Will Investors Need A Pill For Uncontrollable Crying?
36 CommentsBy Ed Silverman // March 28th, 2008 // 9:17 am
Anyone familiar with involuntary emotional expression disorder? This is another way of saying uncontrollable laughing or crying, and a little drugmaker called Avanir Pharmaceuticals hopes to market a pill for this “distinct neurological disorder.” Also known as pseudobulbar affect, the affliction has gotten talked up in recent years and investors are buying into the concept.
Earlier this week, Avanir received commitments for $40 million in funding from a group of venture capital firms, including ProQuest Investments, whose scientific advisors include Howard Scher, a noted oncologist caught up in the conflicts-of-interest scandal engulfing the FDA over the Provenge prostate-cancer vaccine. The proceeds will be used to complete a Phase III test of its Zenvia pill, which used to be called Neurodex.
Is there a market for such a pill? Avanir has spent considerable effort ensuring one exists. As noted by The New York Times three years ago, the drugmaker “recruited neurologists and psychiatrists as scientific advisers…to prime the market by elevating an ill-defined group of symptoms into a condition…in hopes of establishing awareness of it among doctors and patients.” The paper also wrote some critics say the condition may not require meds in people who are fighting more serious health problems, and the syndrome actually has various names and possible treatments.
So there may be some irony in all this: if Zenvia is approved by the FDA, investors may need the pill themselves as they laugh all the way to the proverbial bank. And for those who complain about endless disease mongering, perhaps Zenvia will relieve their undying grief.
HorusCat
OMG,
Even I am rolling my eyes at this one…@@
Healthcare 100 links for 03-28-08 | The eDrugSearch Blog
[...] Will Investors Need A Pill For Uncontrollable Crying? (Pharmalot) [...]
Dan
The DSM book or manual is the psychiatrist’s bible of every imaginable mental diagnosis, as well as recommendations of existing signs and symptoms, followed by treatment for whatever disorder it may be.
Amazingly, over the past few decades, the number of diagnoses in this manual has quadrupled. No explanation offered, except for vague explanations such as ignorance and lack of exploration.
It’s out of control. Novartis, the maker of the ADD drug ritalin, had the audacity to give brochures to children on the disease and treatment with ritalin.
Close to half of children are now on some type of psychotropic medication, because it’s much easier to please another than to oppose them.
Jack2
Close to half of children are now on some type of psychotropic medication, because it’s much easier to please another than to oppose them.
Dan, do you have a CREDIBLE reference for this?
Chris
These investors must be remarkably confident in Avanir’s ability to turn a combination of a cough medicine and an old cardiovascular drug into a successful product. Rarely will a marketing challenge surpass this one. And on reimbursement…?
HorusCat
Dan,
I, too, would like to see some hard evidence that 50% of children are on psychotropics…
Pharma is certainly to blame for some of this, but so are American society and psychiatry: We live in a more and more morally-relative society, where there is no right or wrong, black or white. The approach to dysfunctional behavior is not “knock it off” but “let us try to understand you.” The model for psychology is this– turning what society used to see as disruptive and unacceptable behavior into a “disorder” or a “disease” which must be treated rather than sanctioned. Maybe you have to congratulate pharma for making the most of a business opportunity. An entire culture is growing out of this—ADA encompasses not just the physically handicapped, but those “suffering” from dubious mental “disabilities.” When the entire spectrum of human behavior is subject to moral relativism, then “medical” explanations of the extremes of behavior are going to arise.
Seeks The Truth
Soooo…..
ProQuest Investments, the personal playground of an “esteemed” Howard Scher MD, shows up again in an Ed Silverman post. As “scientific advisor,” Scher throws his weight behind a questionable drug for a laughable and questionable disease while TAKING GREAT PAINS to discredit DNDN’s Provenge after the FDA’s own AC meeting almost exactly one year ago. After a 17-0 vote for safety and a 13-4 for SUBSTANTIAL evidence of efficacy Scher co-authored a letter denouncing Provenge and along with others, managed to get the FDA to turn down
the excellent but revolutionary “new” immuno-therapy for advanced protate cancer.
