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.

Book Review: Ghost of My Father by Scott Berkun

Half of all profits from this edition of Mr. Berkun's book, Ghost of Our Fathers (Berkum Media, 2014) will be donated to Big Brother Big Sisters of America

Our parents, or our primary caretakers when we were growing up, have a profound effect on us for our entire lives. They have this effect whether they like or not, and whether we like it or not. Attachment research has shown that their interactions with us help shape our mental models of both the world and how relationships are supposed to operate under various environmental contingencies (schemas).

The part of the brain called the amygdala, central to our fight/flight/freeze reactions to fearful stimuli, has specific cells that respond only to the face our mothers (or primary female attachment figures) - and nothing else. It also contains cells that respond only to our fathers/male attachment figures - and nothing else.

Even those who have managed to become more self-actualized or differentiated from our families of origin - who can follow our own muse and live according to our own independently formed beliefs - still hear or feel those old tapes of our parents' admonitions whenever we do things of which our parents routinely disapproved. I know I do, and my parents have been gone for decades. We can choose to ignore these tapes, but there is often a nagging doubt that arises in our minds whenever we do.

In his new book, Scott Berkum describes a feeling of being haunted by the past as well as by the ongoing behavior of his father, and does so eloquently using the words of a poet. I'll mention some examples of his beautifully-worded descriptions of some of the phenomena discussed previously this blog shortly.

Most of what I have written about dysfunctional family interactions on this blog as well as my blog on the Psychology Today website concerns what happens when parents give us contradictory or mixed messages about what is important to them, as well as what they expect from us. But what happens when they seem to give us almost no signals at all? When the parent is a big cipher? This is what happened to the author in his relationship with his father, and I suspect, though to a much lesser extent, with his mother.

His father was gone much of the time during his childhood, spending most of it working or at the racetrack gambling. He completely abandonned the family and the patient's mother twice in order to have extended affairs - once when the patient was eight years old, and once when the patient was in his forties. And yet when he returned each time, the mother would want him back, take him in, and take care of his needs.

He seemed to have little interest in what was important to the author. Much of the time he seemed to barely acknowledge his son's presence. The only sustained interactions they had seemed to occur at the dinner table, when the author, his siblings, and his father  would debate political and social issues. Father would seem to purposely take up a provocative position on the issue, and then stick with it no matter what arguments the author came up with.  Dad would never concede a point.

The author was plagued thoughout his life with a feeling that he was unworthy of his father's attention, and that nothing he did mattered to his Dad.

The author tried on numerous times to do what I recommend to my patients in therapy: attempt to empathically confront Dad to try to find out what made him tick and what he was really thinking (metacommunication). Unfortunately, each time he tried he ran up against a brick wall that would never come down. His father seemed to be incapable of discussing feelings. If the author pressed forward anyway, the conversation would devolve into a shouting match.

The book does not describe what was said during these explosions. With my patients in therapy, I try to obtain a blow-by-blow description of exactly what was said,  in chronological order, as best the patient can remember. This often gives hidden clues about the emotional processes that are taking place in both participants during the battle, as well as to why they are reacting the way they are.  In turn, this can suggest ways to have conversations that do not go in the usual direction and do not become fighting matches.

Interestingly, Dad did apologize for his behavior on one rare occasion and even expressed his love, but both the apology and the expression seemed to ring hollow with the author, who more or less rejected them.

Of course, when the author rejected them, he may not have realized that this let his father off the hook as far as further elaborating on the problem at hand- which was likely the father's goal all along. Saying what a family member wants to hear in a seemingly insincere way and/or when it is least expected often leads to such a rejection of the expressed sentiment. The person who does this then walks away thinking, "Just as I thought - he didn't really want to hear that, but at least I tried." This is an example of the game without end.

The author does discuss some genogram information, although whatever therapists he saw may not have not called it that nor known exactly how that information might best be used to design more productive family interactions in the present. The information about his father's upbringing was rather telling, and seemed to explain one statement the father made in the middle of one of the author's attempts to metacommunicate: "Your problem is you remember too much."

The author's paternal grandfather was described as "the quietest man I ever met." The author adds that he "...was always watching professional wrestling when we visited. He'd stare into the television as if he and it were the only thing left on the planet. His social skills, even with his own grandchildren, were non existent...I don't remember him ever saying a word to me."

