Wednesday, July 29, 2009

Twin Studies & Behavioral Genetics

The field of behavioral genetics is of great interest to me.

A lot of very good research has been done in this area for over 50 years.

One of the strongest methods of research in behavioral genetics is the "twin study", in which pairs of identical twins are compared with pairs of non-identical twins, looking at symptoms, traits, behaviors, disease frequencies, etc.

I would like to explore this subject in much greater detail in the future, but my very brief summary of the data is this:
1) most human traits, behaviors, and disease frequencies are strongly affected by hereditary (genetic) factors. Typically, about 50% of the variability in these measures is caused by variability of inherited genes. That is, the "heritability" is typically 50%, sometimes much higher.
2) The remaining variability is mostly due to so-called "non-shared environmental factors". This fact is jarring to those of us who have believed that the character of one's family home (a "shared environmental variable") is a major determinant of future character traits, etc.
3) Hereditary factors tend to become more prominent, rather than less prominent, with advancing age. One might have thought that, as one grows older, environmental events would play an ever-increasing role in "sculpting" our personalities or other traits. This is not the case.
4) Some of the "environmental variation" may in fact be random. Basically, good or bad luck. Getting struck by lightning, or winning the lottery, or not. Such "luck-based" events are mostly (though not entirely) outside our control.
5) All of these facts may lead to a kind of fatalism, a resignation about our traits being determined by factors outside our control. (mind, you, being "lucky" or "unlucky" may be more determined by attitudinal factors such as openness than just by random events: see the following article--

Here is some of my critical response to the above statements:

1) Statements about heritability are in fact dependent upon the average environmental conditions experienced by the population being studied. For example, if we were to measure the heritability of becoming the leader of a large country, we would find heritabilities of nearly 100% in times or places where there are hereditary monarchies, and much lower heritabilities for democracies (mind you, the case of the Bush family shows that the heritability has been non-zero in the U.S.).
2) Non-shared environmental factors are extremely important. This does not mean that the family environment is unimportant. Part of an individual's non-shared environmental experience is that person's unique experience of the family environment. The lesson in this is that families need to pay close attention to how each individual family member is adapting to the family situation, and to also pay close attention to a child's peer and school environment.
3) The influence of shared environmental factors is small, but rarely zero. Usually there is some small percentage of variability accounted for by shared factors. Often this percentage is larger in childhood, and declines towards zero during adult maturation. But it is not zero. Just because an influence is small does not mean that it is unimportant. We have limited control over our genetics, after all, but we do have more substantial control over shared and non-shared environmental variables.
4) Most studies look at the general effect of genetic & environmental factors in populations. Compelling examples are frequently cited of individual twins, separated at birth: perhaps one twin is adopted into a wealthy, privileged home with access to multiple educational resources, while the other grows up in a more impoverished setting. The story typically is that the twins both end up with similar funds of knowledge or intelligence: the first twin reads books available at home, while the other twin develops her inherited interest in knowledge by going out of her way to acquire a library card, and spending all day reading at the local library. Such case examples illustrate how inherited factors can prevail despite environmental differences.

But I'm interested to see counterexamples: examples in which differences in environment between twins did lead to substantial differences in traits later on. It is this type of example that has the most practical value, in my opinion.

5) I have considered the following idea:
For any trait or characteristic having any heritability, there may be environmental variables that can change the outcome of the trait for a given individual. Even for highly, obviously heritable traits. Consider eye color, for example. This seems obviously purely genetic. But suppose there was a medication that could change eye color. This would be a purely environmental factor (though, of course, perhaps the tendency to use a drug to change eye color would be partially inherited). Most people would not use such a drug. Measures of heritability for eye color would remain very high. But, despite this high heritability, there may well be simple, direct environmental changes which, for a given individual, could completely change the trait. Such environmental changes would have to be very different from average environmental conditions. The higher the heritability, the farther would the environmental change have to be from average, in order to effect a change in the trait.

