Randomized Controlled Studies vs. Widespread Clinical Experience: the Case of Lamictal

There has been an increasing debate about whether doctors are using "evidence-based medicine" or instead are merely going by conventional wisdom or listening to pharmaceutical company sales pitches. Often, as I have discussed several times, the so-called "evidence base" consists of randomized controlled studies (RCT's), while clinical experience is written off as "anecdotal." 

An anecdote is a report of a single, or at most a few, specific incidents, such as a patients' seeming to get better after taking a medication, along with the interpretation of the event by an allegedly biased observer. Besides the fact that one or two cases may not be representative of a psychiatric condition, and that other causes for the observed effect have not been ruled out, the description provided by the source of the anecdote may be incomplete or incorrect. And his or her conclusion may be logical, or it may be fallacious in any of a variety of different ways.

Widespread clinical experience — or the clinical experiences of a wide variety of practitioners who are known to do careful diagnostic work-ups and to follow patients closely — is somehow also written off as "anecdotal," but this is just nonsense. 

First of all, as I discussed in a previous post, in psychiatry there are almost no objective diagnostic blood tests or direct measurements of brain function that can tease out the difference between neuropathology and normal neural plasticity in response to environmental factors. Therefore, conclusions drawn in RCT's are based entirely on the self-report data from subjects or by the potentially biased observations of the experimenters. They are just as much anecdotal as widespread clinical experience in that sense. 

Actually, widespread clinical experience is better than most RCT's in determining the efficacy of drugs. It employs a sample size far larger than all the RCT's on a treatment put together. Also, there are several important  limitations with RCT's.

In a paper by G. Parker and S. McCraw (Acta Psychiatrica Scandinavia, 2015: 1-10) about the drug Lamictal (lamotragine), they discuss the disconnect between the reported efficacy of a new psychotropic medication as quantified in RCTs and its actual effectiveness as observed in the 'real world' of psychiatric practice:

"Most commonly any such disconnect is one of degree, with the medication being progressively clinically judged as less or more effective. Less commonly, the medication may be judged to have a different therapeutic 'signal' than for its formal indication. Two examples of the latter are the selective serotonin reuptake inhibitors (SSRI's) which seemingly modulate emotional dysregulation as much as they have antidepressant propensities, and some atypical antipsychotic drugs having utility in augmenting antidepressant medications and in having mood stabilizing propensities rather than being confined to the management of psychotic conditions.

Any such disconnect can reflect multiple factors, as considered now in relation to antidepressant medications. An antidepressant's 'efficacy' is evaluated from RCTs with the 'control' treatment being either a placebo or a comparator drug. In such trials, the duration is often limited to several weeks, the sample constrained by inclusion and exclusion criteria (e.g. non-suicidal, no substantive co-morbid conditions) that do not hold in clinical practice, and which may, depending on recruitment strategies, be weighted to those with potentially spontaneously remitting and/or less severe conditions. 

RCT-evaluated efficacy may he overestimated using a lower-than-usual dose of any comparator medication, or underestimated if the antidepressant is prescribed at what might be later determined to be a suboptimal dose. Biases may emerge if the sponsoring developers provide data only on trials generating superior findings. "

Richard Horton, editor of the medical journal The Lancet, recently observed, “The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue. Afflicted by studies with small sample sizes, tiny effects, invalid exploratory analyses, and flagrant conflicts of interest, together with an obsession for pursuing fashionable trends of dubious importance, science has taken a turn towards darkness.”

In studies used to evaluate medications for treatment of various mood disorders, there is another glaring problem: the use of inadequate and incomplete diagnostic evaluations of the subjects. I have written several posts about the nonsensical expansion of the diagnosis of bipolar disorder, in which researchers lump together Bipolar I with the bogus disorder Bipolar II. 

Readers of this blog know my attitude about the latter: In my practice since I started training, I have seen four patients who actually met the DSM criteria for this supposed disorder when they were interviewed carefully and followed closely, and all four responded to lithium, suggesting that they were just milder cases of Bipolar I. And most patients who were given that diagnosis by previous psychiatrists did not have bipolar disorder at all but had the mood instability characteristic of certain personality disorders. Some studies have shown this to be true.

Worse yet, some studies include patients diagnosed with unspecified bipolar disorder and "bipolar spectrum disorder."  Neither is defined clearly nor is there any agreement on exactly with what criteria these diagnoses are to be made. So the RCTS's are basically comparing apples to oranges.

This particular problem is not discussed clearly in the Parker and McCraw article. In fact, they conclude that the anticonvulsant drug Lamictal (lamotrigine) is probably not effective in bipolar I disorder, but probably is effective in bipolar II disorder - which probably means it may help the affective instability of patients with personality disorders. This puts this drug as a possible alternative to SSRI's, which the authors themselves note "... seemingly modulate emotional dysregulation."  Emotional dysregulation and affect or mood instability are basically the same thing.

(Combining SSRI's and a long acting benzodiazepine such as clonazepam is even more effective in "raising the bar" on the strength of environmental stimuli required to set off an episode of affect dysregulation, as well as in decreasing self-injurious behaviors like cutting. There are no RCT's on this combination for these symptoms; the drug companies won't do them because most of these drugs are generic and the drug companies probably know that it is effective but do not want docs to know this. However, widespread clinical experience by those doctors who know the difference between bipolar disorder and borderline personality disorder backs me up on this).

