Antidepressants only effective in severest depression?

A recent article in JAMA by Fournier et al. is a meta-analysis of antidepressant treatment effects assessed in relation to depression severity. Here's the reference:
http://www.ncbi.nlm.nih.gov/pubmed/20051569

The results show that antidepressants work significantly well, compared to placebo, only for very severe depression (corresponding to Hamilton Depression Rating Scale scores of at least 25).

The analysis is quite well-done, and the results are also presented in a graphical form clearly showing a linear increase in antidepressant effect as baseline depression scores increase.

The authors observe that antidepressants are most commonly prescribed to people who have milder depressions--a population in which they show that medications arguably do not work.

Here are a few of my criticisms of this study:

1) the duration of each trial included in the meta-analysis was between 6 and 11 weeks. In my opinion, depressive disorders are long-term, highly recurrent problems, which have a natural period over at least 6-11 months, not 6-11 weeks. Treatments to address mood disorders of any severity require much longer durations. The short duration could cause a significant under-estimation of treatment effects.

2) the study, like many, looks at "depression alone." In most real-life situations, outside of a research study, individuals have several different problems, such as mild depression + social anxiety, or mild depression + panic attacks, etc. The presence of other symptoms, particularly anxiety symptoms, most likely would increase the likelihood of antidepressants helping.

3) Milder depressions, just like more severe depressions, may actually improve more consistently with a "second step" such as combination with psychotherapy, or combining two different antidepressants. The mildness of a medical syndrome does not necessarily mean that the effective treatments need only to be "mild."

4) Milder depressive syndromes may be more prone to misdiagnosis.

5) current "resolution" to measure treatment effects in depression is quite poor. "Depression" is a very broad category. An analogy could be considering "abdominal pain" to be a diagnostic category. If "abdominal pain" is the only category, and is simply rated on a severity scale (rather than subcategorized to obtain a precise diagnosis), and the treatment offered for "abdominal pain" is appendectomy, then we would probably see no difference in treatment effectiveness between appendectomy and placebo. This is because appendectomy is only effective to treat appendicitis (a subset of the abdominal pain population), and is either ineffective or harmful in treating abdominal pain patients without appendicitis (except, perhaps, for those patients who have a placebo improvement of psychosomatic or factitious abdominal pain, an improvement which they attribute to having surgery).

We currently do not have the science to subcategorize depression in a more clinically meaningful way (there are subcategorization schemes, but they don't have much relevance in terms of treatment).

But we do have a research method which could improve "resolution":
-instead of comparing two populations of depressed individuals, one group receiving antidepressant (or some other treatment), and the other receiving placebo (or some other alternative), the study design could instead be to offer every individual courses of placebo, alternating with antidepressant (or "treatment one" alternating with "treatment two"). Each course of treatment would have to last an adequate length of time. The analysis would aim to show whether there is a subset of individuals who respond to the antidepressant, or a subset of individuals who do better with placebo. The averaged results over the whole group might show that antidepressant effects do not differ from placebo (just like appendectomy might not differ from placebo in treating "abdominal pain"), but the individualized result could show that some individuals improve substantially with the antidepressant (just like appendectomy would save the lives of the small group of "abdominal pain" patients who have appendicitis).

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In the meantime, though, I think it is reasonable to recognize that antidepressants are less consistently helpful when symptoms are less severe.

A Gene-Environment-Phenotype Surface

I've been thinking of a way to describe the interaction between genes, environment, and phenotype qualitatively as a mathematical surface.

In this model, the x-axis would represent the range of genetic variation relevant to a given trait. If it was a single gene, the x-axis could represent all existing gene variants in the population. Or, the idea could be extended such that the x-axis could represent all possible variants of the gene (including the absence of the gene, represented as "negative infinity" on the x-axis). The middle of the x-axis (x=0) would represent the average expression of the relevant gene in the population.

The y-axis would represent the range of environmental variation relevant to a given trait. y=0 would represent the average environmental history in the population. y="negative infinity" would represent the most extreme possible environmental adversity. y="positive infinity" would represent the most extreme possible environmental enrichment.

