The Conflation of Chronic Sadness With Major Depression

When I bring up with many other professionals the idea that major depression is now over-diagnosed by relabeling what used to be called dysthymia as "mild' major depression, a lot of them seem to disagree. Or they just tune out. “That’s just your opinion,” I might hear. Well, luckily the DSM-V now provides evidence that I am on the right track. In the DSM-V, the term “dysthymia” has been replaced! It is now called Persistent Depressive Disorder. 

As I have discussed in many previous posts, my opinion about major depressive disorder is that it is more of a brain disorder than mere unhappiness. The word depression itself is a symptom, not a disorder. It is in the interest of drug companies to conflate chronic psychological unhappiness with major depression so they can sell more antidepressant drugs to people who will not actually benefit from them.  Now,  it is also possible to have both, which is called double depression.

While many of the criteria are the same for the new diagnosis as the previous criteria for dysthymia, there are subtle differences that obscure the difference between that disorder and major depressive disorder. In a percentage of people with the latter disorder, it may become chronic. This is seen in the new definition of the disorder, which reads “This disorder represents a consolidation of DSM-IV-defined chronic major depressive disorder and dysthymic disorder. These disorders should not be consolidated.

There is one additional change which is telling. The only specific criteria for the disorder that has been changed has gone from “The disturbance is not better accounted for by MDD or MDD in partial remission” to “Criteria for Major Depressive Disorder (MDD) may be continuously present for 2 years, in which case patients should be given comorbid diagnoses of persistent depressive disorder and MDD."  Double depression has nothing to do with the length of the major depressive episode.

Drug companies have enlisted academic psychiatrists to become “key opinion leaders” in order to push this idea, and have even advocated the use self report surveys designed to screen for major depression (therefore having a lot of people test positive who don’t really have the disorder  – false positives) as diagnostic instruments.

This has led to a host of articles in the popular press that seem to indicate that antidepressants are nothing more than placebos. Nothing could be further from the truth, but a lot of psychiatry critics like Robert Whitaker have seized on “research” articles (which do a crappy job of making the correct diagnosis) that seem to show this to be the case.  After all, since most anti-depressants are generic,  it's better for drug companies' bottom line if instead of those drugs, expensive new anti-psychotic drugs can be recommended instead.

The critics also use the fact that we don’t know exactly what causes major depression to dismiss the whole diagnosis. The incorrect hypothesis that the condition is due to a “chemical imbalance,” which is sometimes advanced by clinicians, must mean that it is not a real disease. Dumb. Clinicians have often used this oversimplified idea to convince resistant patients to take the medications. Researchers rarely if ever actually said that a chemical imbalance was the cause of the disorder.

Of course, it’s not always easy for clinicians to tell the difference between dysthymia and major depression in a given patient, but in most cases it’s fairly straightforward.  There is nothing that stops anyone from being chronically unhappy when they are not having an episode(the euthymic state) of major depression. And major depression is episodic with normal-for-them baseline mood periods in between episodes.

A good clinician will define a response to antidepressants as good if the patient returns to their baseline. They don’t have to be in a good mood to have had a good response, but may just need psychotherapy like any other dysthymic patient. Nonetheless, many of these patients who have double depression are mislabeled in the literature as “treatment resistant,” which means that docs are encouraged to add still more drugs to antidepressants to “augment” them. There are of course patients who actually are treatment resistant and need this augmentation, but in my 45 years of practice this was a relatively small contingent.

Briefly and in an oversimplified manner, distinguishing the two disorders has to do with the “three P’s” – persistence, pervasiveness, and pathological. (You can tell if a study employs the correct definitions by seeing how the diagnosis was made with their subjects. The P’s are emphasized in an excellent diagnostic interview called the SCID). Persistent: this is the duration criteria. An episode has to last at least two weeks. Admittedly, the two-week criteria is arbitrary, but is put in so clinicians don’t make the diagnosis after too short a period.  The “everything is bipolar” crowd routinely poo poo's the duration criteria.

Pervasive: the symptoms have to be present nearly all day every day no matter what goes on in a patient’s life. This means that if a patient were to win the lottery, it wouldn’t cheer him up all that much.  Pathological: this means that the ways that the patient reacts to any stress is different from the way they might react if they were not in an episode. See the lottery statement. Also, if a lover were to, say, break their heart, this would not always make a whole lot of difference in how bad they feel.

These issues are not seen with good doctors, who not only know how to take a complete bio-psycho-social history but actually still do them.

The Effects of Mothers with a History of Depression on Their Offspring

Judith Morgan, Ph.D.