No doubt Dad's father had done to him pretty much what he did to his own son. 

Clearly this was Dad's unfortunate role model for being a father. Clearly there was a family rule against fathers and sons communicating meaningfully. The author also admits that he shared some traits with his father - at times more than he cared to admit even to himself - demonstrating the intergenerational transfer of dysfunctional traits. The father must have tried to handle his own feelings by trying to "forget" what had happened.

A clue as to the origin of the family rules is that the father's paternal great grandfather  fled to the US from Ukraine in 1902 to avoid being drafted into the army, leaving his brothers behind. Undoubtedly there was a lot more to that story, especially since the brothers died in the Holocaust many years later. Was there some resulting hidden guilt and shame that had to be kept out of mind and never discussed?

The book is supposed to be primarily about the author's relationship with his father, so Mr. Berkum gives limited attention to his relationship with his mother. While he described them as close, it sounds as though certain subjects were off limits with her as well - like why she remained involved with such a distant man, and why she would take him back after a second betrayal.

The only person in the family who seemed to be able to express anger was the author's sister Tracy, who of course went overboard in doing so. Interestingly, the parents seem to keep her around almost as a pet - she lived with them or next door to them even after she married and had kids - until she, like the author himself did as a rather young man, finally moved away to escape. 

No doubt the parents needed Tracy's expressiveness to release some of their own pent-up rage.

Some concepts from the blog that the author describes poetically:

Distancing: "He mastered wounding us just enough that we'd leave the conversation as quickly as we could." (p. 11).

Existential groundlessness: "...we forget when we become adults that the armor made to survive our youth no longer serves us...yet removing it is painful...it puts us at odds with our family and friends, as tribes prefer to stay with patterns of the past. Most people convince themselves that removing their armor is something they don't need to do. And their families, complicit in the same denial, reward the defense of the status quo, ensuring the...same armor, and the same ghosts, will be passed on to the next generation..." (p. 17).

The power of family ties:  "It is curious, perhaps even strange, that the choices of my father would impact me so profoundly at forty years old." (p. 22).

"I didn't realize that just because you're done with the past doesn't mean the past is done with you."

Mutual role function support: "Each person needs the other badly, in the way an alcoholic needs another drink. When one takes a drink of the other...it feels good. It covers certain holes, allowing them, in moments, to be forgotten, but does not fill them. My mother and father love each other for that feeling, and hate each other  for the same reason." (p. 114).

On the feeling of not counting for his father, after a brief encounter after he returned late from the racetrack:  "It was the bottom of the barrel of his day..." (p. 150).

I could go on. This book is a brutally honest memoir, well worth reading.

Intrapsychic Conflict and Dysfunctional Family Patterns

There have not been a lot of studies done looking at how personality problems affect individuals over three generations within a family, and how they may be passed down from one generation to the next. Today’s emphasis is studying mostly biogenetic factors.

However, the few studies that have been done generally show the same types of things. Although there is never a one to one correlation (because people’s development is affected by the chaotic interactions of thousands of different variables – genetic, biological, interpersonal, and sociological), certain issues are highly likely to be passed down.

Earlier studies have shown what is known as intergenerational transfer of certain types of dysfunction for, as examples:

• Boundary disturbances such as maternal overprotection and relationships characterized by lack of affection, enmeshment, and/or parent/child role-reversals (Jacobvitz et. al., Development and Psychopathology, 3, 513-527, 1991).
• Emotional dysregulation with poor disciplining skills with children (Kim et. al., Journal of Family Psychology, 23(4), 585-595, 2009).
• Substance abuse with parental substance abuse combined with abuse and/or neglect and low levels of family competence (Sheridan, Child Abuse and Neglect, 19 (5), 519-530, 1995).

In understanding this process, I try to incorporate concepts from different "schools" of psychotherapy. The most important task in integrating different psychotherapy models is to pose the question of how concepts from different therapies might relate to one another, and how slight modifications to specific aspects of these concepts may make relationships between them more clear.

In this post, I will focus on the relationship between several such concepts. We have the concept of intragenerational transfer of dysfunctional behavior from Bowen family systems therapy. Then we have a primary concept from psychodynamic therapy, intrapsychic conflict. People have conflicts between their innate desires and the values they have internalized as they grew up within their family and culture. 

