Antidepressants and Pharmacogenomics

Tansey et al. Contribution of Common Genetic Variants to Antidepressant Response. Biological Psychiatry. 73(7):679-682, 2013.

PsychCentral posted a news article about this study.

The above mentioned study is a pharmacogenomic study that performed a genome-wide association study of to detect genetic variants that are associated with antidepressent drug response.  Since the previous sentence uses a lot of jargon, I will try to break it down.

Pharmacogenomics is the study of how the genetics of individuals influences their biochemical response to drugs.  Namely, we are interested in how well a particular drug treats the disease that it is designed to treat.  So, these studies are usually an investigation of the main-effects of a drug, rather than an investigation of the side-effects.  (Although the pharmacogenomic approach can also be used to study side-effects, it is hard to get sample sizes that are large enough to find anything with such a study.)  The reason we are interested in pharmacogenomic studies is because drug response is partially genetic.  For many diseases we know that whether or not a drug works for your parent(s) can well predict whether the drug works for you.  So, not only are diseases genetic, but the effective treatments can also be genetic.

To explain how traits can be genetic, first we need to understand what genetic variation is.  Humans have two copies of every chromosome, and we have a distinct sequence of nucleotides (the molecular units that make up DNA) on each chromosome.  There are sites or positions in the genomic sequence where if we look across many individuals, we find that there are multiple nucleotides that appear at that site.  These sites of variation are called single nucleotide polymorphisms (SNPs).  If a SNP is responsible for a disease trait then there would be a single mathematical function that relates for each person the nucleotides that they have at the SNP site to disease trait.  The simplest examples involve single SNP sites that are Mendelian diseases (either recessive or dominant) and have binary disease traits, or traits that either exist or do not exist.  We call diseases complex (or polygenic, meaning that it involves many sites) when the trait is a function of the nucleotides at several SNPs.  Now we have described the generative model, i.e. given the genetic data and a mathematical function, decide what the trait value is for each person.  The aspect that makes this novel research is that the mathematical function linking the genetics to the trait is unknown.  This is why governments and foundations are spending millions of dollars on studies that try to discover these mathematical functions that link genetics to the trait.

The most common type of study that attempts to do this is called the genome-wide association study (GWAS).  These studies are used not only for in pharmacogenomics, but also for studying the genetics of heritable disease.  A GWAS study that looks for an association between some trait, in this case drug response by depressed individuals when given anti-depressant drugs, and the nucleotides at a particular SNP site.  An association (usually meaning a significant correlation) is a specific mathematical function, like the ones that we discussed above, that relates, with few errors, the nucleotides of the individuals at a SNP site to the value of the trait.  (The functions we described above were completely general whereas most GWAS methods rely on correlations which are a restricted class of functions.)

The study that was sited at the top of this post, had two main results.  The first result is a negative result in terms of being able to use the genome of a patient to identify which drugs will most help them.  The second result is a positive result saying that if a patient's close relative responds well to a particular drug then the patient likely will as well.

First, they found many SNPs that are associated with antidepressant drug response.  This means that drug response is polygenic and therefore is a complex trait involving multiple SNP sites.  Knowing that antidepressant drug response is polygenic helps us know what to look for in the genome.  We should be looking for interacting sites that work together to produce the trait.  This is a negative result, because it means that there is not just one genetic site that we can use to test for what drug each person will respond to.

Second, the paper gives results about the heritability of drug response.  Heritability is the fraction of trait variability that is due to genetics.  When we say that the heritability is 42%, we do not mean that there is a 42% chance that a child of a person with the trait will also have the trait.  Rather, we mean that heritability is the ratio of the variance of the trait that is due to genetics and the total variance of a trait.  Heritability is not about the risk of having a trait but rather it is about whether the trait is genetic or not.  A trait having a heritability of 42% means that 42% of the variance of the trait value is due to genetic causes.  This main result of the study is best expressed in this sentence

We find that common genetic variants explain 42% (SE = .180, p = .009) of individual differences in antidepressant response.