University of Pittsburg 

As my readers surely know, the nature-nurture debate in science continues unabated. Especially in psychiatry. When it comes to certain repetitive emotional reactions shown by a given individual, many in the field prefer to believe that the individual was just born that way. The truth, as described in Robert Sopolsky excellent book Behave,  is that we have hundreds or even thousands of genes that make certain behaviors either a little more or a little less likely. No complex human behavior is determined entirely by a gene or group of genes. We are also strongly programmed to tend to react in certain ways to the behavior of our kin group, although we can still make the difficult choice not to once we reach a certain age.

There is without a doubt a strong genetic component to true brain diseases like Major Depressive Disorder or schizophrenia, but the situation for other emotional reaction patterns is that they, IMO, are far more affected by the family environment than by any specific genes.

Some studies sure do point in this direction. For example, in a recent study published in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Judith Morgan, Ph.D., recruited 49 children aged six to eight without a history of psychiatric illness. Half the kids' mothers had a history of clinical depression, and half had no psychiatric history. To measure reward-related brain activity, children played a video game in which they guessed which of two doors contained a hidden token while they underwent functional magnetic resonance imaging (fMRI).

Depression may disrupt parents' capacity for emotional socialization, a process by which kids learn from their parents' reactions to their emotional responses. Positive socialization responses include acknowledgment, imitation, and elaboration, whereas negative or emotionally dampening parental responses may be dismissive, invalidating, or punitive.

Mothers participating in the study completed an extensive questionnaire designed to measure parental emotional socialization by presenting a dozen situational vignettes of children's displays of positive emotions and collecting parents' reactions to them. Children with a maternal history of depression were more likely to have reduced reward-related activity in a part of their brains that handles this, but only if their mothers reported less enthusiastic and more dampening responses to their children's positive emotions, the researchers found.

"In our study, mothers' own history of depression by itself was not related to altered brain responses to reward in early school-age children," said Dr. Morgan. "Instead, this history had an influence on children's brain responses only in combination with mothers' parenting behavior, such as the ability to acknowledge, imitate, or elaborate on their child's positive emotions."

Book Review: The Shattered Oak by Sherry Genga

 

This involving book, based on a true story but with some facts altered, is written as a first person account (although it is not the author's story) from a woman involved in a severely physically and emotionally abusive marriage. The author takes the reader on a fascinating tour inside her mind and thought processes.

The book strongly implies that she made no effort to leave for many years, and says that her parents refused to help her do so, under the rationalization that they were too afraid of her husband. She finally does leave and files for divorce. The narrative does not discuss the husband’s behavior during the divorce, but it appears that it went fairly uneventfully and without any stalking by her ex. She received the house and custody of their three daughters in the settlement, and her ex seems to have made alimony payments regularly.

Three years later she has a “nervous breakdown,” and describes in vivid terms her overwhelming sense of doom due to her depression. She makes three serious suicide attempts, and describes her ambivalence over abandoning her children and leaving her eldest daughter to take care of the other two, while all the while also feeling tremendous guilt over her daughter having had to take care of her in a parent-child role reversal.

She finally gets committed to a horrible mental hospital and given ECT against her will. Although she does not say she was diagnosed with major depressive disorder, her disturbing descriptions of her thoughts and feelings while in the depressed state are impressive, and give the reader a sense of what it might be like to have been in her shoes. It later turns out that she did not have a typical major depressive disorder, but one caused by a medical disorder, Cushing’s disease, which leads to very high level of the stress hormone cortisol, a steroid. A major depressive syndrome is seen in 50%–70% of the cases of Cushing’s syndrome. 

She opines that the high levels of cortisol may have come from high levels of stress, which, she implies, seems to have increased rather than decreased after she got out of the marriage. As it turns out, however, that was not the case at all. Her disorder was caused by a tumor of the pituitary gland.

It does not mean that anyone is “blaming” her for the severe abuse she suffered, but it is extremely important in the mental health field's attempts to prevent others from following in her footsteps, to pose the question of why she stayed with her husband for so long, and why she felt more stressed out after the divorce than during the time she was with her husband. There is no way we can know the answers to this question for certain just from the descriptions in this book, but there are several tantalizing clues.

The usual excuses offered up to justify the behavior of women who repeatedly return to an abusive relationship often do not hold water, but especially so in this case. As per her own description, she was in far more danger of being killed by him over the long run if she stayed than if she left. While they were together, he constantly threatened to kill her and even fired gunshots at her, narrowly missing her head on purpose. There were literally bullet holes in the walls.

She also knew very well that he was violent before they were married, because there were episodes of it back then.