To see how these two concepts can both be valid and also when combined explain certain human behavior, we can take a closer look at the intergenerational transfer question.

The attachment theorist Bowlby first suggested that these transfers occur, not through specific observable behaviors like “abusiveness” or psychiatric diagnoses per se, but through the generation of mental models of interpersonal behavior in the affected children. These working mental models are now called schemas by both psychodynamic and cognitive-behavioral therapists. They are also subsumed under the rubrics theory of mind or mentalization by another set of psychodynamic therapists. We need to look at the subjective experiences of the involved children throughout their development.

Zeanah and Zeanah (Psychiatry, 52, 177-196, 1989) discuss the concept of organizing themes. They mention that studies show that abusing mothers tend to attribute more malevolent motives to their own children compared to other people’s children. More generally, they react with more annoyance and less sympathy to videotapes of crying infants than do non-abusive mothers. To think that these patterns would not be noticed or sensed by children through their daily interactions with their parents, and would not affect the development of their schemas, would be extremely naïve.

In turn, abusive mothers reported more threats of abandonment and role reversals with their own mothers than did control mothers.

These findings are probably the tip of the iceberg in terms of subtle characteristics of repetitive parent-child interactions, and as the Zeanahs say, “Patterns of relating are considered to have more far-reaching consequences than specific traumatic events” (p.182).

When Bowen therapists started doing the genograms of their patients, which describe family interactional patterns over at least three generations, they noticed something that has not really be described much in empirical studies. While some children of dysfunctional parents had problems that were similar to their parents -  such as substance abuse - other children seemed to have developed behavior patterns that were exactly the opposite – they became teetotalers!

I have seen this sort of thing many times in taking genogram-related family histories from my own patients. One son of a workaholic will also be a workaholic, while his brother becomes a complete slacker who can’t seem to hang on to a job, or who does not even bother to look for one and goes on disability of some sort. Or who is enabled by the workaholic father.

In fact, in some families one generation has a lot of alcoholics, the next generation a lot of teetotalers, and the third generation goes back to having a lot of alcoholics. Or impressive successes in one generation are followed by remarkable failures in the next. McGoldrick and Gerson, in their book Genograms in Family Assessment, traced the genograms of some famous people like Eugene O’Neill and Elizabeth Blackwell and readily found such patterns.

If these sorts of issues were entirely genetic, it would be difficult to explain how progeny of the same parents could be so completely opposite from one another, as well as completely opposite from their own parents. So what might be going on psychologically within people that might lead to interpersonal behavior with their own children that generates such bizarre patterns?

This is where intrapsychic conflict may come in. Say a father was a young adult during the Great Depression of the 1930’s. He had grown up feeling that work defined him, and that he was obligated to keep his nose to the grindstone in order to support his family. He was lucky enough to have a job, but his boss made his life miserable. He could not quit because he would not be able to get another job, and therefore he began to subconsciously resent the very values with which he has defined himself.

This could lead him to develop an intrapsychic conflict over hard work which starts to tear him apart. He may relate to each of his sons in a manner that – very subtly - suggests to one son that he too should be just like him, while the other son is subtly rewarded for acting out the father’s hidden resentment towards hard work and self-sacrifice.

Likewise, a patient might come from overly-strict religious parents who had rejected any and all hedonistic pursuits, but who had preached to their child about the evils of alcohol in a highly ambivalent manner. Such ambivalence usually arises in them because of their having received mixed messages from their own parents. Their son may feel pushed to rebel, and therefore lead a licentious, alcohol-drenched lifestyle. Such a person often destroys himself in the process, because if his parents observe him being successful in spite of drinking, this would exacertate the conflict in his parents and destabilize them. This would frighten him. So he becomes a self-destructive alcoholic.

His behavior would be sort of compromise. He would be following the repressed urges of his parents and allowing some expression of them, while at the very same time showing his parents that repressing the urge was indeed the way to go.

In the next generation, his children may “rebel” just like he did, but the only way they can do so is by going to the opposite extreme themselves. They become teetotalers. Their children, in turn, “rebel” by becoming alcoholics.

I’m tremendously over-simplifying this process so the basic outline is clear to the reader, but I see these types of patterns – with many fascinating twists and turns - every day in my practice.