The history of the FDA approval for the drug Lamictal for bipolar disorder is bizarre. Its manufacturer first touted it as a treatment for the depressive episodes in bipolar disorder, although later studies showed it to be ineffective in the acute phase of bipolar depression. Then, when it got the FDA approval for psychiatric use, rather than being given the indication for prophylaxis for (prevention of) episodes of bipolar depression, it was given a general indication for bipolar disorder as a whole. This, even though there was zero evidence that it prevented episodes of mania, or that it was useful in acute mania.

In fact, most of the studies in bipolar disorder with the drug were based on a rather flawed outcome measure. The drug was found to delay, but not to prevent, the emergence of another bipolar episode. Whether the episode was a depressive episode or a manic episode was not specified in the majority of these studies!  

Furthermore, lithium — the standard prophylactic treatment—when used at the dosages which lead to the correct blood levels of the drug in patients who respond to and can tolerate it (about 80% of bipolar I patients) completely prevents the re-emergence of manic episodes. In those cases, the measurement "time until the next manic episode" would essentially be the patient's entire lifetime. 

Delaying episodes of bipolar disorder is better than having them more frequently, but why would you use a drug to do that when there is another drug that can prevent them from happening completely?

Re-labeling Depressive Symptoms as Manic Symptoms by Fiat

They look alike.  Madonna must really be a goat.

Another cartoonishly mischaracterized study described in a journal article was recently published in the Journal of Affective Disorders.  One of the editors of this journal is Hagop Akiskal  (I have discussed my opinion of Dr. Hagop Akiskal’s work in a previous blog post).  The article's title is Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes.  


The authors are Lewis L. Judd, Pamela J. Schettler, Hagop Akiskal [the very same], William Coryell, Jan Fawcett, Jess G. Fiedorowicz , David A. Solomon, and Martin B. Keller.

These authors suggest that the presence of something that they label as subsyndromal manic symptoms (that is, symptoms that they believe are the same as those that are usually seen in mania episodes but which are “below the threshold for mania" - whatever that means) are seen in the major depressive episodes (MDE’s) that are also characteristic of bipolar disorder.  

For those unfamiliar, patients with true bipolar disorder have both manic and major depressive episodes, obviously at different times, that are separated by relatively long periods of normal moods called euthymia.

They discuss how some other authors reported that “the most common manic symptom during bipolar MDEs was irritability (present in 73.1% of the sample), followed by distractibility (37.2%), psychomotor agitation (31.2%), flight of ideas or racing thoughts, (20.6%), and increased speech (11.0%). 

Now, of course, they do not mention that these very same symptoms are also seen in the major depressive episodes of people who never have had or will have a manic episode. And who respond to antidepressant medication and have no response at all to lithium (which is highly effective in bipolar disorder). Back in ancient history (the 70’s and 80’s) we labeled depressed patients who show such symptoms as having an agitated depression.  

Other patients with depression who are not agitated but are in fact extremely slowed down - as if on heavy sedatives - were said to have a retarded depression.  We stopped making this distinction between agitated and retarded major depressive episodes because we found that both types of depression usually respond to the same medications, (although agitated depressions seemed to have, on average, a somewhat worse prognosis for medication response).

This authors of this article state that irritable and agitated qualities of MDEs, defined in various ways, are prominent in the clinical and research literature on bipolar patients with yet another clinical entity called a mixed depressive state. In the opinion of a lot of psychiatrists like myself, a mixed state is something better characterized by the name dysphoric mania. The patient has all the symptoms of mania but, instead of the highly elevated, euphoric mood as most people in a manic state have, they feel awful.

I find I cannot use the definition of a "mixed state" that is used in the official diagnostic manual, the DSM, because it is actually impossible.  To have a mixed state according to DSM criteria, “The criteria are met both for a Manic Episode and for a Major Depressive Episode (except for duration) nearly every day.”  This is impossible since many of the symptoms of mania and depression are polar opposites of one another, so that one cannot have both at the same time!

Anyway, the authors of the article under discussion described their study population thusly:

 “Subjects entered the NIMH CDS at five academic medical centers from 1978 to 1981, while seeking treatment for a major affective episode. Intake research diagnoses were made using Research Diagnostic Criteria (RDC) based on the Schedule for Affective Disorders and Schizophrenia (SADS) interviews ... as well as available medical and research records. Patients with bipolar disorder (type I or II) entering the CDS in a major depressive episode (MDE) were selected for these analyses. We excluded from the analysis all patients who were manic at intake (N=60), along with a small group of patients (N=5) who met DSM-IV-TR criteria for a mixed episode at intake (i.e., had full concurrent MDE plus mania).” 

Notice that they "found" and then excluded anyone that might possibly meet the contradictory DSM criteria for a “mixed state,” which is what they were talking about earlier as if it were the population of patients who were about to be described in their study, which in fact it was not.

52  of their patients were diagnosed as bipolar I and 90 were bipolar II.  As most of my readers know, I think bipolar II is a phony diagnosis in the first place. 

They go on: “Irritability and psychomotor agitation are included in the SADS interview not only as manic/hypomanic symptoms, but also in the depression section of the interview, as qualifiers for the MDE (i.e., specifically for periods of the intake MDE when the subject did not have evidence of a manic syndrome).”