And why would she be more stressed out after she left if, as it seems, her ex was not stalking her? The narrator admits that she still loves her husband even after the divorce despite all the pain he put her through. She offers a very interesting hypothesis about why he abused her: he came from a highly abusive family himself, and was taking his anger out at them on her. The question she keeps asking herself is how she could have helped this man to become less bitter. Presumably, how else. What she had been doing clearly did not work. Her question is consistent with my hypothesis about  this case

Readers of this blog can probably guess what that hypothesis is: the odds are pretty good that she was sacrificing herself so that her husband, whom she loved, could continue to channel his destabilizing anger away from his own parents, and that her doing something like this might have also been her role in her own family of origin. You know, the family that refused to help her leave her husband. At the end of the book we find reasons that this hypothesis would certainly necessitate further exploration. 

She was treated like a servant by her own parents growing up, especially compared to her two siblings, who could seem to do no wrong in her parents' eyes. Her older brother finally tells her that she was the result of an affair that her mother had had with a neighbor, and she was not her father’s biological daughter. Might the father have taken his anger at her mother out on her, with her mother going along with the program in order to keep the family together? You be the judge.

I wonder what her parents' upbringing might have been like.

Words Do Matter in Psychiatry

I was pleased to see that in the June 2018 issue of one of the newspapers for psychiatrists, Clinical Psychiatry News, a psychiatrist by the name of Carl T. Bell wrote about something I have been harping about in this blog and elsewhere for years: the sloppy use of psychiatric terminology by both the public and by many psychiatrists themselves.

Glad to know I’m not the only one who has noticed this.

He brings up three examples: the use of the words (two of which also have a common meaning separate from the corresponding terms in psychiatry): traumatized, depressed, and bipolar.

Colleagues of his had used the word traumatized as something that happened to a person who was the subject of a statement by another person that has come to be known as a “microaggression.” A microaggression is defined as “a statement, action, or incident regarded as an instance of indirect, subtle, or unintentional discrimination against members of a marginalized group such as a racial or ethnic minority.” 

Worrying about that sort of thing has become endemic on college campuses recently. Especially if it unintentional, the result of the big ado is a communication to individuals that they are so fragile and vulnerable that they can’t handle anything. It also has led to a suppression of free speech.

As far as I know, there has never been an example of a microaggression, or even a direct verbal insult, in and by itself leading anyone to develop post traumatic stress disorder (PTSD). According to Dr. Bell, being stressed by something like that, or by your boss chewing you out, is a far cry from being traumatized. Being distressed by something like the death of a parent is a little worse. It can come up from time to time, like on the anniversary of the death. However, in both of these cases, unlike in PTSD, “the mind is able to make peace with the reality…and life goes on.

“Traumatic stress, on the other hand,” he adds, “is an event so painful and disruptive that it runs the risk of breaking the mind’s ability to make peace with the event…[and it] disrupts or destroys normal psychic life.”

I would add that if everyone around you treats you like you are so fragile that the slightest stress will do that, you start to believe it even though you probably aren’t that fragile at all. And if you feel like that, you are probably not going to take measures to actively oppose and undermine things like racism, sexism, and homophobia. If enough people think like that, it is paradoxically a great boon to racists, sexists, and homophobes everywhere.

I’ve already covered the misuse of the term depression in my post of November 24, 2015, Depression is a Symptom, not a Psychiatric Disorder. Major depression is a clinical condition has many physical symptoms and is something that can be quite disabling, while being unhappy, sad, grieving or even demoralized is not the same thing at all. The latter conditions do not respond to antidepressants in the least, but researchers doing current studies on antidepressant efficacy have become very sloppy and often do not exclude the latter people as they should.

Bell then addresses how the term “bipolar” is creeping into common usage to cover things such as being moody and having difficulty regulating one's moods and having a bad temper (especially in kids, I might add). For maybe thirty minutes or an hour. And many psychiatrists just take patients at their word when they misuse the term, and prescribe unnecessary and ineffective mood stabilizers.

In that vein, another article in the April issue of the same newspaper quoting a Gabrielle Carson M.S. talks about the issue of tantrums in children. It advocates investigating the child’s symptomatology to rule out bipolar and other mental disorders, as well as clearly behavioral problems like so-called disruptive mood dysregulation disorder, ADHD, and oppositional defiant disorder. 

The only mention of environmental factors that might lead to the tantrums is a quick and superficial reference to child abuse and school bullying. But the article says absolutely nothing about the far most common cause of frequent tantrums by children (as discussed by child psychologist and columnist John Rosemond as well as other people who actually look at what goes on in the child’s home): problematic parenting practices such as acting like a friend to your kids instead an authority figure, letting them make decisions that should be made by the adults, compulsive yelling or lecturing, and inconsistency in administering discipline.

A Psychiatric Diagnosis: Behavioral Problem or Brain Disease?