We could say that the tendency to kill and devour wildebeest is heritable, among the different wild creatures of the African savanna. The genetic differences between lions and giraffes would completely determine the likelihood of such creatures devouring a wildebeest or not. We could say that lions inherit a tendency to eat wildebeest, while giraffes do not. Yet, I suppose that it is true that we could train and/or medicate lions (and also keep them well-fed with a vegetarian diet!) so that wildebeest are totally safe around them. In this way, we would be introducing a set of environmental changes which would cause a radical change in lion behavior. This does not change the fact that the heritability for lions' killing wildebeest is extremely high, it just means that the environmental change necessary to change the trait must have to be something radically different from the environmental experience of the average lion (most lions are not trained to be non-predatory!).

The clinical applications I have based on these observations are the following:

1) Many psychological phenomena are highly heritable. This does not mean that these phenomena are unchangeable though. It does mean that, in order to change the trait or behavior, an environmental change needs to occur which is substantially different from the environmental experiences of most people, or of the "average person". This may help us to use our efforts most efficiently. So, for example, it would be inefficient to merely provide everybody with a typical, average, 2-parent family living in a bungalo. The evidence shows that such "average" environmental changes have minimal impact on psychological or behavioral traits. It would be important to make sure each individual is not deprived or harmed, and has access to those basic environmental elements that are required for them to realize their potential. If there are problems, then the means of addressing those problems may require a substantial, unique, or radical environmental change.
2) The most influential environmental variables are those which are unique to the individual, not the ones which are shared in a family. This does not mean that family experiences are unimportant, but that a child's unique experience of his or her own family environment, is much more important than the overall atmosphere of the home. A chaotic household may be a pleasure, a source of boisterous social stimulation, for one child, but an injurious, disruptive, irritating source of stress for another. A calm household may allow one child to grow and develop, while it may cause another child to become bored or restless.
3) The higher the heritability, the more pronounced the environmental (or therapeutic) change is required to change the trait, compared to the average environment in the population.
4) The motivation to have a certain style of home, or parenting, etc. should logically not primarily be to "sculpt" the personality of your child, but to allow for joyous long-term memories, to be shared and recounted as stories by parent and child, and to pay attention to the unique nature of each individual child, providing for any healthy needs along the way.

Some references:

Segal, Nancy L. (2000). Entwined Lives: Twins and what they tell us about human behavior. New York: Plume.
{a 2009 review including a look at "epigenetics", the notion that one's genes are changeable, therefore identical twins are not truly "identical" in a genetic sense}
{genetics of PTSD}
{a look at how genetic factors influence environmental experience}
{a look at how choice of peers is influenced by heredity, moreso as a child grows up}
{some of the research showing different genetic influences coming "on line" during different stages of childhood and young adult development}
{a recent article by TJ Bouchard, one of the world's leading experts in twin studies}

Low-dose atypical antipsychotics for treating non-psychotic anxiety or mood symptoms

Atypical antipsychotics are frequently prescribed to treat symptoms of anxiety and depression. They can be used in the treatment of generalized anxiety, panic disorder, OCD, major depressive disorder, PTSD, bipolar disorder, personality disorders, etc. At this point, such use could be considered "off-label", since the primary use of antipsychotics is treating schizophrenia or major mood disorders with psychotic features.

But there is an expanding evidence base showing that atypicals can be useful in "off-label" situations. Here is a brief review of some of the studies:
{this is a good recent study comparing low-dose risperidone -- about 0.5 mg -- with paroxetine, for treating panic disorder over 8 weeks. The risperidone group did well, with equal or better symptom relief, also possibly faster onset. But 8 weeks is very brief -- it would be important to look at results over a year or more, and to assess the possibility of withdrawal or rebound symptoms if the medication is stopped. Also is would be important to determine if the medication is synergistic with psychological therapies, or whether it could undermine psychological therapy (there is some evidence that benzodiazepines may undermine the effectiveness of psychological therapies) }
{an open study from 2006 showing significant improvements in anxiety when low doses of risperidone, of about 1 mg, were added to an antidepressant, over an 8 week trial}
{this 2008 study shows significant improvement in generalized anxiety with 12 weeks of adjunctive quetiapine. It was not "low-dose" though -- the average dose was almost 400 mg per day. There is potential bias in this study due to conflict-of-interest, also there was no adjunctive placebo group}
{in this 2006 study. patients with a borderline personality diagnosis were given quetiapine 200-400 mg daily, for a 12 week trial. As I look at the results in the article itself, I see that the most substantial improvement was in anxiety symptoms, without much change in other symptom areas. The authors state that patients with prominent impulsive or aggressive symptoms responded best}
{in this large 2006 study (the BOLDER II study), quetiapine alone was used to treat bipolar depression. Doses were 300 mg/d, 600 mg/d, or placebo. There was significant, clinically relevant improvement in the quetiapine groups, with the 300 mg group doing best. Improvements were in anxiety symptoms, depressive symptoms, suicidal ideation, sleep, and overall quality of life.}

