Nutrient Based Psychiatry
Articles
Psychiatric Genetic Analysis: developing a targeted mechanistic-based pharmacotherapy
In the recent decades, advancements in genomic technologies have made it possible to sequence the complete human genome. In doing so, much progress towards decoding the information stored in DNA that influences complex human behavior has been achieved. This includes advances in understanding the genetic underpinnings of psychiatric conditions and their treatment. This article discusses the basics of DNA, genes, alleles, the history and current use of pharmacogenomic testing, the tenants of psychiatric genetic analysis and how it may be used to complement the current practice of psychiatry. We are writing this for lay persons, medical professionals and researchers, so do skip to the next section if the information is too technical or remedial.
The Book of DNA
Imagine a book consisting of 2 million pages telling the stories of thousands of characters. About 99% of the pages are written in text that we are unable to really understand, leaving 1% or approximately 20,000 of the pages containing two versions of a sentence that may be identical, but frequently have differences that impart subtle or stark twists to the story. One of these sentences was inherited from the two authors of the book (our parents). Numerous possible versions of the sentences including variations in the words, letters and how frequently they are read exist. These minor differences that occur across many pages account for significant changes in the characters’ stories including their origins, lifespans, relationships, interests and fates. Let us focus on one named Sera (serotonin). In one version of the book, she may be a prominent figure, highly active with low levels of anxiety and depression and in another, elusive and withdrawn with higher levels of these symptoms. An in-depth understanding of her story allows for the possibility of influencing or re-authoring her story arc with the aim of reducing her suffering.
Of course, the broad categories of anxiety and depression are influenced by an intricate web of other neurotransmitter stories as well as characters involved in chapters of the book that deal with inflammation, the immune system, hormones etc. Some characters have tragic story arcs, a single tragic flaw or an Achilles’ heel, if you will, that affect not only them, but the entire book. Sicell (sickle cell anemia) is a literally twisted character that is unable to efficiently bring food (oxygen) to other players in the book. The most severe version leads to a hero’s downfall along with much pain and suffering. With the progression of awareness of the existence of the book of DNA, how to read it, how to interpret it and more recently, the technology to literally edit or rewrite the words on the page known as CRISPR, came the ability to successfully transform the story of Sicell from one of tragedy to triumph. At this point, having a single tragic flaw lends itself to re-authoring via this technology. We are, however, still in the infancy of understanding this book of DNA. It is as if we are learning a new language and can utter the words, but truly understand very few of them. In the case of complex psychological issues that may be ailing a character like Sera, we do not have sufficient understanding of the consequences of changing the text of her story. This includes pinpointing what to change and when to change it. Owing to tremendous complexity, psychiatry could be one of the last branches of medicine that employs CRISPR technology. Instead, we can focus on changing the frequency with which certain pages are read and how they are interpreted without changing the actual text. For example, if the book indicates that Sera encounters difficulty going from one place to another, we may be able to partially or fully circumvent the problem by skipping over that page or changing the way she interacts with other characters she encounters. Although our understanding of this book is limited, the rapid expansion of our knowledge places us ever closer to the role of the editor as well as the reader.
DNA, Genes and Alleles:
DNA or deoxyribonucleic acid is a complex molecule that exists in the nucleus of most of our cells. It contains the information necessary to create the structure and carry out the metabolic processes of our bodies. Genes are discrete sections of DNA that contain a code or instruction which is used to make proteins or strings of amino acids. These proteins make up our tissues, enzymes, receptor sites and messengers that influence the functioning of other genes and systems in our bodies. There are approximately 20,000 protein coding genes in humans which account for only about 1% of our DNA. With the exception of certain genes on the X and Y chromosomes, humans have two copies of every gene, one from each parent. There are multiple variations in segments of genes and associated regions of DNA that can often confer differences in how frequently a gene creates its protein and how that protein functions. These differences are called alleles. One's genotype refers to which alleles a person has inherited from each parent. As more research on genes and specific alleles emerges, one's genotype can provide information about the functioning of that gene. For example, if the gene codes for an enzyme, a particular allele might result in decreased functioning of that enzyme along with downstream effects. In some cases, the influence of one specific allele can exert a profound effect on a person (recall Sicell). For complex neuropsychiatric conditions, the effect of a single allele is usually more subtle. However, when the mechanistic impact of alleles are understood, additive and synergistic relationships across large numbers of them can help explain why different combinations are associated with the same diagnosis. It may also explain why a particular intervention for the same condition often produces differential therapeutic and adverse effects. An analysis of the alleles an individual with a particular diagnosis possesses can give insight into which treatments may be the most effective.