When the first edition of the DSM (the manual of psychiatric diagnoses published by the American Psychiatric Association) came out in 1952, it listed about 100 different psychiatric diagnoses. By the time the fifth edition was published in 2013, it listed over 550 separate ones! One has to wonder if early psychiatrists were just missing a bunch of them, or if normal but repetitive everyday problems in living due to trauma, stress, and interpersonal dysfunction have been turned into diseases. I vote for the latter.

At any rate, the DSM uses the word “disorder” to fudge this question somewhat, leaving a “to be determined” answer as to whether any of the diagnoses are brain diseases or just psychological or behavioral problems experienced by normal brains. So how do we go about making an educated guess as to which it is?

The question is complex because the phenomena under discussion are very complex. While our understanding of the brain is increasing by leaps and bounds, it is still very rudimentary. That is because the brain is literally the most complicated and complex object in the entire known universe, with about a trillion constantly changing connections between nerve cells. Remember when computers would go crazy and produce the infamous “blue screen” when two programs would conflict, and you would have to restart it? Imagine what might happen if the computer were not hard wired!

A lot of people, including many in the various mental health professions, seem to be prone to highly simplistic “either-or” thinking. If even one of the 550 DSM diagnoses is a brain disease, then they all must be. Or if one is a behavioral/psychological disorder, then they all must be. That is just stupid. But throughout the history of psychology and psychiatry, the field has often lurched back and forth between brainlessness and mindlessness (as described in Chapter One of my last book), incorporating what turned out to be ridiculous or misguided theories.

Autism is caused by refrigerator mothers. Schizophrenia is just a different way of experiencing the world or due to being placed in a double bind by your family. Sexual promiscuity is a genetically determined trait, and certain races are genetically inferior to others. Acting out by children is caused by underlying bipolar disorder. Obsessive compulsive disorder is caused by harsh toilet training. A central part of women’s psychology is penis envy. The list of nonsensical and grossly mistaken theories like these is nearly endless. I’m surprised that no one ever theorized that the memory deficits in Alzheimer’s disease are really a result of the defense mechanism of repression.

But even without such simplistic thinking, determining which diagnoses are truly diseases and which are primarily behavior problems caused by problematic learning and stress is not easy. You cannot just do an fMRI brain scan, as I described in an earlier post, because that test alone does not distinguish an abnormality from a normal conditioned response to a particular social environment.

And even if something is a brain disease, family stress and dysfunction can make it worse – just like with many physical diseases. Then there’s this: having a parent who gets manic and runs naked through the streets creates huge stresses for a child who observes it. Such children are at risk both genetically and environmentally.

Not only that, but you get into a chicken and egg situation: does having a controlling family create anorexia nervosa, or is having a child who is starving herself to death lead parents to become overly controlling? A child who is more temperamental is often somewhat more difficult to raise than one who is not, leading some parents to engage in problematic parenting practices with one of their children but not others.

The whole question of “what causes” a disorder is further complicated by the fact that with the vast majority of psychiatric diagnoses, there are no necessary or sufficient causes of any sort – only risk factors that increase the odds someone will develop a disorder, and mitigating factors that decrease those odds. And there are usually hundreds of these factors operating over time.

So what standards do I use in forming my opinions about various disorders? To me, by far the most important metric is whether the symptoms of the disorder only appear under certain social conditions, and disappear when the social conditions change. Real brain diseases like schizophrenia do not do that; they are present almost all the time. You see victims “responding to internal stimuli” whether you are talking to them one-on-one or observing out of the corner of your eye on a ward in a state hospital them when they don’t realize they are being observed by staff. They show them no matter who is talking to them, or even if they are put alone in a room in a psychiatric ER with a hidden video camera keeping a watchful eye on them.

Someone with, say, a melancholic depression reacts at a snail’s pace compared to the way they usually react (psychomotor retardation) every waking moment no matter where they are or who they are with, and stay in that state all day every day, sometimes for weeks at a stretch. Luckily, when I trained we could keep patients in the hospital that long so we could see this; today’s trainees do not get to do that any more, so are more easily fooled.

On the other hand, borderline personality disorder symptoms are not like that at all. I would see patients with the disorder acting out with staff in a psychiatric hospital, but behaving completely appropriately with the other patients when they didn’t know I was observing them. In fact, they are famous for acting one way in the presence of certain staff members and exactly the opposite when in the presence of others, leading the two groups to fight with each other (the staff split)!

I’ve seen people I know who have the disorder out and about at music festivals and theaters acting as normally and appropriately as anyone else. In therapy, certain emotional reactions and provocative behavior would come out of them if the therapist did one thing, but would disappear quickly if the therapist changed to doing something else.

