A seminal paper if the conclusions follow from the actual data (which I can’t find)

        Organic chemists have spent a lot of time hoping to synthesize molecules to treat psychiatric illness.  The commonest, of course, is depression with a lifetime risk for women of 25% and for men of 10 – 15%.  It’s also one of their greatest successes, e.g. the SSRIs (Selective Serotonin Reuptake Inhibitors).  Zillions of compounds have been made which block the single protein (the serotonin reuptake protein/transporter) which schleps serotonin back into neurons, leaving more serotonin to float around the nervous system. While we have just one gene for the transporter we have at least 14 genes for serotonin receptors and some of them have multiple splice variants, so just where the extra serotonin goes and how getting there helps depression is still under study.  Theories abound.

       The paper  [ Proc. Natl. Acad. Sci. vol. 108 pp. 8189 – 8193 ’11 ], if true, provides a plausible explanation for (1) why attempts to replicate reports linking various genes to depression fail so often (2) ditto for studies of drug efficacy for depression.  It also points to a far better way to test drugs for efficacy in a variety of psychiatric conditions. Clearly important stuff.  If you don’t have it already, youl’ll need to pick up some background  in molecular biology.  This should be all you need — https://luysii.wordpress.com/category/molecular-biology-survival-guide/.   Also, it might be worth a look at this — https://luysii.wordpress.com/2010/08/29/some-basic-pharmacology-for-the-college-student/ 

       The biological susceptibility model posits that some genotypes are highly susceptible to environmental influences (orchids) while others are not (dandelions).  The claim is made that postpartum depression (PPD) occurs in 10 – 20% which I think is extremely high (depends on how it is diagnosed).  Major depression is defined in the DSM-IV as 3 or more depressive symptoms lasting over 2 weeks during which there is dysphoria or anhedonia (aren’t these depressive symptoms?).  The sample of 1,206 mothers gave an incidence of PPD of 17% using these criteria in the first year after the birth of a child (1 year is quite long. the postpartum period is medically defined as the time maternal physiology returns to near pre-pregnancy status, which is about 6 weeks).




       To cut to the chase (details to follow) — women of low socioeconomic status (SES) with high risk variants for depression of the serotonin transporter were shown to have a higher incidence of postpartum depression (unsurprising).  It is known that women of low SES are twice as likely to have depression.  The paradigm shifting result of the paper is that women of high SES with the same ‘high risk’ variants of the transporter had a decreased incidence of postpartum depression.  Truly counterintuitive! !  Think about what this result implies while I plunge into the details of the study. 

      The Fragile Families and Child Wellbeing study (FFCWS) is a sample of children born in large cities between 2/98 and 9/00 with an oversample of kids born to unmarried parents (75%).   Interviews were conducted within 3 days and subsequent interviews were conducted when the child was 1, 3, 5, and 9.  DNA samples (saliva) were taken at age 9.   The marker used for socioeconomic status (SES) was maternal education (not out of wedlock births) — either seems reasonable to me and I’ll analyze their results both ways. They used post-high school education as the determinant of SES. It’s a little hard to figure out how many women of the 1206 were in the high SES group.  So I had to eyeball figure 1.D (p. 8190) to get a number around 30% giving 362 women of ‘high’ SES.       

       The study looked at gene variants (polymorphisms) of the serotonin transporter 


       Previous studies have focused on just one polymorphism of the serotonin transporter gene at a time– this study looked at two  — however 6 different polymorphisms of the gene are known.    One was in the 5′ regulatory region of the gene (called 5HTTLPR) the other was a 17 nucleotide variable number of tandem repeat (VNTR) in the second intron — (called STin2 VNTR).  

      The 5HTTLPR polymorphism: there is a short (S) 14 repeat and long (L) 16 repeat of a 23 nucleotide incomplete repeat.  Other less common repeats are also found.  At any rate the S allele has been associated with higher rates of mental health poblems including depression in many studies.

      The two most common alleles of STin2 are a 10 and 12 copies of a 17 nucleotide repeat.  The 12 repeat allele has been shown to be associated with higher rates of mental health problems. 

      The number of S and 12 alleles was determined for each mother and totaled. So each mother could have 0, 1, 2, 3, 4  of the ‘risk’ alleles for depression. The effect of 0, 1, or 2 risk alleles was neglible (in both high and low SES groups)  but effects were seen if the mothers had 3 or 4 of the ‘high risk’ alleles.  So the 3 and 4 high risk allele group are orchids while the 0 – 2 group are dandelions. 

       It is likely that inclusion of more polymorphisms would make the interaction even more pronounced.  

       There are all sorts of calculations in the supplemental material, but I’d love to see the actual numbers for the women with 3 and 4 of the bad risk alleles — how many were there?  How many in this group developed depression?  We’re talking 25% with married parents (bringing the total down to 300 in this group).  Then reduce this to 17% (the average rate of depression in the total group) and we get an expected 51 cases.  Next reduce number 300 by the % of the study population having the 3 of the high risk alleles and we have even less — from figure 1.C it looks to be around 35% (again I had to eyeball this, I couldn’t find an explicit number.   So we now have an expected 17 cases in this group.  Not a great number to play around with. 

        The above assumes that married mothers have less stress than unwed ones.