Pharmacogenomic Testing:
Pharmacogenomics refers to the study of how a person's genotype might influence response to a medication. The main goal of this is to provide information to clinicians which can help to select medications that are most likely to be effective in addressing a particular symptom or condition while minimizing adverse effects. Pharmacogenomic testing was first approved by the Food and Drug Administration (FDA) in 2005 and focused only on drug metabolizing enzymes (DMEs). Over time, more of these enzymes were added to the array of information provided. Understanding how these enzymes function can be valuable because if a patient metabolizes a medication very slowly or very quickly, it may mean that a particular medication is not an appropriate choice or the dose would need to be adjusted up or down accordingly. Prior to the availability of this data, the only way to determine the efficacy of a medication was to administer it to the client and monitor its therapeutic and adverse effects. Of note, it was and still is crucial to gather historical information about how a patient has responded to trials of medications that are similar to the medication that is being considered as well as how close relatives of the patient have responded to specific medications. Since psychiatric conditions are influenced by genetics and tend to occur or “run” in families, it is imperative to gather this type of historical information.
Pharmacogenomic testing not only yields important data about drug metabolizing enzymes, but other enzymes crucial to metabolic processes that impact our biochemistry. It has long been stressed that diet plays an important role in our mental and physical well being. Advances over recent years in the disciplines of biochemistry, physiology, genetics and medicine have helped elucidate the reasons that this appears to be true. One such example of this involves an important metabolic process known as methylation. In order for our bodies to make use of many of the vitamins we ingest via diet and supplementation, the process of adding a chemical group called “methyl” is required. Methylation essentially turns a vitamin into a co-enzyme capable of increasing the rate of a chemical reaction. These co-enzymes are required for the efficient production of virtually all neurotransmitters. Certain alleles of a gene called MTHFR, which are quite common, impair the body's ability to carry out the process of methylation. When integrated into the full clinical picture, this type of data helps to identify DNA based metabolic issues that may directly contribute to the expression of symptoms related to various psychiatric conditions and more precisely prescribe medications, supplements, dietary and lifestyle changes that effectively address symptoms in a more targeted way. So, if a client has one of these MTHFR mutations, it is possible to bypass the relative lack of methylation ability by supplementing with vitamins that are already methylated. The simple intervention of consuming a co-enzyme via supplementation can have broad positive impacts on a number of psychiatric and medical conditions. In psychiatry, where much of the clinical information is subjectively based on historical recollection and self-report as opposed to objective data (for example, an x-ray showing a broken bone), finding the right interventions can be time consuming and quite frustrating for patients who routinely undergo multiple trials of medications that are either ineffective, only partially effective and/or have untoward side effects before finding one or more that works. DNA data can be an effective tool that may now be integrated into clinical medical decision making. We are currently developing and refining an approach to this called psychiatric genetic analysis (PGA).
What is psychiatric genetic analysis (PGA)?
Personal genotyping vs whole genome sequencing vs imputation:
Personal genotyping analyzes approximately 0.02% of the entire genome. This sounds like a very small amount, but recall that human DNA is composed of approximately 20,000 genes which code for proteins accounting for approximately 1% of the entire genome. Whole genome sequencing, as the name implies, more fully analyzes the genome to various degrees of depth. The drawbacks of whole genome sequencing are cost (approximately $300 - $900 versus personal genotyping at approximately $100) and having a much larger file size (up to 200 Gb vs approximately 20 Mb). Imputation is a process that uses computer algorithms to guess the genotype will be at a particular location based on available data from personal genotype data with a pre-specified degree of certainty (usually 80%). This process which costs about $10 amplifies data yielding a file size of approximately 1 GB. In my experience, when analyzing data from personal genotyping non-reported or missing data at specific loci occurred quite frequently (perhaps 40% of the time) while using imputed data reduced this to approximately 10% or less. Imputation, is essentially a hedge between cost and data size.