In looking at neuroscience evidence, an important metric in distinguishing disease from mere dysfunction is the sheer number of different types of brain anomalies and other neurological findings. As I said, a single fMRI finding alone tells you nothing. But a whole bunch of different fMRI abnormalities with some of them completely unrelated to the symptoms of the disorder suggests a brain disease. For example, people with schizophrenia tend to have a lot of different abnormalities, many of which have nothing to do with delusions or hallucinations. One cannot be certain, of course, but I would be hard pressed to explain many of these neurological findings in terms of conditioned responses to particular social environmental stimuli.

Depression is a Symptom, Not a Psychiatric Disorder

Lately there have been a slew of articles about "depression" that seem to go out of their way to avoid discussing any specific psychiatric diagnosis listed in the DSM - instead strongly implying that "depression" is itself a disorder. These articles appear in the popular press, but, frighteningly, also in newsletters and newspapers for psychiatrists and psychologists. They explore such questions as "Do antidepressants work?" and "What is better for depression, drugs or cognitive behavioral therapy?"

These types of questions are completely meaningless. Depression is discussed as if it were a single phenomenon that, at best, exists on a continuum from "mild" to "moderate" to "severe." This type of wording is in fact completely ignorant, but does not necessarily reflect real ignorance. In many cases, different entities such as big Pharma have a vested interest in conflating several different psychiatric conditions.

In truth, "depression" is just a mood state, and as a symptom, it can be part of many different psychiatric disorders that are, despite some overlap in symptomatology, as different as night and day when it comes to their clinical presentations as well as their response to various treatments.

To name but a few actual diagnoses, there is major depression (both as part of unipolar and bipolar disorder), dysthymia, adjustment disorder with depression, depression due to a medical condition, and depression due to a substance. Medical conditions that can lead to depressive symptoms include hypothyroidism and some strokes. Substances that can do that include some steroids like prednisone and the "crash" that results when an acute cocaine high wears off.

Furthermore, "depression" as discussed in every day conversation can be a normal mood that is part of chronic unhappiness, or that occurs in response to grief at someone's death or due to any other loss or misfortune.

The most important diagnostic distinction for this discussion is between major or clinical depression and dysthymia. Although we don't know enough about the brain to know the exact causes of either one, and there is some overlap in symptomatology, they appear for the most part with very distinct clinical presentations, especially in their classic forms.

Dysthymia appears to be more of a psychological reaction, while major depression probably involves the more primitive part of the brain called the limbic system. The latter, unlike the former, is accompanied by a whole array of chronic, persistent (lasting all day every day for at least two weeks), and pervasive (coloring all aspects of the patient's mental life) physical symptoms - all at the same time - involving sleep, appetite, ability to experience pleasure, energy level and motivation, and concentration. Sufferers may have an unrelenting and constant sense of foreboding accompanied by inexplicable hopelessness and helplessness. We used to refer to these types of symptoms as vegetative symptoms.

Furthermore, someone in a major depressive disorder episode reacts completely differently to life's every day ups and downs than they do when they are not in the middle of such an episode. It's almost Jeckyl and Hyde territory.

These people stay depressed no matter what life events occur around them. They could literally win the lottery and would not really feel a whole lot better for more than a few minutes.

The most severe form of major depression is called melancholic depression. Most people who have never worked in a mental hospital have never seen a case, but the anti-psychiatry types who have not seen it blather on about depression incessantly as if they knew what they were talking about.

People with melancholic depression exhibit something called psychomotor retardation. People with this symptom move and think at a snail's pace.  It takes them longer to respond to any verbal interactions. They can even appear to have significantly impaired memory, although it is actually a more severe form of concentration impairment. That clinical picture is sometimes referred to as pseudodementia. 

You cannot spend more than an hour with such people without realizing that this condition has next to nothing in common with the type of "depression" people see in their everyday interactions with others, and that there is something seriously wrong with their brain functioning.

In severe major depression, doing any kind of psychotherapy (short of telling them, "take these pills") is a complete and utter waste of time. Sufferers literally do not have the mental wherewithal to deal with any kind of problem solving or other interactions with a therapist. And I say that as a major advocate of psychotherapy.

The symptom of depression in dysthymic disorder, on the other hand, rarely responds to antidepressant medication at all (although the drugs can be useful for other symptoms seen in patients with dysthymia such as panic attacks, obsessive ruminations, and the affective instability characteristic of borderline personality disorder). For these folks, psychotherapy is essential.

In my experience a very high percentage of the people who do drug and psychotherapy outcome studies, at least in adults, make almost no meaningful effort to differentiate dysthymia from major depression by: 1) Not spending any time making certain that patients understand the pervasiveness and persistence criteria that differentiate the symptoms of the two disorders; and by 2) Not taking a complete biopsychosocial history to distinguish psychological from limbic system factors.