“We have included these two characteristics of intake MDEs as subsyndromal manic symptoms because we believe they are clinically indistinguishable from criteria A-2 and B-6 for mania and may, therefore, represent a subtle and little recognized form of mixed bipolar MDE.”

The authors are subtly defining by fiat any depressed person with irritability as having a “subthreshold” manic symptom!  Sez who??  This is especially interesting considering that they used what is essentially a symptom checklist to make their diagnosis in the first place, and were not really using clinical judgment to tease out differences in the presentation, pervasiveness, and persistence of symptoms that may just look alike during evaluations done at one point in time.

The similar symptoms are, in fact, clinically distinguishable, precisely because the symptoms occur in different clinical states – that is, manic episodes and depressive episodes.  The authors use the word “may” in the sentence about the symptoms being a little recognized form of mixed bipolar, and then proceed entirely from the assumption that they are just that. 

To really sort this out, maybe they should have compared a sample of patients with bipolar depressive episodes to patients with unipolar depressive episodes (patients who get depressive episodes but not manic episodes).  But of course, if these authors found these symptoms in unipolar depressives, they could easily redefine the unipolars as bipolars because of the symptoms.  


Voila! Almost anyone who has a depressive episode is immediately re-categorized as bipolar!  Because they define it that way.

Actually, retarded depression is more common in bipolar patients than agitated depression.  

About the only valid conclusion one can draw from the data presented in the article is that bipolar patients who have an agitated depressive episode may have a somewhat worse prognosis, and may be more likely to experience a quick shift into a manic state, than bipolar patients who have retarded depressive episodes.


Of course, we knew that decades ago.

Some Suggestions for Avoiding Bad Psychiatrists

"Letters, we get letters

We get lots and lots of letters"

(Apologies to the producers of the old Perry Como TV Show, if any are still living.  Damn I'm old!)



A blog reader sent me a very interesting e-mail with some important questions about the treatment one psychiatrist was providing her daughter.   Maybe I should start a newspaper advice column.  Or maybe not.  Anyway, I'll try my hand at it this one time.

The behavior of the doctor that she describes, assuming that the description is accurate, seems to be typical of the way a lot of bad psychiatry is administered these days. I thought readers might appreciate some tips on how to avoid it.

You can find many additional tips on how to pick a psychiatrist or a psychotherapist who deals effectively with family dysfunction in Chapter Ten of my book, How Dysfunctional Families Spur Mental Disorders.

The names in the letter have been changed to protect the innocent - or in this case, the name of a doctor who is perhaps guilty:

Dear Dr. Allen,

I just recently ran across your blog and became distressed because I fear my daughter is a victim of the over diagnoses of bipolar II. I took her to Dr. XXX because she was nearly suicidal after her father threw her out of her apartment (which he owns) because of her drug and alcohol use. She had no money saved to get an apartment, she wrecked her car and had no vehicle to go back and forth to college and work, and she was on a downward spiral. I told my daughter that I would help her get on her feet financially if she saw a psychiatrist (fearing she was suicidal). She found Dr. XXX’s name in the yellow pages and off we went.

Within 10 minutes he had her diagnosed as BP II. Perhaps we were relieved that there was a medical explanation for her state or perhaps his insistence that “of course this is BP II; I am an expert in the field and should not be questioned” but we did not get a second opinion. After 11 months of ‘treatment’ she is still not ‘normal’ which he blames on her not being compliant in his instruction about when to take medication, eat, sleep, etc. She does not want to continue with the treatments as the drugs are messing her up with extreme tiredness, swelling up like a balloon on the face and extremities, hypothyroid, there are constant blood tests, and on and on.

Dr. XXX refuses to help her wean off the medications stating that he can not do that when he knows she needs the meds and he took an oath. Who can help or how can we proceed to get her safely weaned off the numerous drugs she is currently taking (Equatro, lithium, lyrica, synthroid, zyprexa) to see if now that she is no longer abusing drugs and alcohol, if she can function normally? Should we get a second opinion? What should we do? Please help!

Best regards,

Mrs. ZZZ

Hi Mrs. ZZZ,

Obviously I can not make a diagnosis of your daughter or fairly evaluate her treatment based on an e-mail, but I can make some generalizations that relate to some of what you said. The following should in no way be interpreted as medical advice, but of course that does not mean you need to discount what I say.

First of all, if any psychiatrist makes a diagnosis with certitude after just ten minutes, it is not only time to get a second opinion, but to completely ignore the first one.

If a doctor does not really address a patient’s or the family's concerns but instead just says, “Trust me, I am an expert,” ditto.

The medications you describe would be for bipolar I, not II, and fibromyalgia, which is a wastebasket diagnosis for pain we do not understand. Also, your list includes two mood stabilizers (lithium and carbamazepine [“Equatro” – a brand named drug when a much cheaper generic is available]), as well as an anti-psychotic.

Whenever I see patients on such a bizarre mix of medications, some of which are for symptoms such as psychosis which they do not in fact have, the odds are extremely good that the patient has been highly overmedicated and misdiagnosed, and the doctor has been just throwing meds at the patient willy-nilly to see what sticks.

Blaming the patient for a failure of medications, while possibly true if the patient is not taking them as prescribed, is usually counterproductive. If a patient is not compliant, maybe it is because the meds are creating more problems than they are solving.

A doctor can not make a legitimate diagnosis of a mood disorder if a patient has been using drugs throughout the entire period in which symptoms occur – because the effects of the drugs can and often do mimic the symptoms of a mood disorder.