        Another way to look at is is to figure out the percentage of women with more than a high school education (this is the actual marker they used for socioeconomic status), which looks to be around 30% (see figure 1.D p. 8190) this gives a group of 362 women, and at a 17% rate of depression gives 61 expected cases.  How many in this group had the 3 or 4 risk alleles?  Again about 35% of them do making 128 educated women with risk alleles (this contains possibly an unwarranted assumption to be discussed later).  Again the expected number of cases of depression would be 128 *.17 = 21 cases.  Presumably there were fewer cases of depression than expected by chance — but how many fewer – 1, 2, —- 10?   I can’t find the data.  They are making a very important conclusion based on at most 21 missing cases of depression.   If there were 3 cases of depression in the groups the results would be conclusive, if there were 19 cases instead of 21 the results would be unimpressive.  Which was it? 


       This also assumes that people in the high SES group have less stress.  Maybe so, but a reading of any 19th century Russian novel would argue otherwise.

       Another interesting way to look at the data, would be to see if the high number of risk alleles was over represented in any subgroup, married vs. unwed, high SES vs. low SES — they certainly have this data, but I couldn’t find it.  The calculations in the previous paragraphs assumed that the distribution of risk alleles is identical in all groups — married, unmarried, high SES, low SES and various subgroups made from these (married and low SES, married and high SES etc. etc.).  The authors certainly have this data, but I couldn’t find it.  It should be a simple matter to put it on a spread sheet and print the results.

       ( It is an interesting mathematical question to compare the histogram of risk factor distributions in the various populations married/unwed, high SES/low SES and see if they are essentially the same.  How would you explicitly define two distributions as being ‘essentially the same’ ?  I’m sure this has been done, and that someone out there knows the answer.  If you do how about a link? )

       This is yet another example of why I hated reading the medical literature when I had to (for some other horrible examples, if you have the stomach see — https://luysii.wordpress.com/2009/10/05/low-socioeconomic-status-in-the-first-5-years-of-life-doubles-your-chance-of-coronary-artery-disease-at-50-even-if-you-became-a-doc-or-why-i-hated-reading-the-medical-literature-when-i-had-to/.)  The results could be a statistical fluke.   

       Small numbers are no barrier to a definitive conclusion.  Here’s a very recent example — a recent study on prophylactic use of antiretrovirals in couples one of whom was HIV1 positive. 1793 couples were studied in which one partner was HIV1+.  Half started antiretroviral therapy (type not specified), the other half didn’t (presumably all the partners didn’t have clinical AIDS or a low CD4 lymphocyte count, as it wouldn’t be ethical to withhold treatment from them, and presumably if they did develop this over the course of the study, treatment would have been started).  6 years on the study was stopped (it planned to last 10 years) when preliminary data was analyzed.  Of the 39 uninfected partners who become infected, 28 were infected from their regular partners (there’s a way to know if they got their partners HIV1). 27 of those infected from their partners were in the group where the partner had not begun antiretrovial therapy.  Absolutely unequivocal despite the small numbers. A slam dunk.

       Perhaps this is true of the depression study as well, but I can’t tell from the paper.  Too seminal to ignore, too fantastic to believe without the actual numbers.  Irritating — yes.  Fairly typical — unfortunately.

       There’s tons more for the drug developer and pharmacologist to think about.  Perhaps the results of this paper (if true) account for some of the problems replicating risk factor and efficacy results of other studies. 






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  • luysii  On June 1, 2011 at 10:55 pm

    I sent the following to the lead author of the paper today. I’ll post the response in the comments here

    1 June ’11

    Dr. McClanahan:

    A truly fascinating paper, for many reasons. If broadly applicable, it may explain the failure to replicate a lot of association studies of genes and psychiatric disorders (not just depression). It may also explain why drug efficacy studies in a variety of conditions are so hard to replicate, as well.

    I have several questions.

    l. How many high SES women were there in the 3 and 4 risk factor class, and how many cases of post partum dperession did they have?

    2. Ditto for low SES women in the 3 and 4 risk factor class.

    3. Were the distributions of risk factors overall the same (or at least statistically similar) for high/low SES, married/unmarried mothers?

    4. The study is a real paradigm shifter, so it must be replicated. Is anyone doing this?

    Thanks for a truly fascinating paper.

  • luysii  On June 2, 2011 at 1:38 pm

    Got this back today. Stay tuned.

    Thank you for your interest in our paper. I am traveling right now and can’t access all of my data files, but I think I can answer your questions. I will check once I get back to Princeton and let you know if I am remembering incorrectly.

    1 and 2) So I believe that both High and low SES had similar distributions of alleles. So about 25% had 3 and 10% had 4.
    3) I don’t remember the test for married/unmarried mothers, but I am fairly confident that is something we would have noted had it been different (but I will check when I return).
    4) I completely agree this should be replicated. Of course the difficulty is finding a study that has: 1) maternal depression in the first year after birth, both 5-HTT markers, and 3) a very wide distribution of education. Many studies have 1 or 2 of these, but we have yet to find another with all 3. In particular having both 5-HTT markers is very rare, and we have many more low SES women than most genetic studies. If you have any suggestions of possible studies please let us know, we are very interested in having it replicated. As you say it could have a significant impact, but we really need to make sure that our finding isn’t an anomaly. Again, thank you for your interest.

    Colter Mitchell, PhD

  • Panama corporation  On June 18, 2011 at 9:56 am

    This study will explore brain function related to depressive symptoms and will examine DNA for genes that may be involved in depressive disorders particularly genes that regulate synthesis and metabolism of the brain neurotransmitter catecholamine. It will compare findings in patients with major depressive disorders who are in remission with those in normal healthy volunteers..Patients with remitted major depressive disorders and healthy normal volunteers between 18 and 60 years of age may be eligible for this study. For this procedure the patient lies on a table that is moved into the scanner a narrow cylinder and wears earplugs to muffle loud knocking and thumping sounds that occur during the scanning process.

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