Since that tragic rejection a year ago, THOUSANDS of dying men afflicted with advanced PCa were denied a life-prolonging therapy.
Why was Scher so anxious to negate a Provenge approval?
Why, to protect the multi-BILLION dollar oncology/chemo-therapy cartel, of course.
Oh, and did I mention that while Scher sat on the AC panel deciding the fate of Provenge, he was a LEAD investigator for a COMPETING prostate cancer treatment produced by Novacea.
Are you kidding me??
How could ANYBODY not see a serious conflict of interest?
So what happened?
DNDN’s Provenge approval was and is shelved, while the use of Scher’s Novacea product in clinical testing was SUDDENLY DISCONTINUED because, my God, it was UNSAFE AND INEFFECTIVE!!
What a travesty for those deprived of Provenge therapy.
In my many, many years of clinical medicine I never saw one patient with “uncontrollable” laughing or crying.
On the other hand, there are TENS OF THOUSANDS of men, right NOW, who have advanced prostate cancer.
Why hasn’t Scher thrown his considerable academic and clinical power behind Provenge?? It’s a sad tale indeed.
Go to CareToLive.com to learn more about one of the most tragic episodes in FDA history.
If YOU have prostate cancer and are reading this, you MUST visit the CareToLive site!!
Justice in Michigan
I hope some will forgive the reference, but I think it was Marx who said, “History repeats itself. First as tragedy, and then as farce.”
Kyoto27
Bouts of uncontrollable laughter as Howard looks back at how he ‘duped’ the media in his ‘can’t sleep’ Cancer Letter rant against Provenge is now probably taking a toll on the poor doc; Proquest and Michael Milkman probably think they can help Howie –and also help themselves to a few bucks by backing Zenvia.
One thing is certain—Howie’s bouts of uncontrolled laughter will get Zenvia over the FDA’s goal line (if for no other reason than to protect Pazdur’s valued FDA advisory panelist from making a fool of himself during any ODAC deliberations).
(FYI, today is the first anniversary of the overwhelming FDA positive panel for Provenge approval—which, of course, led to its rejection behind FDA closed doors on May 9th. )
The Medical Quack: Is Depression Contagious?
[...] there a pill for uncontrollable crying when the pressures mount? According to this article there is work in this area of “involuntary emotional expression”…I had no idea what it was until [...]
Lisa Van S
Jack2, Horus
Psychtropics are rising check out this post on Pharmalot and dont forget to read Medcos Press Release. Remember this doesnt include Medicaid and others
http://www.pharmalot.com/2007/05/more_teenagers_on_more_meds_wh/
Lisa Van S
Jack2,Horus,
another link, bottom of page gives rates of increase
http://www.webmd.com/parenting/news/20070517/prescription-drug-use-up-in-teen-girls
Nathan: See what your girls have to look forward to!!
Dan
Readers,
The percentage of kids I stated on psychotropic meds was based on hearsay from a public elementary school. So no, I found it was, nationally speaking, an exaggerated percentage, so forgive me.
However….
Kids under state care can be forced to go on such meds if somehow they are determined to have an abnormal mental state, and often are. As a result, the percentage of kids on these meds are higher in that population. In fact, one could posit that because a kid in foster care, it seems, that kid is to some degree already labeled predisposed to such mental disorders, one could argue.
Public school children are required to undergo mental health testing by non-medical professionals. So while I believe I exaggerated without intent earlier about the number of kids on such meds, several variables as well as locations and situations play a role in the frequency of intake of what I consider damaging drugs to children. I also consider such psychotropic meds are prescribed to children as the drugs seem to be a perceived easy fix for what some moron determined was an abnormality, and therapy with such drugs at such a young age has not been determined to be safe for them now or in thier adult life.
Overmedicating children is not a new concept, and is worth researching.
Over the last couple of decades, the prescribing of such meds to children has increased draumatically, as if these drugs are some sort of chemical restraint.
Chris
Interesting but what has any of this to do with the topic of this post? The pediatric/psychotropic debate pervades.