If a patient with a diagnosis that has been made under the above circumstances needs to be weaned off meds, he or she may have to consult with several psychiatrists before being able to find one that is willing to help the patient do that. But it is definitely worth the effort.

Last, I think that bipolar II is not a legitimate diagnosis to begin with, but I am in a distinct minority of psychiatrists on that point. 

Sincerely,

David Allen

Let the buyer beware!

More Bipolar Disease Mongering in a Respected Journal.

“The drug companies learned a while back that the best way to sell drugs was to sell diagnoses… selling the diagnosis is a way of opening up the new market. New diagnoses are as dangerous as new drugs, at least in psychiatry.”~ Dr Allen Frances, chair of DSM IV task force - Selling Sickness conference, 2011.

One of the main themes of both my book How Dysfunctional Families Spur Mental Disorders and this blog has been the incredible expansion of the bipolar diagnosis to anyone who is moody, chronically depressed and irritable, or chronically agitated. 

This has been done predominantly by some egocentric blowhard psychiatrists trying to make a name for themselves in conjunction with a well-documented and highly successful plan by several pharmaceutical companies to enlarge the market for their brand named, so-called atypical antipsychotics.  This marketing plan was documented with the release of Eli Lilly's own company marketing memos as part of a US Justice Department investigation - the so called Zyprexa Documents. These medicines are potentially toxic and do nothing to solve the interpersonal and psychological problems of many of the mental health patients to whom they are prescribed.

My colleague in Australia, Peter Parry, told me,  "Our director of training for psychiatry in our state quipped sarcastically that we may as well subsitute “mental disorder” with “bipolar disorder” and have the “DSM of Bipolar Disorders” and then recategorise subtypes like ‘adjustment bipolar disorder,’‘personality-based bipolar’ etc."  With some of the psychiatrists I know personally, this would actually be considered a good idea!

Many of the adults misdiagnosed with bipolar actually carry the diagnosis of borderline personality disorder and not bipolar. While medication can help these folks with some symptoms, most of these patients are in dire need of good psychotherapy.  Unfortunately, a lot of therapists do not like to work with them, so many end up seeing psychiatrists who use antipsychotics basically to shut them up.

"Disease mongering" is a term used for marketing techniques designed to accomplish what Dr. Frances alluded to at the top of this post.  The ongoing mongering of bipolar disorder by the pharmaceutical companies uses many tricks.  Often so-called researchers and practitioners alike do totally inadequate diagnostic evaluations using highly inaccurate and misleading symptom checklists; others employ the completely unvalidated concept of bipolar spectrum, or b.s. as I like to call it.

Bipolar ver. 4.1

A highly transparent example of disease-mongering was just published in a respected psychiatric journal, the Archives of General Psychiatry.  521 hospital-based or community psychiatrists in 18 countries in Asia, Europe, and Africa between April 1, 2008, and April 30, 2009 were involved in a “research” project which was designed to shape their thinking and diagnosing, and altering diagnostic paradigms in those countries.



The article is titled “Prevalence and Characteristics of Undiagnosed Bipolar Disorders in Patients With a Major Depressive Episode” and was “designed, conducted and prepared” by Sanofi-Aventis. Sanofi-Aventis markets an atypical antipsychotic named Solian, which is the brand name of the drug amisulpride.  It is not FDA-approved in the United States, which is probably one reason why this study was done overseas.

The supposed "results" of the study:

“These results are from a large, 3-continent, culturally generalizable study conducted by practicing psychiatrists. The data indicate that, whereas with application of the DSM-IV-TR criteria, 16.1% of patients with Major Depressive Episodes met criteria for either bipolar I or bipolar II disorder, this rate rose to 47% with application of the bipolarity-specifier criteria.

These results suggest that bipolar features are more frequent in patients with MDE than indicated by DSM-IV-TR criteria. Almost half of the entire 5098 cohort presented the core symptoms of bipolarity (elevated mood, irritable mood, or increased activity), and these symptoms led to unequivocal changes in behavior that were observable by others in a similar proportion of patients.”

What this means is that, if this were true, half of patients who exhibit Major Depressive Episodes are actually bipolar and should  be taking “mood stabilizers.” Not lithium, I suppose, but antipsychotics. 

The article  goes on to state: “Major depressive disorder, the most common psychiatric illness, is often chronic and a major cause of disability. Many patients with major depressive episodes who have an underlying but unrecognized bipolar disorder receive pharmacologic treatment with ineffective regimens that do not include mood stabilizers.”

All of the "researchers" recruited received fees, on a per patient basis, from Sanofi-Aventis in recognition of their participation in the study. The key lead authors, all with significant Pharma connections, did not disclose their personal ties. Quite a transparent example of how cultural beliefs are manufactured, and how direct involvement with Pharma is normalised.

So what's wrong with the study?  Well that hinges on the meaning of the term "bipolarity specifier" that was added to the usual, DSM criteria for bipolar disorder.  This assumes that this additional test has been validated as being predictive of actual bipolar disorder, which is a "fact" not in evidence.  It sounds in the study as if this were an established and valid measure.