The z-axis would represent the phenotype. For example, it could represent height, IQ, extroversion, conscientiousness, etc.

In my opinion, current expressions of "heritability" represent something like the partial derivative dz/dx at x=0 and y=0; or perhaps, since the calculation is based on a population sample, heritability would be the average of derivatives dz/dx over various sampled (x,y) points near x=0 and y=0.

Conventional heritability calculations give a severely limited portrait of the role of genes on phenotype, since it condenses the information from what is really a 3-dimensional surface into a single number (the heritability). This is like looking at a sculpture, then being told that the sculpture can be represented by a single number such as "0.6", based on the average tilt on the top centre of the artwork.

A more comprehensive idea of heritability would be to consider that it is the gradient, a component of which is dz/dx. This gradient would not be a fixed quantity, but could be considered a function of x and y.

It is particularly interesting to me to consider other properties of this surface, such as what is the derivative dz/dy at different values of y and x? This would determine the ease with which environmental change could change a phenotype regardless of genotype.

A variety of different shapes for this surface could occur:

1) z could plateau (asymptotically) as y approaches infinity. This implies that the phenotype could not be changed beyond a certain point, regardless of the degree of environmental enrichment.
2) z could appear to plateau as y increases, but this is only because we do not yet have existing environments y>p, where p is the best current enriched environment. It may be that z could increase substantially at some point y>j, where j>p. I believe this is the case for most medical and psychiatric problems. It implies that we must develop better environments. Furthermore, it may be that for some genotypes (values of x), z plateaus as y increases, but for other genotypes z changes more dynamically. This implies that some people may inherit greater or lesser sensitivity to environmental change.
3) dz/dx could be very high near the origin (x,y)=(0,0), leading to a high conventional estimate of heritability; but at different values of (x,y), dz/dx could be much smaller. Therefore, it may be that for some individual genomes or environmental histories, genetic effects may be much less relevant, despite what appears to be "high heritability" in a trait.
4) dz/dx could be very low near the origin, but much higher at other values of (x,y). Therefore, despite conventional calculations of heritability being low, there could be substantial genetic effects on phenotype for individuals with genotypes or environmental histories which are farther from the population mean.

The idea of x itself being fixed in an individual may also not be entirely accurate, since we now know of epigenetic effects. Also, evolving technology may allow us to change x therapeutically.

In order to describe such a "surface", many more data points would need to be analyzed, and some of these might be impossible to obtain in the current population.

But I think this idea might qualitatively improve our understanding of gene-environment interaction, in ways that could have practical applications (current heritability estimates are typically 0.5 for almost anything you can think of--this fact seems intuitively obvious, but is not very helpful to inspire therapy or change, can sometimes increase a person's sense of resignation about the possibility of therapeutic change, and can distort understanding about the relative impacts of genes and non-genetic environment).

Non-human Primate Models of Psychiatric Treatment Effects

Before starting the main body of my post, here's a little introduction:

I've been doing quite a bit of reading lately about the history of psychiatry (in particular, an excellent book by Lisa Appignanesi; I'll write a post about it when I've finished, which could be in a while, since the book is 5 cm thick!). Also I've been reading about cultural psychology (another very interesting field), after finding a free set of university lecture notes published online. I'd like to write another post about this subject as well, when I get around to it.

What does this have to do with "non-human primate models of psychiatric treatment effects?" Well, I'm becoming more strongly aware of the powerful effects of culture upon the manifestations of psychological (and, possibly, physical) health and distress. The book I'm reading deals with cultural change through history; these changes have influenced the presentation, management, and course of many psychiatric phenomena. Even terms like "psychiatric phenomena" or "symptoms," etc. are culturally influenced jargon. The cultural psychology subject also deals, of course, with cultural differences, but in this case mainly with the way different groups of people in the present era around the world experience or perceive emotions, psychological distress, social interactions, or cognitive processes. I suspect that cultural differences may exist between families as well, within the same geographical area.

