After two years walking around HAM-D =21? Cures? Celexa? 40mg? Hello?

Remember, this is open label. These people, who presumably have been in psychiatric treatment for a long time (mean length of illness 15 years), know that they are taking 40mg of Celexa. Not a new experimental drug with a new mechanism of action. Celexa. 1/3rd get cured. After all this time.

BTW, the people who failed this Celexa study get moved into Star-D II. What is the relevance of this? Well, in this study 63% were female, 75% were white, 40% were married, 87% were high school grads or greater, 56% had jobs. It is the opposite of this demographic that is most likely not to have gotten better.

July 9, 2006

STAR-D Augmentation Trial: WRONG!

This is what a $150 subscription to the NEJM gets you:

From the abstract:

Conclusions Augmentation of citalopram with either sustained-release bupropion or buspirone appears to be useful in actual clinical settings.

I can't be the only person who actually reads the articles and not just the titles, can I? There has to be at least one other person?

565 Celexa failures (i.e. did not achieve remission) from the previous STAR*D trial were then randomized to Celexa (avg dose 54mg) + Wellbutrin or Celexa + Buspar. 30 percent of the augmented patients (either Wellbutrin or Buspar) achieved remission.

From this it is concluded "These findings show that augmentation of SSRIs with either agent will result in symptom remission."

How the hell do you conclude that? Is it a mere coincidence that the remission rates of Celexa+Wellbutrin in this group were the same as Celexa alone in the other study (30%)-- and the same as almost every other monotherapy trial for every other antidepressant?

In other words, how can you be sure it was the combination of Celexa+Wellbutrin that got the patients better, and not the Wellbutrin alone? What would have happened if you had given these patients Wellbutrin but taken them off Celexa? They would have done half as well? Are you sure?

I'm not saying that it might not be true that two drugs are better than one, I'm saying that this study doesn't show that. If anything, this study actually supports switching as a strategy (i.e. fail Celexa, so switch to Wellbutrin)-- because two drugs are not proven here to be twice as good as one alone, but I can certainly prove they carry twice as many side effects and are twice as expensive.

Here we have a massive expenditure of tax dollars that will undoubtedly lead to treatment guidelines that will be clinically misleading and economically wasteful. How much did the NIMH pay for this? And for CATIE? I'm not a Pharma apologist, but what was wrong with forcing Pharma to pay for their own studies which we get to pick apart? These government sponsored studies are no better. Gee-- the generic came out on top?

Understanding Antidepressants

From the Last Psychiatrist - July 17, 2007

No, Not Effexor, Too!?

Let's review the idea of sequential binding. A drug with affinity for multiple receptors doesn't bind to all of them simultaneously, but rather sequentially, like an aging polygamist, starting with the system for which it has the greatest affinity. Eventually, this maxes out, and it goes and adds the receptor system for which it has the second greatest affinity.

Once it has maxed out a receptor system, pushing the dose doesn't get you any more of that effect (or side effects.) You don't get less, but you don't get any more. You know what else is like that, sort of? Chlamydia.

Let's look at an SSRI, Celexa. That first S stands for selective (serotonin reuptake inhibitor.) All of its clinical effect is coming from one single receptor system; this rum fountain has only one level-- and it's not that deep. By about 20mg, you've gotten as much serotonin effect as you are going to ever get.

Certainly, by 40mg, you're all done. Do you expect the clinical difference from 10mg to 20mg to be significant? Maybe. How about 20mg to 40mg? Not so much. 40mg to 60mg? You woke me up for this? Don't touch me.

In other words, there's only one level in Celexa's rum fountain, and it's pretty much filled by 40mg. Pushing it to 60mg ("Now, with 50% more citalopram!") gets you a whole 3% more serotonin transporter binding. Which is embarrassing. I said don't touch me. Do it again and I'm calling an adult.

So what about Effexor, the serotonin/norepinephrine reuptake inhibitor, invented at Wyeth Labs by Kirsten Dunst, aka Vitamin C?

From the American Journal of Psychiatry study:

la, la, la , la , la, la ,la ,la ,la ,la
la ,la ,la,la, la,la
yeah, yeah, yeah,
la, la, la, la, la, la, [repeat x 36]
we will still be friends forever [sic]

Which is exactly the point. You don't get both S and N at all doses, it is, again, sequential: level 1 is S, maxed out by 75mg; and level 2 is N. Guess when level 2 (N) really kicks in? 150mg.

So anything after 150mg is really two systems at once, with the N increasing from there. 300mg is the same amount of S as 150mg, but the N is more.

Would you expect 75mg Effexor to be generally more efficacious than 40mg Celexa? No, because they are both doing the same thing: blocking about 80% of serotonin transporters. But what about after 150mg, when you have S and N?

From An Inconvenient Truth, 2006

This is why Effexor studies only show superior efficacy at doses above 150mg-- because at 150mg, you start adding N on top of your already maxed out S. It's not adding more of the same drug, it is like adding a second drug. It's not more Effexor; it's taking a maxed out SSRI, and adding a NRI. It's like being with Princess Leia, but then adding Princess Ardala. And if you understood that joke, you should put down Yars' Revenge and kill yourself.

Let me be clear: I'm not saying Effexor is or is not better than an SSRI. I am saying that

1. it would be impossible for it to be better then SSRIs, across a population, at less than 150mg.
2. if it is going to be better, it would be better after 150mg, and only because you are adding a second system.
   
3. If you are a doctor who "went all the way" up to 75mg Effexor for depression (or 300mg Seroquel for psychosis, etc, etc) and then stopped it because "it wasn't helping at all" then you should probably punch yourself in the testicles/uterus, you have missed the point. How one responds at 75mg IS NOT AT ALL PREDICTIVE of what might happen at 150 or more (or, for Seroquel and psychosis, 500mg or more) again, and for the last time, because higher doses aren't more, they are different.(2)
   

You can see this most clearly if you look at an MRI:

which is self-explanatory.(3)

What you may want to ask is this: why haven't you heard this stuff before? You think I discovered all this, in my basement lab, the one I use to create Jessica Simpson clones? I'm the Ponce de Leon of psychiatry?(4) Why the accepted delusion that a drug is the same, regardless of dose? Perhaps it's because this supposedly only applies to the newer drugs? The old ones-- Thorazine, Elavil, Pamelor, Remeron, Wellbutrin-- all blunt instruments, single receptor system drugs?

Why do we think that an inanimate object has a fixed identity, when even a person doesn't?

Next up: Aren't Two Drugs Better Than One?

--------

1. From the Celexa package insert: (warning: PDF-- clear your schedule)

2. Punching yourself in the testicles/uterus is not likely to help you learn this, it is more for my benefit.

3. It's technically an fMRI, bt the point is the same.

4. Ponce de Leon did not actually discover psychiatry, but he was the first to make it available to the masses.

IF YOU LIKE IT, DIGG IT, OR SEND ME RUM--