Here's the defintion:

“This bipolarity specifier attributes a diagnosis of bipolar disorder in patients who experienced an episode of elevated mood, an episode of irritable mood, or an episode of increased activity with at least 3 of the symptoms listed under Criterion B of the DSM-IV-TR associated with at least 1 of the 3 following consequences: (1) unequivocal and observable change in functioning uncharacteristic of the person’s usual behavior, (2) marked impairment in social or occupational functioning observable by others, or (3) requiring hospitalization or outpatient treatment. No minimum duration of symptoms was required and no exclusion criteria were applied.”

People sleeping less, talking more, and doing more. This is how mental illness is now being defined in psychiatry’s leading journal.

One of the dead giveaways that this article is bipolar diseases mongering is the sentence:
“No minimum duration of symptoms was required and no exclusion criteria were applied.”
This means that any person who has a suddenly angry, agitated, or elated response to an environmental trigger (like a big fight with a family member or winning the lottery) could be labeled bipolar.

This would also mean that if they had an episode of emotional dysregulation for the same reason, the reaction would be labeled a bipolar episode. This makes almost anyone who has borderline personality disorder suddenly bipolar.

23.2% of their subjects had experienced episodes of elevated or irritable mood triggered by antidepressants and were also defined as bipolar.  This is almost comical. Irritibility is a common side effect of drugs like prozac and has absolutely nothing to do with bipolar disorder (unless tranquilizers cure mania, because they sure do cure that side effect). This incredible nonsense is straight out of Hagop Akiskal’s dishonest playbook. I heard him say once that if someone who is depressed gets agitated on an SSRI, he just “knows” that person is bipolar.

The word bipolar, in the sense advocated by this piece-of-you-know-what study, is showing up in common discourse everywhere, particularly among young people describing their unpredictable and volatile classmates.  You can even hear the word in pop songs used as a synonym for moody (e.g. “Hot and Cold” by Katy Perry).

Someone... call the doctor
Got a case of love bi-polar

The drug companies have really done a masterful job in bastardizing the diagnosis of real bipolar disorder, which is a serious mental illness.  The harm to both the field and to patients alike has been staggeringly immense.

A Stupid Study and an Even Stupider Headline

http://www.medwire-news.md/47/90919/Psychiatry/Hypomania_common_in_young_adults.html.

A news article posted at the above website, MedwireNews, had the headline, "Hypomania common in young adults."  It reported on a study about to be published in the Journal of Affective Disorders by Serge Brand and others (currently available on line) and states rather unequivocally, "Hypomania affects around one-fifth of young adults..." 

Hypomania is supposedly a mood episode characteristic of a disorder called bipolar II in which a person has an elevated mood, but does not have the severe, often psychotic form found in a full-blown manic epsiode.

Wait a minute. Twenty per cent of all young adults may have bipolar II?  I mean, unipolar hypomania (recurring hypomanic episodes without any history of episodes of clinical depression, otherwise known officially as Major Depressive Episodes), is nowhere to be found in any version of the diagnostic book in psychiatry, the DSM, past, present, or future. 

If these research subjects - and actually they were all college students in Switzerland - really were having hypomanic episodes, then they should all have "Bipolar II" disorder.  That would be a preposterously high proportion of this population.

Furthermore, the journal article described in the news story also distinguished two subtypes of hypomania, the "bright side" and the "dark side" types.  This is the way that the news article summarized this finding from the Brand article: "Participants with dark-side hypomania had significantly higher levels of depressive symptoms, sleep disturbances, stress, negative coping strategies, and lower self-efficacy."  Dark side hypomania?  Sorta an oxymoron.  Gee, it sounds more like symptoms of an agitated depression than hypomania to me.

Of course, in my opinion - after having been in practice in two states with a wide variety of clinical populations (private practice, private hospitals, medical school outpatient department including screening potential patients for studies, state hospitals, county hospitals, and a veterans' hospital) since finshing my training in 1977 - the whole diagnosis of bipolar II is a figment of Hagop Akiskal's imagination. 

Hagop Akiskal is an academic psychiatrist I used to know. He did some of his early work where I am now on the faculty, at the University of Tennessee (UT) Department of Psychiatry.  Not coincidentally, he is also one of two editors-in-chief of the Journal of Affective Disorders, along with a Dr. C. Katona - the journal that is publishing the study in question.

I had tentatively formed a rather skeptical opinion of Dr. Akiskal's diagnostic procedures and acumen in mood disorders from listening to a few stray remarks from a couple of people who worked with him when he worked at UT, but I never had a chance to directly observe him in action with patients or research subjects.  However, I did hear him speak at a "Grand Rounds" (academic speak for an invited lecture) not too many years ago.  He made a couple of what to me were amazing proclamations.

First, he said that if a depressed patient was given an anti-depressant like Prozac and had became more agitated as a result, he just knew that the patient was bipolar. So I guess benzodiazepines like Xanax or Klonopin must be a cure for bipolar disorder, because they make the side effect of agitation go away immediately.

Second, he said that if he was referred a depressed patient who immediately displayed an angry, nasty attitude when they first met (I can't recall his exact words, but that was clearly the gist of what he was saying), then he just knew the patient was bipolar. Of course, patients who have borderline personality traits, as well as other personality problems, act like that all the time, so it sounded to me like he might be either unable or unwilling to tell the difference.

He had also told me in private on an earlier occasion that he knew that a lot of his "bipolar" patients had been abused as children - another characteristic of patients who have personality problems but something not exceptionally common in patients with true bipolar disorder. I have never personally heard of him saying anything about this in public.