HorusCat
Thanks, Lisa. And thanks for your civil tone. We are really off-topic, sorry Chris! Ed needs to set up a chat room for IMing. In the vein of not continuing to be off-topic, Lisa, let me say that in many ways, I share your concerns about over-medicating children. Perhaps unlike you, I wouldn’t blame it all on pharma. What really shocked me was the Type II diabetes med use! and sleeping pills?
Lisa Van S
HorusCat,
They coincide with use of antipsychotics.
Off topic, not really. Antidepressants and Antipsychotics can cause Uncontrolable laughing/crying,.. so I can see the prescribing of this drug skyrocketing.
HorusCat
Lisa,
You had me until the “antidepressants and antipsychotics can cause uncontrollable laughing/crying…” At some point, you have to admit that these drugs have a useful place in medicine. Now, I am with you on the kid issue. Again, I think we need to look at social attitudes toward behavior, problems with violence and disruption in school, parents and teachers who want an easy fix rather than the hard work of discipline and support of their children…
Tony F
Ed, as usual, you keep your readers up-to-speed by tying the loose ends together…in this case, i.e. Scher and Proquest Investments.
For those unfamiliar with the Scher/Proquest references above, Scher gained access to sit in judgment of Provenge at the March 29th FDA Advisory Committee. In order to do so, Scher certified to the FDA that he had but 3 Conflict of Interests (COI).
Interestingly, 17 (SEVENTEEN) Conflicts of Interest for Dr. Howard Isadore Scher have been found on the internet and are:
[NOTE particularly items 1 & 17]
1. NOVACEA: grants & research support; STUDY CHAIR of DN-101
…. and DIRECT COMPETITOR to Provenge
2. GPB BIOTECH: financial conflict of interest per Scher in MedPage
3. PHARMION: financial conflict of interest per Scher in MedPage
4. SANOFI-AVENTIS: grants & research support
5. BRISTOL MYERSSQUIBB: consultant, grants & research
6. MILLENNIUM PHARMCEUTICALS: grant of research support
7. COUGAR BIOTECHNOLOGY: principal investigator; advisory board;
8. INNOVIVE PHARMACEUTICALS: principal investigator
9. INFINITY PHARMACEUTICALS: principal investigator
10. BIOGEN-IDEC: jointly held stock with spouse
11. PFIZER: jointly held stock with spouse
12. GENTA: scientific advisory board (as of Mar 6, 07; since removed but cached)
13. CONFOMA THERAPEUTICS: scientific advisory board
14. DEPARTMENT of DEFENSE: Principal Investigator PC Clinical Trials-P1 & P2
15. AMBRILIABIOPHARMA INC: Principal Investigator PCK3145, Phase I/II
16. MEDIVATION, INC: principal investigator MDV3100
17. PROQUEST INVESTMENTS, Board of Directors, Advisor. Novacea Investor
Oh, what a tangled web one weaves……
… while 83 men die daily from prostate cancer.
Today is the 1 year anniversary of the FDA AC meeting; since the FDA turn-down last May 9th, 26,864 men have died from prostate cancer….
26+ THOUSAND!!!!!!
Lisa Van S
Horuscat,
Absolutely does,.. It can be found in the DSMIV under substance induced mood disorders. May I suggest you spend some time on Laurie’s website paxilprogress, and speak with individuals who are going through withdrawal.
Check out GSK’s Marketing Cartoon (Screaming Bussiness Woman) http://www.paxilharmschildren.com/doc/paxil_wheresmy.pdf
HorusCat
Lisa,
What is it about Paxil that bothers you more than the other SSRIs? I’m just curious. They have a really obnoxious rep here who yells at people, but maybe that’s because she NEEDS Paxil.
I will check out Laurie’s website.
pg
Horus, maybe - and very likely - that “obnoxious rep” is already ON paxil - or Zoloft, or Effexor, or any other ‘atypical antidepressant’ which is after all, what SSRIs and SNRIs really are - nothing special, just ‘atypical antidepressants’.
Sam
Paroxetine (Paxil and a few other brand names) had the highest number of adverse reactions reported to the FDA’s Adverse Event Reporting System (AERS) between 2004 and 2006 with 66,919 adverse reactions reported in 18,846 Individual Safety Reports for 15,637 cases (patients) including 1,308 reports of suicidal ideation, 495 attempted suicides, 841 completed suicides, 119 instances of homicidal ideation and 54 homicides (the act, not the number of people killed) with 158 reports of hypomania/mania (which fits the definition of “uncontrollable laughing/crying”) all attributing Paxil (paroxetine) as the Primary Suspect Drug (that’s the FDA’s wording).