These factors complicate the study of psychiatric therapies, perhaps in many ways that could be subtle but powerful.

I've been interested in finding more evidence about the effect of physical and psychological treatments for psychiatric symptoms in non-human primates. In this case, cultural or personal history biases could be much more carefully controlled.

There are a lot of studies done in rodents, of behavioural therapies and of medication, including a very questionable rodent "model" of antidepressant effectiveness. I think that possible conclusions are much more limited, about human therapies based on research done in mice, etc.

Monkeys or apes are much closer to humans, in terms of genetic similarity and brain structure. They may exhibit behavioural problems that are much more closely analogous to psychiatric symptoms in humans. So, I have been looking for good research about medication and "psychotherapy" effects in primates. Here's a start:

http://www.ncbi.nlm.nih.gov/pubmed/19383215

This 2009 article describes self-injurious behaviour in rhesus macaques. These animals may bite themselves severely; this is thought to be due to an underlying vulnerability combined with social deprivation in infancy or being isolated in captivity. About one-third of macaques experiencing solitary captivity exhibit self-directed stereotypic behaviour. The behaviour is exacerbated by separation from the social group, by disruption of daily routines, or by exposure to a fear-provoking stimulus (for animals, this could be an unfamiliar person trying to interact with them closely). It is interesting to consider that analogous behaviours in humans are probably related to similar vulnerabilities, deprivations, or triggers.

The experiment described in the article is about treating these self-injuring monkeys. Each group started off with 4 weeks of baseline observation, followed by 4 weeks of placebo, before randomization to fluoxetine, venlafaxine, or placebo for the final 4 weeks.

The individuals in the fluoxetine groups, at higher doses in particular, had substantial reductions in self-injurious behaviour (at least 50-75% less self-injury than the placebo group). The venlafaxine group did not improve as much.

There were no changes in "general behaviour" aside from a reduction in "aggressive displays." In particular, there were no signs of sedation or reduced engagement, etc.

I don't mean to make too much of results of this type, but I do think that this is strong evidence that the effect of an SSRI is not simply of an elaborate active placebo, influenced by cultural expectation. Also, just because a symptom is reduced doesn't necessarily mean a problem is solved...however, reducing a problematic behaviour such as self-injury may be a necessary prerequisite to resolving other types of psychological problems.

This type of study would be strengthened if it was extended for a year or more, and if it was to include data about other "quality of life" indicators, such as social integration, longevity, physical health, etc.

Here's another study, showing that tryptophan administration over a 4-week period substantially decreased self-injurious behaviour (again, by 50-75%) in small monkeys. There was also a decrease in previously high levels of cortisol. The dose of tryptophan was over 100 mg/kg per day, which would be a bit inconvenient to administer to humans:
http://www.ncbi.nlm.nih.gov/pubmed/19383216

Here's another study of self-injury in macaques. In this case, housing the animals outdoors led to significant reductions in self-injury. I think the message here could be that a healthy environment which optimizes freedom of movement, space, and natural sensory cues (e.g. of light, sound, and temperature), leads to diminished stress and and diminished symptoms of psychological distress. We could confidently generalize this statement to humans, I think.
http://www.ncbi.nlm.nih.gov/pubmed/16995645

Here is a relevant review on the subject of self-injury in human vs. non-human primates:
http://www.ncbi.nlm.nih.gov/pubmed/16713051

Here's an amusing (and, unfortunately, not very strong) study showing that hearing music leads to increased affiliative behaviour and decreased aggressive behaviour in chimpanzees. There were different degrees of responsiveness to different types of music:
http://www.ncbi.nlm.nih.gov/pubmed/17203919


I'll try to add to this post later. In the "psychotherapy" realm, some of the first important animal studies in primates were done by Harlow. I'm interested to find some more recent stuff in the research literature. I guess there won't be much on cognitive therapy in monkeys, since there is a bit of a problem encouraging non-human primates to keep written diaries with thought records...similarly, psychoanalytic studies are probably in short supply (!) Yet, in all seriousness, I suspect that the key elements for successful therapy in non-human primates involve positive, gentle, consistent relationships; and gentle, non-punitive behavioural education & modeling.