In any event, I became concerned that he might be making rather hasty diagnoses before he had even done a complete psychiatric evaluation, and was seeing bipolar disorder where there was no bipolar disorder at all.

Hagop Akiskal

But even if bipolar II exists, a fifth of all young adults?  Please.  Interesting, the MedwireNews article neglected to mention any of the limitations of the study that were in fact mentioned in the actual journal article.  One of these limitations: "The pattern of results [of this study] may be due to other characteristics such as psychiatric disorders (e.g., eating disorders, personality disorders, and addictions) or motivation, which were not assessed in the present study." 

The study was entirely based on a self report instrument, the HCL-32,  that clearly should be limited for use only in screening subjects for an actual diagnostic interview.   All such screening instruments, as I have mentioned in previous posts, are designed to have a lot of false positives, meaning that many of the people who seem to be positive for a disorder based on the test do not have it.  They are meant to cast a wide net so that the experimenters do not miss subjects who falsely appear to be negative for the disorder. 

In the article that "validated" this self-report instrument by Angst et. al. (Isn't that a great name for a psychiatrist?), also conveniently published in the Journal of Affective Disorders (88 [2005] 217-233),  it states:  "Despite the use of broader and slightly differing criteria for BP-II, the HCL-32 still showed good discrimination between the unipolar and bipolar samples. The cut-off of 14 offered the best trade off between sensitivity (true bipolars) and specificity (true non-bipolars) with the total scale showing a sensitivity of 80% and a specificity of 51% for both BP. 

In other words, the instrument totally mis-diagnosed at least half of the population it was validated against as bipolar when they did not have the disorder.  This is typical of a screening measure, as I mentioned above. 

Unlike some of the other phony instruments used for diagnosing mania, the HCL-32 at least tries to address the duration criteria for a hypomanic episode mentioned in the DSM.  In order to distinguish reactive mood changes due solely to environmental events from true bipolar disorder,  a manic or hypomanic episode has to go on non-stop for at least a few days, last all day every day, and be completely atypical of a patient's usual functioning. 

The HCL-32 asks the subjects about the "Length of your “highs” as a rule (on the average)."  However, it does not address any environmental events the subjects might have been experiencing at the time; nor does it even mention anything about how the "high" feeling they were asking about should essentially never abate throughout the entire episode.

Many of the symptoms listed on the HCL-32 may be characteristic of people who are highly engaged in what they are doing, such as going to college classes, when they are in fact actively engaged, but which may later go away when things slow down.  What follows are some of the symptoms as they are described in the test. Answers are either "yes" or "no" with no opportunity for subjects to qualify or describe any complexity in their answer:

Please try to remember a period when you were in a “high” state.  How did you feel then? Please answer all these statements independently of your present condition. In such a state:


2. I feel more energetic and more active
3. I am more self-confident
4. I enjoy my work more
8. I spend more money/too much money
10. I am physically more active (sport etc.)
20. I make more jokes or puns when I am talking
21. I am more easily distracted
22. I engage in lots of new things
29. I drink more coffee

Do you know any active people who do not have periods like this?  I don't think I do.

The instrument also asks subjects to answer only for those periods when they were not high on drugs.  I do not know about Swiss college students, but a lot of American students use stimulants like Ritalin and Adderall as "academic steroids."  I wonder how many of the Swiss students might have thought that using these meds, since they are prescription drugs, did not qualify as times during which they were high on drugs? 

We will never know, because they were never asked.  Sleep deprivation can also lead to some of these symptoms.  They were not asked about that either.  Know any students who party a lot and don't sleep as much as they should?

The MedwireNews article makes it sounds like the Brand study is conclusive.  I talk in more detail about the process involved in the journey of facts that have not been at all established as they become accepted by doctors and the public alike as if they were established facts in my book, How Dysfunctional Families Spur Mental Disorders. 

In my opinion, the bastardization of news may have become another one of big PhARMA's strategies to expand psychiatric diagnoses so they can sell more drugs.

Counting Symptoms that Don't Count

A horrible trend has been taking off for the last decade in psychiatric offices across the country. As fees for psychiatrists were ratcheted down by managed care insurance companies, especially for psychotherapy, psychiatrists have tried to keep up their income by becoming primarily prescription writers and seeing as many patients per hour as they possibly can. This has let to the infamous ten or fifteen minute "med check." In this short period of time, the context of the patient's life experiences as it affects a patient's psychological condition is seldom even evaluated, let alone taken into account, in making a determination of which medications and dosages are appropriate for a particular patient.

The time squeeze has also adversely affected the patient's initial diagnostic evaluation. A comprehensive evaluation takes at least forty five minutes, even if the doctor only superficially touches on all the relevant information that needs to be elicited from the patient. Initial evaluations now are often squeezed into a half hour, which often includes the time the doctor has to write his note, return phone calls, and/or go to the bathroom. If any reader plans to see a psychiatrist who does not schedule an hour for a new patient, I would advise that reader to run as fast as you can in the opposite direction!

So what does a doctor who spends so little time with a patient do to save time? I mean besides completely ignoring the patient's relationships, history of truama, humanity, etc. (One of my patients reported being screamed at by his last psychiatrist, "I don't want to hear about your mother!! I just do meds!"). Well, one thing they can do is ask only about symptoms, and blindly accept the patient's yes or no answer without even checking to see if the patient understands the difference between a transient mood state and a psychiatric symptom. Better yet, before the doctor even sees the patient, he or she can have the patient fill out a symptom checklist, and base his diagnosis entirely on that. (Of course, his secretary could make a diagnosis doing that, so the patient really wouldn't even have to talk to the doctor at all).