All of the fancy biological research is not being complemented by good old fashioned clinical typing.

Furthermore, with the private Contract Research Organizations that do a lot of the studies, experimenters get paid only if they recruit a subject, and subjects get paid only if they get recruited - giving a financial incentive for everyone to exaggerate symptoms in order to qualify.

And people with suicidal ideation, comorbid (other, co-occurring) conditions, and significant personality pathology are excluded from studies. Those "exclusions" eliminate the vast major of subjects that have any of the psychiatric disorders in which depression is a symptom.

Garbage in, garbage out.

By the way, you can also have something called double depression. Such people are generally dysthymic but every so often can have a superimposed episode of major depression. So they have both conditions.

Once a major depressive episode starts to occur, it takes on a life of its own. However, being chronically unhappy, anxious, or stressed out may be risk factors for triggering a major depressive episode to begin with.  If you are genetically vulnerable to an episode of major depression, being chronically unhappy might make an episode more likely.

This is another reason why the question, "Should you treat these people with medications or therapy" is a really stupid question. It's a bit like asking, "Which treatment should people who have extensive, severe, cardiovascular disease get, bypass surgery or high blood pressure medication?" 

These treatments address completely different aspects of the disorder. In major depressive disorder, drugs should be used during the acute disorder, but psychotherapy should be given later to address personality  and relationship risk factors - in order to reduce the likelihood of subsequent episodes.

Increasing Placebo Responses in Psychiatric Drug Studies

In 2013, authors Rutherford and Roose  [American Journal of Psychiatry, 170  (7),  723-733] wrote a paper that discussed the results of a previous study that had found that the placebo (inactive "sugar" pill) response rates in random clinical trials (RCT's) of antidepressant medication had risen at a rate of 7% per decade over the past 30 years. Consequently, the average difference between active medication and placebo observed in published antidepressant trials decreased from an average of 6 points on the Hamilton Rating Scale for Depression (HAM-D) in 1982 to only 3 points in 2008.

Now the lead author of that paper and his colleagues have found something similar going on in RCT's between 1960 and 2013 of anti-psychotic medications for schizophrenia (the findings were published on line in October in JAMA Psychiatry). Most interestingly, in the 1960's, patients who received the placebo in such studies actually got worse on them.  By the 2000's, however, they were getting better on placebo.

Even more striking, the average RCT participant receiving an effective dose of medication in the 1960s improved by 13.8 points on the Brief Psychiatric Rating Scale (BPRS), whereas this difference diminished to 9.7 BPRS points by the 2000's.

What the heck is going on here? Are the medicines somehow becoming less effective than they used to be?

In their article from 2013, Rutherford et. al. try to explain this by looking at such things as expectancy (what do subjects think is going to happen with their symptoms), a statistical phenomenon known as  regression to the mean (see this post for a definition), the amount of contact subjects have with the study doctors, the social desirability of certain responses, and the “Hawthorne Effect” (subjects in an experiment improve or modify the aspect of their behavior under study simply by virtue of knowing that the behavior is being measured).

While the expectations of the average John Q. Citizen that antidepressants will work may have increased somewhat over the decades because of such things as celebrities describing their experiences with depression or commercials for Cymbalta and Abilify, there has also been a lot of negative information on that same score on television shows like Sixty Minutes and from the anti-psychiatry rants of Scientologists and others.

Whether these two influences completely cancel each other out is debatable, but I think it is safe to say that many of these possible reasons for a change in placebo response rate advanced by authors have in fact not changed significantly since the 1960's. In fact, if people in the 60's didn't think antidepressants would work, expectancies would have been lower, not only in the placebo group, but in the active treatment group as well.

If certain factors that affect placebo response rates have not changed a lot, then those factors can not explain the rise in the placebo response rates

The authors also mention a couple of factors that I believe to be more on the mark: first, that assessments of eligibility for a clinical trial may be biased toward inflated symptom reporting at the beginning of the study - when investigators have a financial incentive to recruit patients - and second, that most research participants in the 1960s and 1970s were recruited from inpatient psychiatric units, whereas current participants are symptomatic volunteers responding to advertisements.

The biggest change in research with RCT's over the period in question is that many studies are no longer done in medical schools, but by private entities called Contract Research Organizations (CRO's). The doctors who run the studies are paid for each subject they recruit, and subjects only get paid if they are recruited. This means that there are not just one set of financial incentives for everyone to exaggerate their symptoms at the beginning of a study, but two! This tendency will lead to a higher placebo response rate because after they are recruited, subjects no longer have an incentive to exaggerate their symptoms. So they seem to get better.

It is very easy to bias a research diagnostic interview. I'll get to that in a minute, but first a digression.