And since the FDA’s AERS only receives reports on from 1 to 10 percent of the actual incidence of adverse reactions, multiply those figures above by a conservative 10 and you get well over half a million adverse reactions occurring during a three year period.
Paxil (paroxetine) is the worst of the SSRIs (it’s the most egregious of all psych drugs) in terms of frequency of adverse reactions according to the reports submitted to the FDA’s AERS.
Ed Silverman
Hmmm…..From Provenge to antidepressants. Lots of interesting comments here. Any thoughts on the issue raised in the initial post?
Jane
Wow, a pill for anybody who cries. That is a big potential market for this pill. But really, this disorder, “involuntary emotional expression” seems to me to be contrived. And for whose benefit is this pill to be given? The person crying or for the benefit of those people that have to listen to the crying or for the drug company Avanir? Is Zeniva just another antidepressant with a different marketing approach?
HorusCat
Ed,
I have never heard mention from any of my docs this issue of uncontrollable crying or laughing, and despite what Sam says, that is not the definition of mania or hypomania. I’ve never even seen anyone with the problem, except for Holly Hunter in that one movie (Network News?). I am going to start asking about it. It does occur to me that there may be some of this in the demented elderly, but that raises all sort of questions about the appropriateness of treatment for the “disorder.”
I’m going to go to pubmed and see if I can find out what the MOA of this drug is.
HorusCat
Ed,
Here is one abstract I culled from pubmed; date was 2007. There was another one that indicated those with MS may have PBA.
“Pseudobulbar affect (PBA) is a dramatic disorder of emotional expression and regulation characterized by uncontrollable episodes of laughing and crying that often cause embarrassment, curtailment of social activities, and reduction in quality of life. The disorder occurs in patients with brain injury caused by many types of neurological disease, including stroke, tumors, and neurodegenerative gray and white matter disorders. Although the pathophysiology is unknown, PBA may relate to release of brainstem emotional control centers from regulation by the frontal lobes. Diagnosis of PBA can be difficult and relies on careful characterization of episodes and differentiation from depression. Although there are no US Food and Drug Administration-approved treatments for PBA, several agents have been shown to be effective, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and a new agent containing dextromethorphan and quinidine. The growing number of treatment options, some of great benefit to patients, highlights the importance of accurate diagnosis of this disorder.”
Perhaps this is like narcolepsy–not many people suffer from it, but for those who do, it have devastating consequences.
Ed Silverman
Hi Horuscat,
Fair enough. Although the last line does seem to jive with the report from the NYT about various treatment options. In any event, the irony I pointed out would still stand, yes?
Also, out of curiosity, did the authors whose work appeared in PubMed disclose who funded their work? I ask because the earlier story raised the point that the company was actively lining up support in the medical community, where skepticism about the matter seems to exist.
Cheers
ed
HorusCat
Ed,
I messed around in pubmed for awhile. The research about pseudobulbar effect goes pretty far back. The pharmacologic treatment studies are pretty concentrated in the past five years, and most of them appear to be connected with Avenir. This makes sense, because what is weird about this product is that it is basically cough syrup. It is cough syrup with quinidine, which is a drug that inhibits liver enzymes, which apparently is necessary because dextromethorphan gets metabolized so quickly by the body. It makes sense that someone would only do the clinical work behind this is they were being funded by a pharma company–the money just isn’t there otherwise.
I don’t know enough about the patenting process to know how they are getting dextromethorphan plus quinidine patented.
It does appear that PBA commonly occurs in diseases like ALS and MS, as well as traumatic brain injury. Who’d of thunk it?
What I think the medical community may legitimately be skeptical about is any effort to generalize what appears to be a legitimate, but very specific, syndrome to those not suffering from diseases like MS and ALS. And the legitimate question of whether one would treat the syndrome in those suffering from really severe problems like MS. I am good friends with a MS researcher; I’ll ask him how often he sees it, if he treats it and what he thinks about this.