Here's a reference to a lengthy and detailed report from the FDA about quetiapine safety when used to treat depression or anxiety:

In summary, I support the use of atypical antipsychotics as adjuncts for treating various symptoms including anxiety, irritability, etc. But as with any treatment (or non-treatment), there needs to be a close review of benefits vs. risks. The risks of using antipsychotics for treating anxiety are probably underestimated, because the existing studies are of such short duration. Also the benefits over long-term use are not clearly established either.

For risk data, it would be relevant to look at groups who have taken antipsychotics for long periods of time. In this group, antipsychotic use is associated with reduced mortality rates (see the following 2009 reference from Lancet:, which looks at a cohort of over 60 000 schizophrenic patients, showing reduced mortality rates in those who took antipsychotics long-term, compared to those taking shorter courses of antipsychotics, or none at all--the mortality rate was most dramatically reduced in those taking clozapine. Overall, the life expectancy of schizophrenic patients was shown to have increased over a 10-year period, alongside substantial increases in atypical antipsychotic use)

It is certainly clear to me that all other treatments for anxiety (especially behavioural therapies, lifestyle changes, other forms of psychotherapy) be optimized, in an individualized way, before medication adjuncts be used.

But I recognize that suffering from anxiety or other psychiatric symptoms can be severely debilitating, can delay or obstruct progress in relationships, work, school, quality of life, etc. The risks of non-treatment should be taken very seriously. My view of the existing evidence is that adjunctive low-dose antipsychotics can have significant benefits, which can outweigh risks for many patients with non-psychotic disorders. As with any medical treatment decision, it is important for you and your physician to regularly monitor or discuss risks vs. benefits of ongoing medication therapies, and be open to discuss new evidence which is coming out.

Wednesday, July 15, 2009

Benefits and Risks of Zinc Supplementation in Eating Disorders, ADHD, and Depression

Zinc supplementation may help treat anorexia nervosa, ADHD, and treatment-resistant depression.

Zinc is a metallic element involved in multiple aspects of human cellular function, metabolism, growth, and immune function. It is required for the function of about 100 human enzymes. The human body contains about 2000-3000 mg of zinc, of which about 2-3 mg are lost daily through kidneys, bowel, and sweat glands. The biologic half-life of zinc in the body is about 9 months, so it can take months or years for changes in dietary habits to substantially change zinc status, unless the intake is very high for short periods.

Red meat is a particularly rich source of zinc. Vegetarians may have a harder time getting an adequate amount from the diet. The prevalence of zinc deficiency may be as high as 40% worldwide.

When referring to zinc dosage, it is best to refer to "elemental zinc". Different types of zinc preparations (e.g. zinc gluconate or zinc sulphate) have different amounts of elemental zinc. For example, 100 mg of zinc gluconate contains about 14 mg of elemental zinc. 110 mg of zinc sulphate contains about 25 mg of elemental zinc.

Here are references to articles written by a Vancouver eating disorders specialist between 1994 and 2006, advising supplementation of 14 mg elemental zinc daily (corresponding to 100 mg zinc gluconate daily) for 2 months in all anorexic patients:

Here's a 1987 article from a pediatrics journal, showing improvement in depression and anxiety following 50 mg/d elemental zinc supplementation in anorexic adolescents:

In this 1990 open study, anorexic patients were treated with 45-90 mg elemental zinc daily, most of whom had significant improvement in their eating disorder symptoms over 2 years of follow-up.

Here's a 1992 case report of substantial improvement in severe anorexia following zinc supplementation:

Zinc depletion may lead to an abnormal sense of taste (hypogeusia or dysgeusia). This sensory abnormality improves with zinc supplementation. Here's a reference:

Here's a randomized , controlled 2009 Turkish study showing that 10 weeks of 15 mg/day zinc supplementation led to improvement in ADHD symptoms in children. However, a close look at the study shows a bizarre lack of statistical analysis comparing the supplemented group directly with the placebo group. When you look at the data from the article, both groups improved to a modest degree on most measures, with perhaps a little bit more improvement in the zinc group. The analysis here was insufficient, I'm surprised a journal would accept this.