What can we as potential users of antidepressants take away from all this?  First, it will be a while until the science advances to the point that it can predict which drug will work best for us.  Second, the best predication about which antidepressants would work well for us is the list of antidepressants that work well for our relatives.

In the wider discussion of which psychotropic drugs may be helpful to a person, it might be quite reasonable to assume that there is heritability of drug response.  For example imagine two siblings, one who has anxiety and one who has schizophrenia.  (This example is quite plausible because we know that families having bipolar or schizophrenia also have a lot of anxiety and depression.)  At any rate, in our imagining, the sibling with the anxiety was diagnosed first and found Zyprexa to be a very useful drug for pro re nata treatment of anxiety.  The second sibling, when diagnosed with schizophrenia, recognizes that Zyprexa has worked for their sibling and tries that drug to good effect.  As another example, suppose antidepressants cause a family member with bipolar to become manic.  Then it might be good for other family members to avoid that class of drugs regardless of which diagnoses they may have.

Although there is not much research yet that elucidates the heritability of psychotropic drug response, the experience of patients indicates that this is a critical aspect of successful treatment.  I fervently hope that the research will move in the direction of attempting to elucidate the heritability of drug response, because it would lead to successful treatment.

Depression

Many people have an image of depression as the monster that keeps a person in bed all day, saps their energy, and colors their emotions blue.  This post is about another kind of depression that creeps up on a person, saps their energy, but does not put them in bed.  In this kind of depression a person is functional but has little motivation and little ability to accomplish things.  Neither of these depression types is more sever than the other, they are just different.  I choose to focus on this last type of depression, because it is the kind that I can speak about from personal experience.

Recognizing Depression

Here is a list of symptoms of depression as taken from the Major Depression category of the DSM IV-TR.

1. Depressed mood most of the day.
2. Diminished interest or pleasure in all or most activities.
3. Significant unintentional weight loss or gain.
4. Insomnia or sleeping too much.
5. Agitation or psychomotor retardation noticed by others.
6. Fatigue or loss of energy.
7. Feelings of worthlessness or excessive guilt.
8. Diminished ability to think or concentrate, or indecisiveness.
9. Recurrent thoughts of death (thoughts of suicide)

Symptom (4) sleep disturbances is stereotypically taken as the most indicative of depression.  It is understandable that changes in sleep patterns are easy to notice and certain to draw attention.  On the other hand, for people that do not experience disruptions in sleep, detecting the presence of depression can be more difficult due to the subjective nature of most of the other symptoms.  Particularly if one does not feel very 'blue' as in symptom (1) depressed mood, recognizing depression is challenging.

I am in the category of people who do not experience symptom (4) sleep disturbances.  In addition, I do not seem to experience (1) depressed mood or (3) weight gain/loss.  This leaves me with the following symptoms diminished interest, fatigue or loss of energy, feelings of guilt, diminished ability to think or concentrate.  Now, people that know the DSM and that are counting may have noticed that I did not list 5 symptoms of depression which is the threshold for a Depression diagnosis.  They would be correct.  Recall also that I have had diagnostic issues, perhaps partly for this reason.  Despite this issue, I feel that I have indeed experienced depression.

This leaves me with a problem, how do I detect the onset of depression?  All the easy indicators like thoughts of suicide and sleep disturbances are not appropriate.  While my strategy may evolve further, I am currently using an activity log to track my engagement in work.  This is similar to a time-sheet, but it involves extreme honesty about when I am actually working productively.  (This is for my eyes only, so I do not have to worry about a negative opinion from my supervisor.)  I track the time that I work productively each day and each week.  Then I can watch the trend over time.  If I start to become fatigued, uninterested in work, or lack the ability to concentrate, my weekly productive time drops.