So, is it not true that the DSM, the diagnostic Bible in psychiatry, just lists symptoms as diagnostic criteria, and says how many of them you need to make a given diagnosis? No! It requires a doctor to also make a clinical judgment about the diagnostic significance of any symptom a patient reports. This involves asking follow up questions like a good newspaper reporter. Just because a patient reports staying up all night without feeling tired for seven days in a row does not mean that the patient also remembered to report that he was sleeping during the day, or was on a cocaine binge.

To illustrate better what I mean, I would like discuss the contents of an article called Avoiding Diagnostic Deficit Disorder in Bp Magazine. Bp Magazine is a periodical about patients' experiences with bipolar disorder. The disorder, which used to be called manic depression, is characterized primarily by distinct periods of severe mood elation and other periods of severe depression, separated by normal periods (euthymia) in between.

I was not able to find much online about the publishers of this magazine, and what I found may be faulty, but apparently the publisher, Green Apple Courage Inc., was founded by one Bill MacPhee, a patient with schizophrenia who was finally stabilized on medication and became productive again.

The primary advertisers for BP Magazine were listed on one web site as "Platinum sponsor Pfizer Inc. and Gold sponsors Bristol-Myers Squibb Company, Otsuka America Pharmaceutical, Inc. National mental health association advertisers include the Child and Adolescent Bipolar Foundation, Depression and Bipolar Support Alliance, Mental Health America and the National Alliance on Mental Illness." I started getting the magazine in the mail for free unsolicited, which usually means a pharmaceutical company is paying for mailing the publication to psychiatrists like me. Draw your own conclusion about whose interest the magazine might be best serving.

Anyway, the article expresses concern that bipolar patients might be misdiagnosed with something else, when the real danger nowadays is that a patient with something else will be misdiagnosed as "Bipolar II," which in my humble opinion is part of the Bipolar, My Ass Spectrum Disorder.  So it advises potential patients to tell their doctor about symptoms such as agitation, impulsivity, racing/obsessive/cluttered/busy thoughts, hypersexuality, hyperbuying, euphoria, decreased need for sleep, and use of alcohol or other agents to relax.  It advises that they report these other symptoms last: depression, anxiety, panic, and trouble concentrating.

The article neglects to point out the fact that in mania, these symptoms all have to occur at the same time, and be totally atypical for the way the person normally functions. I mean, true bipolars are like Jeckyl or Hyde (not both at the same time) for an extended period of time.  They do things while manic that are totally out of character for them. These characteristics of the symptoms are absolutely essential for determining their diagnostic significance.

We speak of the three p's: pervasiveness, persistence, and pathological.  The symptoms of mania in particular have to affect every aspect of the person's life regardless of the person's changing external circumstances, they have to continue for a full week at the very minimum, and they have to cause significant distress or impairment.  (Hypomania, hallmark of bipolar II, only has to last four days.  Not four minutes, four days.  It is the only condition in the entire DSM that does not require distress or impairment).  One also has to take into consideration the state of a patient's current relationships in order to rule out normal reactive mood changes.

But wait, there's more!  Every symptom that the article recommended reporting first is non-specific.  That means that each and every one of them can be symptoms of several different psychiatric disorders, depending on their other characteristics, or they may just be normal personal variants or the result of having a bad day.  I mean, anyone here ever go on a spending spree and buy more than they should have?  The nation's huge credit card debt screams out that this is hardly a phenomenon only seen in manic or hypomanic patients.

Let's take irritabilty, for another example. It can be a symptom of mania, but it can also be a symptom of major depression, dysthymia, generalized anxiety disorder, panic disorder, a personality disorder, the abuse of a variety of different drugs and alcohol, side effects of medications, having just had a big fight with your mother, or just feeling irritable for that day for no particular reason at all.

Now, the doctors who think everyone who comes to them is bipolar and is in serious need of drugs object to the DSM bipolar criteria for duration of symptoms.  That may be a legitimate criticism, but so far there is not a single shread of evidence linking brief mood swings like going into a rage to true bipolar I disorder.  The doctors pushing this idea basically pulled the idea that they are related out of their asses. 

To prove this, however, they do studies in which they diagnose people who do not meet the duration criteria for mood episodes as "bipolar not otherwise specified (NOS)," which is a diagnosis that is listed in the DSM.  What the NOS designation is supposed to be used for is people who just barely miss DSM criteria, like someone having manic symptoms for six rather than the required seven days. It is not supposed to be used for people who miss the criteria by a country mile, like a person having a ten minute mood episode.  I would call the tactic of using the NOS category for patients like that as Nothing Other than Stupid.

They then do studies which include patients that they have diagnosed with their version of the NOS disorder, thereby gathering a sample of subjects that contains a certain number of people who have ten minute mood swings.  They then look at their overall sample to see how many of their "bipolars" have this symptom, and voila!  A significant percentage do, therefore "proving" that bipolars can have ten minute mood swings.  If you don't understand the term circular argument, you can look up the term circular logic.  It might say that circular logic means the same as circular reasoning.  If you don't know what circular reasoning means, you can look that up and find out that it means the same as circular argument.