Here's a 2004 reference to a study showing that 6 weeks of 15 mg elemental zinc daily as an adjunct to stimulant therapy improved ADHD symptoms in children, compared to stimulant therapy plus placebo. In this case, there was a valid statistical analysis:

Here's a 2009 study showing that zinc supplementation improves the response to antidepressants in treatment-resistant depression. The dose they used was 25 mg elemental zinc daily, over 12 weeks.

Here's an excellent 2008 review article about zinc deficiency, and about the potential role of zinc supplementation in a wide variety of diseases (e.g. infections ranging from the common cold, to TB, to warts; arthritis; diarrhea; mouth ulcers). The review shows that zinc may have benefit for some of these conditions, but the evidence is a bit inconsistent:

Here is a warning about zinc toxicity: {hematological toxicity from taking 50-300 mg zinc daily for 6-7 months. The toxicity was thought to be due to zinc-induced copper malabsorption leading to sideroblastic anemia}

Here is a nice website from NIH summarizing the role of zinc in the diet, in the body, some of the research about health effects, and about toxicity. It sticks to a recommended daily intake of 10-15 mg elemental zinc for adults, or about 5 mg for young children. It states that the maximum tolerable daily intake levels are about 5-10 mg for young children, 20-30 mg for adolescents, and 40 mg daily for adults:

Here is a reference to another excellent review of zinc requirements, benefits, and risks. It makes more cautious recommendations about zinc supplementation, advising no more than 20 mg/day of zinc intake in adults. In order to prevent copper deficiency, it also advises that that the ratio between zinc intake and copper intake does not exceed 10.

So, were I to make a recommendation about a zinc supplementation trial, I would advise sticking to amounts under 20 mg (elemental) per day for adults, and to ensure that you are getting 2 mg of copper per day with that.

Wednesday, July 8, 2009

Prazosin and other treatments for PTSD-related nightmares

Nightmares are a common symptom of post-traumatic stress disorder (PTSD).

Various psychotherapeutic approaches can help people to deal with nightmares, both to be more psychologically prepared for them, and to be able to let them pass with a smaller amount of distress. Techniques include simply keeping a written record of the nightmares, with or without doing some cognitive therapy exercises based on this record; practicing relaxation techniques; exposure therapy during the daytime (by evoking the imagery of the nightmares, possibly "rescripting" the sequence of events); or by planning for a "rescripting" of the nightmare during the nightmare itself. Here is a reference to a review article about psychotherapy for nightmares:

Sedative drugs can change dreaming activity, but often times these medications are problematic: tolerance or oversedation may develop, or sometimes the nightmares continue despite other types of sleep improvement.

Prazosin is a cardiovascular drug which blocks alpha-receptors, and is commonly used to treat high blood pressure. Alpha receptors are stimulated by adrenaline, which causes constriction of blood vessels, therefore increased blood pressure. In the brain, increased stimulation of alpha-receptors may be one of the mechanisms driving PTSD-related sleep disturbances such as nightmares. Prazosin has been shown to help reduce PTSD-related nightmares. Here are a few references: {a good review article} {a 2007 randomized, controlled, crossover study published in Biological Psychiatry, showing pronounced reduction in PTSD-related nightmares with 10-15 mg bedtime doses of prazosin} {a 2003 randomized study published in The American Journal of Psychiatry showing substantial benefit in PTSD-related sleep symptoms with prazosin at an average of 10 mg/d}

There is the suggestion in these studies that prazosin, if dosed in the daytime as well, could help treat other PTSD symptoms.

Prazosin has been used for over 35 years in the treatment of hypertension. Interestingly, it is also one of the treatments of choice in the medical management of severe scorpion stings. It may also be a promising option in the treatment of alcoholism (reference:

Prazosin is well-tolerated by the majority of people taking it. It appears to have minimal psychiatric side-effects. Sedation does not seem to be common. If the dose is too high, too soon, it can cause excessive postural blood pressure drops, with dizziness and a risk of fainting (syncope). It may cause nasal congestion or headache. Priapism (a medically dangerous sexual side-effect) is possible but very rare.