Authoritative, Authoritarian, and Permissive Self-Parenting

Here's a nice summary of different parenting styles:
http://en.wikipedia.org/wiki/Parenting_styles

The authoritarian style is strict and dictatorial, with no dialog between parent & child.

The permissive or indulgent style is lenient, with little discipline or rules.

The authoritative style is balanced: there are clear rules, clear boundaries, which are consistently enforced, but lots of empathy, understanding, dialog, and flexibility. Strong consideration is given to the child's point of view.

I think these different styles could be applied to one's own individual mind -- I encourage aiming for a healthy, balanced, authoritative style.

Authoritarian styles will be oppressive, and foster resentment, unhappiness, anger, and rebellion within oneself (sometimes an "underground" rebellion manifesting itself as depressive self- harm).

Permissive styles could feel liberating, but could lead to an experience of drifting, with a lack of direction, without a feeling of growing or developing one's potential.

An authoritative style would lead to a healthy balance between freedom and self-discipline, allowing for growth, challenge, and happiness. It could also tame the wilder forces within your mind, not by suppressing them, but by hearing them and guiding them in a well-boundaried, safe context.

Becoming a "Self Whisperer"

Well, you may accuse me of having sentimental tastes in film, but I really did enjoy the 1998 movie with Robert Redford, called The Horse Whisperer. It's about a reclusive Montana rancher who has an almost mystical ability to gently connect with and rehabilitate horses (and humans?) who are wild, traumatized, or out-of-control.

Since 2002, a dog trainer named Cesar Millan has called himself "the dog whisperer," and has a TV show, website, and has sold millions of books. His approach is basically one of gentle, calm authority: maintaining clear and consistent boundaries without losing one's cool or becoming excessively punitive. Mind you, I see that there is a little bit of debate about some of his techniques. And it's a bit dicey to apply animal training ideas to humans.

Recently, however, people have been trying to generalize these ideas a little bit, to the subject of parenting. Hence the idea of becoming a "child whisperer." Many parents have unhelpful interactions with their children: perhaps there are behavioural or discipline problems, but often times the parents are losing their cool, the parents are resorting to excessive and ineffective punishments, or the parents are giving a lot of praise but without any discipline. Sometimes the timing of praise or discipline is out of synch with the child's behaviour. Some methods of discipline may be harmful to both child and parent. Sometimes misbehaving children seem to be ruling the house, leaving the parents frustrated and exhausted. An exhausted parent in this situation may end up just spending less and less time parenting, in order to find distractions from the problems, or in order to escape. While respite is necessary, this tactic would of course make the parent-child dynamics even worse.

Here's an article from the New York Times on this:
http://www.nytimes.com/2009/11/22/fashion/22dog.html

I would like to generalize this idea one step further, to consider ways to become a "self whisperer."

This may involve nurturing a sense of calm, gentle understanding and authority over the various forces within your own mind:

-in this sense exercises to relax or meditate need not be considered exercises in tolerating an unhealthy state, but rather exercises to produce a stance of calm, loving, gentle authority, which is ideal in "self-whispering."

-part of the process may involve setting very clear boundaries within your own mind, without becoming excessively punitive, bossy, critical, or authoritarian towards aspects of yourself or others. Various therapy styles can help in this sense, including cognitive-behavioural ideas. Methods of non-harmful self-discipline may need to be learned and practiced.

-it can be important to have "respite", but it will be important "to do activities together" with the more challenging aspects of your mind, to be an effective "self whisperer." There needs to be time for reflective, empathic dialog with self, provided there is a benevolent structure, healthy boundaries, and clear safety rules.

--I'll have to edit this posting a bit, I think it's in a formative stage right now, but I thought I'd put it up here as the start of an idea I found enchanting in the moment--