Ed Silverman
Hi HorusCat,
Thanks for peeking. And someone else raised the point about the drug being a combo of a cough syrup and CV med. Interesting.
Anyway, I think you hit the nail on the head - yes, PBA has been fingered, but the issue is/was the extent to which Avanir’s new name for the affliction, and its assorted efforts, are an attempt to generate a wider clientele.
Depending upon one’s frame of reference, the number of MS and ALS patients taken together may or may not be a lot. But then add others who exhibit what appear to be the symptoms of IEED, such as it is. Potentially, that’s a much bigger market. Hence, interest from investors. Whether managed care will laugh or cry at the idea of coverage remains to be seen.
Regards
ed
Dr Aust
Hmm. New to this blog - very interesting reading.
I’m not sure I would be wanting my mother or other elderly relative to be dosed up with an antiarrhythmic drug with a long list of adverse effects and inconvenient interactions (quinidine) just because she was a bit tearful. And if I had MS or ALS I might think emotional outbursts were a natural response to the depression that would almost automatically tend to go with such miserable conditions.
This is another of those “drug / disease mission creep” stories, isn’t it? Like several above, I can believe a few people have this problem in a very disabling way, to the point where a treatment would be useful, but it does have that “medicating the normal behaviour spectrum will make us $$$” feel to it.
And as for the company and their “rounding up a coalition of the like minded…” Hmm. Nothing terribly surprising there, sadly - probably standard practise. Though given that drugs already exist which might do something for this, I am surprised a bunch of hard-nosed venture capital types would front up a heap of cash for (as Horuscat described it) “cough syrup plus quinidine”. It will certainly take a lot of marketing campaign. Perhaps their idea is to get all those folks to take it who are either terrified of taking tricyclics/SSRIs, or would refuse them “because I’m not depressed”.
Anyway, if I was feeling cynical I might be tempted to say “As usual, one person’s syndrome focus group is another persons’s disease mongering”.
HorusCat
Dr. Aust,
Welcome! Glad to have you. Yes, I would hate to be the rep that has to sell that drug. I do a lot of work with geriatricians and geriatric psychiatrists. I think they would be extremely skeptical of using quinidine in their population. Although in all the talk I’ve heard about dementia, I’ve never heard anyone say anything about PBA.
The literature does report instances where MS was first diagnosed BECAUSE of uncontrollable emotional outbursts, which I find very interesting, just from an intellectual standpoint.
I think what the literature describes as PBA is a real problem–we aren’t talking occasional outbursts, but disruptive, embarrassing incidents that occur frequently. But I am with you totally that of course Avenir will try to make this into a more commonplace “disease.” I have to say though, that I get around as much as the next person, you know, going to the grocery store and church and the gym, and I have never seen anyone laughing or crying uncontrollably. Where are all these people?
Sam
HorusCat,
If “involuntary emotional expression disorder … another way of saying uncontrollable laughing or crying” is not a description of mania (which the Oxford English dictionary defines as: “mental illness marked by periods of excitement, delusions, and overactivity”), then what is the psychiatric definition for mania and hypomania? Please state a reference, not your opinion.
Bob Freeman
Hmmm, this “disease” was quite prevalent in films from the 30s and 40s, affecting mostly mad scientists and women in gothic themes. The most effective treatment was a slap in the face, efficacy measured by the patient uttering the words, “Thanks, I needed that.”
HorusCat
Sam,
From Medscape:
In This Article
The Phenomenology and Diagnosis of Mania
Prognosis
The Management of Acute Mania
Maintenance
——————————————————————————–
References
From Medscape Family Medicine/Primary Care
Topics in Adult Primary Care - Bipolar Disorder Expert Column
The Recognition and Management of Mania
Posted 08/26/2004
William Coryell, MD
The Phenomenology and Diagnosis of Mania
A manic episode distinguishes bipolar I disorder, a condition estimated to have a lifetime prevalence of 1.6% in the United States.[1] In contrast to the female predominance that characterizes other affective disorders, the sex ratio of bipolar I disorder is nearly even. Onset occurs most often in the 20s, but childhood and adolescent onsets have been increasingly recognized in the past decade with the realization that the phenomenology and course at these ages differ from typical presentations in adults.[2-5] Numerous medical conditions can produce manic syndromes,[6] and the first occurrence of a manic episode in older individuals should invite a careful screening for underlying conditions.