I was fortunate to train at a time when patients could be kept in the hospital for several months if necessary, so we got to see the patients in depth over a considerable time period, and could watch medication responses. People who have trained more recently do not see this any more.  Antidepressant responses clearly took a minimum of 2 weeks  - and then only if the patient responded to the very first drug given at the first dose given.

Because most patients do not understand this, the doctor can usually discriminate a placebo response from a true response by observing when the patient starts to get better combined with the rate at which they improve. Since subjects don't know what to expect, being on this timeline could not be due to the expectancy factor, which in turn is necessary for a having a good placebo response.

I can tell you that a severe, properly diagnosed melancholic depression almost never showed a significant placebo response.  The placebo response rate was probably about the same as the placebo response rate to a general anesthetic.

Another thing we observed was that patients with an acute schizophrenic reaction did not seem to get any better at all with such things as additional contact with doctors, which might be expected if a placebo response were taking place. In fact, the more you spoke with them, the more likely it would be that you would hear evidence that patients had a significant thought disorder than if you just had a briefer, casual conversation with them.

A thought disorder is at least as important as delusions and hallucinations in showing that someone is, in fact, someone with schizophrenia. People with a thought disorder see relationships between things that are completely illogical (loose associations). For example, the first patient I ever saw with schizophrenia in medical school believed that everyone who wore oxblood-colored shoes was a descendant of George Washington.  

Huh?

Anyway, back to the question of biasing diagnostic exams. This is particularly easy when diagnosing a clinical depression. It is important to distinguish them from those people who are merely chronically unhappy.  People with a clinical major depression, especially with so-called melancholic features, are a very different breed of cat.  

The  symptoms of both disorders do overlap a bit, so there are some cases in which it is really hard to tell one from the other. However, in the majority of cases it is a fairly easy call. It is, provided you do a complete psychiatric assessment, over several days, to see if a symptom of depression meets the requirement known as the Three P's: 

The symptoms need to be pervasive (they do not go away depending on what the patient is doing at a particular time), persistent (lasting almost all day every day for at least two weeks), and pathological (the patients symptoms and functioning differ to a highly significant degree from the patient's usual state). In addition to the three p's, all of the patient's symptoms have to always occur simultaneously.  

These types of characteristics do not usually show up on the type of symptom checklists used to assess patients in clinical trials, because the checklists are mostly based on a patient's self report.  Unfortunately, the majority of people do not know the difference between a clinically significant symptom and one that is not. The rate of false positive responses on checklists is staggering.

Many studies instead use something that is called a semi-structured diagnostic interview (such as one called a SCID) to make a diagnosis. It is called semi-structured because it tells the examiner to ask certain questions exactly as they are posed verbatim. However, the examiner is then free to ask any follow-up questions needed to clarify the clinical significance of any symptom the patient reports.

If you want to diagnose major depression regardless of whether or not the patient actually has it, all you have to do is accept every "yes" answer a patient gives to a question about a symptom without any follow-up questions to see if the symptom is characterized by the three P's. If the patient answers "No" to a question, however, you keep pumping the patient for additional clarification until you can find something the patient says that will justify changing the "no" answer to a "yes."  Voila.

New and Better Ways to Falsely Expand the Definition of Bipolar Disorder

Angst redefines angst!

Blowing Hot Air

The Journal of Affective Disorders, which really should be called the Disordered Journal of Bipolar My A--, is helmed by one Hagop Akiskal, about whom I have previously blogged (A Stupid Study and an Even Stupider Headline, 2/1/2011). On its website, the journal describes itself thus: “The Journal of Affective Disorders publishes papers concerned with affective disorders in the widest sense.” I think they must mean the wildest sense.

In several previous posts, I have described how the authors who regularly contribute to this journal are constantly on the lookout for new and improved ways to re-label patients with depression, anxiety, chronic ongoing interpersonal strife, and, in particular, borderline personality disorder (BPD) as really suffering from some form of mania.  Any form of mania.  Their creativity in spreading this outrageous nonsense is truly impressive.

In a journal article described by my post of 3/6/12, Relabeling Depressive Symptoms as Manic Symptoms, authors suggested 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.  

As I stated in that post:

“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.”

In another article described in my blog post of 8/13/2011, More Bipolar Disease Mongering in a Respected Journal, the authors found another way to create the fiction known as “subthreshold” mania – this time in another, major psychiatry journal, the Archives of General Psychiatry.

In this article, they introduced the term bipolarity specifier as if this were an established and valid measure.

As I described in the previous post, here's the definition:

“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.”