You might ask if keeping an activity log is difficult.  I find that it is not (of course I sometimes lapse), but I have integrated the activity log with my lab notebook which records my research/work activities.  So, the log has a dual purpose.  Also, I use a computer to compute statistics like average productivity.

This tool is very important to me, because at the beginning of a depression it is easy to rationalize the symptoms.  I will end up thinking that I just need a break to recharge when in reality a break might only make the depression worse.  This tool allows an objective view of the time I spend being active and helps cut through the subjectivity of the situation.

Preventing and Treating Depression

For me, the primary prevention and treatment of depression is medications.  It has been critical to have the right combination of psychotropic medications and to treat physical illnesses that could cause depression.  Additionally, I use a motivational tool which turns out to be the activity log described above.

On the topic of medications, being a person with a bipolar family history of sensitivity to SSRIs, I avoid antidepressants.  I rely mostly on the antidepressant properties of Lithium.  I have experienced an instance where a failure to treat a thyroid problem appeared to result in depression.  So, I also keep on top of my general health.

The motivational tool that I use is the activity log mentioned above.  In a bad depression, I try to do at least one activity a day.  Once each activity is complete, I log it in the activity log making the log into a sort of achievement wall.  I get to feel good about each thing that I accomplish.  By continuing to track my active hours each day, I can also see whether the depression is improving which also makes me feel more positive.

The activity log could also be viewed negatively, if one were to focus on how little they accomplished each day.  To avoid this, I strongly subscribe to a view of life that everyone can improve from where they are at.  This view is typically accepting of whatever activity level I find myself at during a depression, and it helps to keep me focused on improvements, no matter how small.

Does anyone else have depression strategies to share?  If you do, please post them in the comments.

Bipolar Episodes

The establishment subscribes to 2-3 types of bipolar episodes:

1. mania - high of euphoria, activity, grandiosity, impulsiveness, etc.
2. depression - low of activity, energy, negative thoughts, suicidal thoughts, etc.
3. mixed states - properties of both mania and depression, perhaps including psychosis

Believe it or not, there is still debate on whether the third type actually exists.  I have encountered prominent doctors at a university who subscribed only to the traditional bipolar I and II distinction in which bipolar I is thought to involve both mania and depression and bipolar II is thought to involve hypomania (baby mania) and depression.  These doctors would not discuss mixed states, but instead discuss schizoaffective disorder as the third disorder that can explain bipolar-like symptoms.

The first two types of episodes are what give bipolar its a name where the 'bi' refers to mania and depression, and the 'polar' refers to the presumed spectrum on which mania and depression sit at opposite ends.  It is fairly easy to see that the name bipolar comes from the traditional description of bipolar I and II.  The addition of mixed states is an acknowledgement that there is actually not a depression-mania spectrum for some people, and opens a diagnostic category for the people having episodic bi-polar-like symptoms that are not clearly related to schizoaffective disorder.

What are mixed states?
It is thought that they look different in everyone that experiences them.  And, one person might experience more than one type of mixed episode.  (Keep in mind that this discussion is not very scientific, as the definition of a mixed episode is still being developed.)  I like to think of it this way, and notice that my view is different from the traditional definition: mania is an episode centered around feeling good and depression is an episode centered around feeling bad.  I believe there are other feelings that can anchor an episode such as anger, or fear.  In each case, the trademark of bipolar is that these episodes take an emotion and make an extreme experience.  So that anger becomes a rage episode and fear becomes a paranoia episode.

These emotional episodes are called mixed, because they are said to have symptoms of both classical mania or depression.  For instance a rage episode might be considered energetic and may also involve suicidal thoughts.  Or a paranoid episode might be sleepless and may also involve difficulty with concentration.

Personally, I find the task of identifying both mania and depression symptoms in an episode to be difficult.  I would prefer to see descriptions of multiple types of emotion centered episodes.  But we will see where scientific discovery takes mixed episodes.  Hopefully we will see progress in the near future.

Does anyone else have thoughts about the distinction between mania, depression, and mixed episodes?