Monday, July 6, 2009

Melatonin: benefits and risks

Melatonin is a hormone synthesized in the pineal gland, and is thought to be important in the regulation of circadian (day-night) rhythms.

It has been used to treat insomnia and sleep-phase abnormalities.

The most interesting study I found regarding long-term use of melatonin was published in JAMA in 2008:
In this prospective, blinded study, elderly patients with dementia were given 2.5 mg melatonin near bedtime, over an average of 15 months of follow-up. Patients in another group were exposed to bright light during the day (approximately 1000 Lux indoors, from 10:00 AM to 6:00 PM). A third group received both melatonin at night and bright light in the day. Placebo groups received no melatonin, or were exposed to typical indoor office lighting, of about 300 Lux.* Interestingly, caregivers were not able to tell whether their site had the ordinary lighting or the bright light (the increased light intensity was measurable with a meter, but was not noticeable subjectively).
The results showed that melatonin consistently improved sleep, particularly helping reduce the time required to fall asleep, and increasing total sleep time.

However, the group receiving melatonin alone showed worsening mood (less positive affect & more negative affect).

The group exposed to bright light in the day, plus melatonin at night, did not show worsened mood.

The authors conclude that bright light in the day helps with mood, cognition, and function in elderly dementia patients. Melatonin alone helps with sleep but has a negative impact on mood. Bright light plus melatonin had a positive impact on all the symptoms studied.

Based on this study, I would encourage anyone using melatonin at night to ensure that they get plenty of bright light during the daytime. It also suggests that any study looking at melatonin treatments should also consider daytime bright light exposure as an important variable which could affect response to melatonin.

Here's a reference to a study showing that 2 mg of sustained-release melatonin improves sleep:

In this study, children with intellectual disabilities experienced relief of their insomnia (including reduced time to fall asleep, reduced time awake, and increased total sleep time) with 5 mg melatonin supplementation over a 4-week period:

Here's a study showing improved sleep, with no adverse effects, due to melatonin administration to autistic children:

Here's a study showing improved sleep in children with epilepsy who were treated with adjunctive melatonin (6-9 mg). There were no significant side-effects:

High-dose melatonin (1 mg/kg body weight) has been used experimentally to treat intractable epilepsy, but more research is needed to evaluate effectiveness & safety. Here is one reference:

This study showed improved sleep in adolescents with ADHD, when they were given 5 mg melatonin over a 30-day trial. However there was no improvement in ADHD symptoms:

Melatonin has been associated with autoimmune conditions. Here is a case report associating melatonin use with autoimmune liver disease:

Here is an article about melatonin possibly exacerbating rheumatoid arthritis (various reports show increased melatonin levels in rheumatoid arthritis patients):

Yet, in various other reports, melatonin has been shown in animals to protect the liver from various forms of artificially-induced toxicity. (e.g.

In conclusion, melatonin appears to be have a reasonable safety profile, and is a potentially effective treatment for insomnia, particularly "initial insomnia" in which there is difficulty falling asleep at the beginning of the night. Typical doses of melatonin range from about 2 mg - 6 mg.

The one main concern about adverse effects concerns possible exacerbation of autoimmune diseases such as rheumatoid arthritis, although the evidence is not clear on this point. Other types of toxicity, while possible, appear to be rare. Melatonin may even protect cells from a variety of different types of harm. But it is important to recognize the possibility that there could be other unknown adverse effects over long periods of time.

As with any treatment, we have to balance risks against benefits: insomnia itself clearly has a variety of negative long-term health effects (ranging from increased risk of physical and psychiatric illness, to increased risk of accidents). Other treatments for insomnia have their own risk/benefit profiles.

Cognitive-behavioural therapies for insomnia are clearly the safest and most beneficial, and should be optimized before any other medical therapy. But it appears to me that melatonin ought to have a place in the medical treatment of insomnia, alongside other established therapies.

*here are some measures of light intensity in different settings, to help give you some reference points to compare:
50 Lux -- family living room
100 Lux -- very dark overcast day
300-500 Lux -- recommended office lighting
400 Lux -- sunrise or sunset on a clear day
1000 Lux -- overcast day
10 000 Lux -- clear day (not direct sun)
100 000 Lux -- direct sun