Identification of Candidate Alleles:
We have identified genetic variants (alleles) that influence drug response, gene protein transcription level, gene protein product activity and disease susceptibility to neuropsychiatric conditions using evidence from the published literature organized by neurotransmitter system starting with serotonin, arguably one of the most pivotal. These genes have been further classified based on their function: enzymes (TPH, i.e. tryptophan hydroxylases), transporters (mainly SLC6A4, i.e. solute carrier family) and receptor sites (HTRs, i.e. hydroxytryptamine receptors). Due to considerable heterogeneity in the literature with respect to the association in various populations and disease subgroups, we have grouped evidence into several different categories:
- Associated variant reported by meta-analysis or reported as associated by three independent studies
- Associated variant with a known functional effect
- Association of variants in linkage with the same variant by at least two other reports
- Association of the variant detected in multiple neuropsychiatric conditions
- Consistency in the direction of the reported allele in several studies
- Role of the variant in disease susceptibility or drug response
Implementing Genotypic Data from Candidate Alleles into Clinical Practice:
The ultimate goal of PGA is to help guide treatment recommendations by integrating genetic information into a circumspect psychiatric intake process and formulation. Biochemical interventions [pharmaceuticals, essential nutrients, dietary supplements, other interventions that influence biochemistry (transcranial magnetic relation, electroconvulsive therapy, bright light therapy, for example) and lifestyle changes] used in PGA are designed to augment the functioning of neurometabolism via these specific mechanisms:
- augmenting the transcription of specific genes
- interacting directly with receptor sites or ion/neurotransmitter channels
- augmenting the activity of enzymes associated with neurotransmitter metabolism
- augmenting the storage or release of neurotransmitters
- exerting an undefined influence on one or more neurotransmitter systems
When treating a client with a psychiatric condition or symptom, there are multiple reasonable interventions a physician might consider. While the information derived from PGA when considered in isolation from a comprehensive psychiatric examination can still prove to be applicable, when incorporated into a full intake, it can become a highly effective tool in prescribing. For example, by understanding differential diagnosis, family history and interventions that have been tried in the past, PGA can help explain this data mechanistically and direct prescribers to interventions that are more likely to be targeted and effective. It is commonplace for a client with depression or anxiety to be prescribed one of the SSRI medications which block the reuptake channel encoded by the gene SERT. Blocking this channel increases the level of serotonin in the synapse. This would be like building a dam to retain water in an area affected by drought. In many cases, this is an effective intervention whose use could be supported by data from PGA. For example, if the client had alleles associated with greater SERT activity, they would tend to have less serotonin in their synapes. In this case, an SSRI would directly address this issue. However, if a client with depression had alleles associated with normal or decreased functioning of the SERT gene in conjunction with alleles associated with reduced functioning of the enzymes required to make serotonin, treating with an SSRI could still be effective, but would not be directly addressing the issue. In this scenario, having an under active TPH2 gene, which codes for the rate limiting enzyme that synthesizes serotonin from the amino acid tryptophan could be a preferred target. Interventions that upregulate the expression of TPH2, improve enzymatic function or bypass the bottleneck in metabolism (tricyclic antidepressants, methylfolate and 5-HTP, respectively) could be better choices addressing a metabolic issue upstream of the serotonin reuptake channel. One of these interventions would be like increasing the amount of water that is flowing towards the drought stricken area. This could then eliminate the need to build a dam (use an SSRI) or allow for a smaller dam (reduce the dose). This is not to imply that in all or even most cases, following the allelic evidence would be the fastest or safest route to symptom alleviation. However, for some clients this application has yielded impressive results. Additionally, it is commonplace that some treatments that would otherwise have been further down the decision tree are prioritized and their application earlier in the course of treatment reduces the duration and intensity of symptoms.
There is a complementary relationship between PGA and NBP (Nutrient Based Psychiatry). PGA is an additional source of objective biological data akin to labs designed to expand upon and identify interventions that would be considered within the NBP approach to treatment. NBP allows for the consideration of nutrients as evidence based interventions targeting genetically influenced metabolic issues identified by PGA.
There are numerous examples of interventional guidance based on NBP and PGA that have been making their way into client care. Soon we will release a sample PGA report on serotonin to further illustrate the utility of this method. In order to increase the accessibility of PGA, we are developing a computer based application for medical professionals and clients. Initially, the analysis will focus on the serotonergic system. Later, other systems including GABA, dopamine, norepinephrine, cannabinoid, opioid, glutamate, glycine, adenosine, melatonin, oxytocin, inflammatory, immunomodulatory, endocrine, etc will be analyzed. Advancements in this method will provide important data to help implement more effective treatment strategies for those with psychiatric conditions.
We welcome any feedback, commentary and ideas for collaboration.
Emanuel Frank, MD and Sandeep Grover, PhD