Some manic episodes develop with remarkable speed, although gradual onsets spanning weeks to months occur as well. An individual being treated for depression may abruptly switch into a manic phase and mania may evolve quickly to depression.
The DSM-IV definition of mania lists 8 symptoms and requires euphoria or irritability. Either of these may occur alone or in combination with the other, and either may be ascertained by the patient’s subjective report or by clinical observation.
Patients with mania experience the decreased sleep that is present in many other disorders. The distinguishing quality in mania is the absence of resultant fatigue. A useful probe is, “Have you found that you need less sleep than usual to feel rested and energetic?”
A decreased need for sleep is typically accompanied by another manic symptom — increased activity. Whereas individuals with depression or anxiety disorder who are unable to sleep often remain in bed and brood about their need for sleep, manic patients are likely to be up and busy at night. Increased activity should be apparent to others in the patient’s environment to be included as a manic symptom.
Manic patients may or may not acknowledge racing thoughts, but the examiner often appreciates a flight of ideas on interview. The patient typically moves rapidly from one topic to another but, in contrast to the thought disorder of schizophrenia, the connection between thoughts is usually perceptible. Patients with pressured speech are not simply circumstantial, but speak rapidly and expressively. In clinical settings, such patients are more likely than other patients to address all present and to be socially intrusive.
Grandiosity may shade from modest overestimation of talent, intelligence, or economic prospects to grandiose delusions in which the individual has worldwide or cosmic importance. These beliefs are often complicated by persecutory delusions that may then dominate the clinical picture.
The sense of optimism and invulnerability that accompanies grandiosity often combines with increased activity to fuel reckless behavior. This feature is responsible for much of the morbidity consequent to manic episodes. Excessive spending is perhaps its most common form, but patients often also come to regret impulsive sexual liaisons, abrupt travel, ill-advised business decisions, and excessive alcohol use.
The distinction between bipolar I disorder and bipolar II disorder hinges on the boundary between mania and hypomania. Patients with mania experience a mood disturbance that is, according to DSM-IV, “sufficiently severe to cause marked impairment in occupational functioning or unusual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.” Those with hypomania do not, by definition, have this level of severity. This may seem an arbitrary separation of syndromes, but the results of family[7] and follow-up studies[8,9] support its validity. Bipolar II disorder occurs far more frequently in the families of bipolar II probands than in the families of bipolar I probands, and patients with only a history of hypomania are much more likely to develop manic episodes during extended follow-up periods than are those with histories of mania.
I think I experienced an episode of hypomania the weekend I painted my entire kitchen and dining room–a process that involved 5 coats of paints.
The literature on PBA (the uncontrollable crying/laughing describes an actual physical defect between the frontal lobe and the area that controls emotion. A person in a manic or hypomanic episode would not have such an actual physical deficit.
Lisa Van S
Ed & Horus,
Uncontrollable laughing/Crying can also occur in stroke patients, and patients w/sleep disorders. Looks like a Pretty wide market to me.
HorusCat
Lisa,
Yes, I wondered about the geriatric market (where most stroke patients are) for this–I suspect that dementia patients of all kinds (AD, Parkinson’s, Lewey Body, CVA-related) may have emotional outbursts. Still, the questions about giving the elderly quinidine are important ones. Stroke patients and dementia patients may indeed have neuronal deficits between their frontal lobes and the limbic system.
I don’t know if such neuronal defects exist in sleep disorder patients. Do you? Or are the emotional outbursts of sleep disorder patients driven only by their lack of sleep? If so, the obvious solution is to help them sleep.
But still, I have to ask–where are these people? Apart from nursing homes and the hospital wards…sleep disorder patients are everywhere, supposedly. Shouldn’t we be seeing random strangers breaking out into hysterical laughter or uncontrollable weeping? I’m being sarcastic, obviously–I too have my skepticism of “expanding the market” efforts on the part of pharma.