One blog reader asked me why I do not believe in brief mood swings.  Of course I believe in them.  They are just not symptoms of bipolar disorder.

Twenty, Twenty, Twenty-Four Hours a Day, I Wanna Be Sedated

The Ramones sang those lines quite a while back. Without knowing it, they were singing about how anti-psychotic and anti-convulsive medications really work on folks who carry the pseudo-diagnoses of bipolar II or childhood bipolar disorder but who really have personality disorders, anxiety disorders, and/or a family relationships environment that is more like a war zone than the refuge that a home and family should provide.


So why do patients and the parents of patients keep coming back for refills, and why do the doctors keep prescribing them? Well, they kind of "work." What happens is they calm the person down somewhat, because almost all of them are sedating and function like a tranquilizer. This is a side effect of the medication, not the main effect, however.


After a while, the tranquilizing effects of these drugs tend to diminish, and the drugs seem to "stop working." The doctor then will switch them to another drug or add a drug from a different class. This is why many patients come to me after having been on a wide variety of different drugs at different times, or on crazy combinations of drugs. Uppers in the morning, downers in the evening, sugar at suppertime.


I see this happen a lot in my patients with borderline personality disorder (bpd), who have severe and incapacitating agitation very frequently. Just about any half-way sedating thing that you put them on "works" for a month or two to diminish their agitation somewhat, although if they get upset enough, it breaks through. After that, most medications (except, ironically, benzodiazepines- actual tranquilizers like Klonopin) no longer have much of this effect.


Not surprisingly, most drug company-sponsored drug trials in patients who have borderline personality disorder do not follow the subjects very long, and the companies purposely try to leave the impression that any beneficial effects are not just side effects, and that they will go on as long as the patient stays on the medication.


A few years ago the old anti-psychotic drug Haldol was touted for use in bpd. The chairman of the psychiatry department at UAB at the time was one of the people doing the touting. Finally a longer-term study was published in the American Journal of Psychiatry which showed that indeed the drug seemed to stop "working" after a couple of months. Of course, the guy at UAB did not mention this study when I saw him speak.


The pharmaceutical companies know they are mixing up the side effects of their drugs with the therapeutic effects, and will almost never compare their drugs in a study to an actual tranquilizer like a benzodiazepine (the Valium- or Klonopin-like drugs). In the past, sedating drugs were at least advertised as what they are - sedatives.


Below is an advertisement first published in February, 1959 in the Post Graduate Medical Journal. It is an ad for the sedative Equanil, or Meprobamate, which was also called Miltown. It is a serious downer with much of the same properties as major barbiturates like Secanol or Nembutol ("Reds" and "Yellows" on the street way back when), drugs highly addictive and potentially fatal in overdose. Drugs like these have been replaced by the much safer benzodiazepines.


What strikes me about this ad is that the drug is being advertised as a treatment for temper tantrums, which according to the quacks and snake-oil salesmen selling the concept of pediatric bipolar disorder, are often a symptom of mania. If Equanil worked, it must therefore be a mood stabilizer? Well, maybe if you are not bipolar.

The Zyprexa Documents

In January 2009, drug company involvement in promoting the explosion of new and phony bipolar disorder diagnoses was clearly demonstrated by company memos that leaked out as part of a Justice Department settlement against the maker of the atypical antipsychotic Zyprexa (Ely Lilly) for off-label marketing of the drug. These memos were supposed to be kept secret, but were obtained by reporter Alex Berenson of the New York Times, as mentioned in an article in the paper on December 18, 2006. They were later put on the internet by another reporter, Philip Dawdy of the Seattle Weekly, on his Furious Seasons website (http://www.furiousseasons.com/zyprexadocs.html).

One of their strategies was marketing for “NCE’s” (New Clinical Entities) which were off-label indications. They specifically targeted doctors who would be seeing patients with substance-related disorders, anxiety, aggression, or borderline personality disorder. Family practitioners and other primary care doctors were singled out, but psychiatrists were also affected.

While admitting that Zyprexa was not indicated for "bipolar II," they nonetheless tried to convince doctors that relatively high functioning patients who were susceptible to "bouts of depression, low self esteem and pessimism about the future, then rebounding with bursts of high energy and social engagement" really had bipolar disorder. They knew doctors did not like using lithium and that they might feel that there was too much to manage with depakote, so that they could be easily convinced to use Zyprexa.

Their vision for primary care docs was to expand Lilly's market by "redefining how primary care physicians diagnose and treat complicated mood disorders." Marketing messages were to be aimed at "patient's symptoms and behaviors (rather than diagnosis)." The doctor was to be made to understand that the company reps were not talking about the seriously ill patient but the "complicated patient who has mood symptoms of irritability, anxiety, poor sleep and mood swings."

Fellow training director Aftab Khan describes a certain type of patient that he labels as having "Crappy Childhood Syndrome (CCS)." He says that whenever a particular patient has several of these diagnoses at the same time: Major depressive disorder, panic disorder, PTSD, generalized anxiety disorder, bipolar disorder not otherwise specified, bipolar II, intermittent explosive disorder, or somatoform pain disorder - or their diagnoses changes from one provider to the next or from one admission to next - then CCS is most likely what they really have.

I could not have said it better myself, although I would add that these patients continue to have highly negative interactions with their dysfunctional social systems even as adults.