That last one, No minimum duration of symptoms was required and no exclusion criteria, is key. It 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 also makes almost anyone who has borderline personality disorder suddenly bipolar. The “research team” also included in their subthreshold category those patients who had experienced episodes of elevated or irritable mood triggered by antidepressants. Irritibility is a common side effect of drugs like prozac and may have absolutely nothing to do with bipolar disorder.

Some of my colleagues and I tore this study apart in a letter published in the Archives, and were answered with purposely misleading, phony “arguments,” as I described in my post of 6/19/2012,  Disease Mongering in a Respected Journal and Plausible Deniability.

Now comes another doosie of nonsensical research study, recently published online in the Journal of Affective Disorders, called Subthreshold bipolar disorder in a U.S. national representative sample: Prevalence, correlates, and perspectives for Psychiatric nosography by Hoertel, Le Strat, Angst, and Dubertret.  Jules Angst was also one of the authors of the Archives article as well.  I guess one could say that Angst is trying to redefine angst.

Jules Angst, M.D.

In this article they employ yet another brand new way to define “subthreshold” mania.  The criteria they used, in addition to the presence in a patient of an episode of major depression but who have not met the full criteria for an episode of mania or hypomania, is to include for purposes of the study anyone who answers in the affirmative to any one of three screening questions for bipolar disorder.

As I have mentioned many times in this blog, screening questions and questionnaires are purposely designed to cast a wide net, so that a lot of people who do not have the disorder are questioned further to make certain one way or  the other (false positives).  Their purpose is so researchers do not waste a lot of time questioning potential subjects who clearly do not have the disorder (false negatives). In other word, using screening questions to define a clinical entity is completely bogus by definition!

The reader can easily see why this is so by looking at the screening questions used in the paper:  1. In your entire life, have you ever had a time lasting at least one week when you felt so extremely excited, elated or hyper that other people thought you weren't your normal self? or (ii), In your entire life, have you ever had a time lasting at least one week when you felt so extremely excited, elated or hyper that other people were concerned about you? or (iii), In your entire life, have you ever had a time lasting at least one week when you were so irritable or easily annoyed that you would shout at people, throw or break things, or start fights or arguments?

Almost every patient with borderline personality disorder would answer at least one of these three questions in the affirmative.  Especially that third one.

The results of the study showed that people who met this screen for “subthreshold” hypomania (and who therefore had a "disorder" that had been merely defined into existence) were found, compared to depressed patients who did not, to be more likely to have been American born, and never to have been married. They were also less likely to earn more than $70,000 year.  They were more likely to have additional (comorbid) psychiatric disorders, especially personality disorders (other than borderline, interestingly, for which they mention later in the article they did not even bother to assess the subjects!) These included anxiety disorders, substance use disorders and dysthymia.

All of these findings are also true of patients with borderline personality disorder, which may have been what a significant percentage of these “subthreshold” manic patients had all along.

“But this sample of patients all were found to have had episodes of major depressive disorder (MDD),” you might protest. “So are you saying there is a sizable contingent of patients with borderline personality disorder who have co-morbid major depressive disorder?” Well, yes, that is true. But it is even more complicated than that.

The episodes of major depressive disorder seen in patients with borderline personality disorder are often qualitatively different from those in depressed patients who do not have this disorder.  These differences were described beautifully by my friend and colleague Kenneth Silk of the University of Michigan medical school in an article called, The quality of depression in borderline personality disorder and the diagnostic process, in the February 10^th 2010 issue of the Journal of Personality Disorders (24:1, pp. 25-37).

Ken Silk, M.D

He describes how MDD in BPD is less likely to be characterized by a full contingent of physical or vegetative symptoms (poor appetite, energy, slowing of thought and behavior, and so on), and less likely to respond to the earliest antidepressant medications (tricyclics).  Their depression was far more likely to be characterized by emptiness, loneliness, and desperation over their interpersonal relationships. Their depressive symptoms tend to be far more changeable (labile) and liable to come on suddenly in response to environmental events than patients with MDD without BPD. 

Patients with BPD are also most likely to be dysthymic, or chronically depressed, when they do not seem to be in the midst of a major depressive episode. In other words, as Dr. Silk says, “…these patients may suffer from chronic dysphoric mood that is being misinterpreted [by psychiatrists] as a [medication] non-responsive major depressive episode.”

The depression of patients with BPD is also much more likely to be characterized by high levels of anxiety. In fact, again according to Dr. Silk, their depression may stem from their exhaustion and demoralization from their unsuccessful battles with their overwhelming anxiety. Patients with an anxious depression are the very ones that will be labeled with subthreshold manic symptoms in articles such as the one under discussion.

By the way, these qualitative differences in the experience of certain patients with depression are not sorted out by the research diagnostic interviews and symptom checklists frequently used in psychiatric studies.  Imagine that.