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Selective Reuptake Inhibitor Therapy Moving Toward Genetically Based Biopharmacotherapy

 

Most of us have heard of or even taken an SRI drug for a psychiatric diagnosis.  Among dozens of others, common names include Prozac, Effexor, Fetzima, Savella, Remeron, Zoloft, Celexa and Lexapro.

As more research surfaces, some surprising developments have directed the course of prescribing for unipolar depression.  The newest drugs offered are extremely selective in their action and have a higher rate of remission than many precursor medications.

In a simplified view, the neurotransmitters implicated in depression the most are serotonin (5HT), dopamine, (D) and norepinephrine, (NE).  These chemicals are released into the gaps between brain cells (synapses) and bind to neurotransmitter sites on receptors.  There are many different types for each monoamine neurotransmitter, and newer drugs are targeting very specific sites on receptors.  A monoamine is a chemical synthesized in the body that serves a specific purpose.  There are relatively few, and they get their name because they are an amine molecule (terminating in or containing NH2).

Transport proteins are responsible for moving the monoamines from the synaptic cleft, or gap and into the receptor site.  Enzymes known as monoamine oxidases then eventually metabolize and inactivate the monoamine-turned-neurotransmitter, after which it and its byproducts are removed by the liver and kidneys.

Each neurotransmitter is transported by its own protein, known for our purposes as the serotonin, dopamine active and norepinephrine transporters, SERT, DAT and NET.

It's now believed that depression is frequently caused by a phenotypical overexpression of receptor sites, implicated greatly in genetics, and the action of the Selective Reuptake Inhibitor drugs cause downregulation (removal and inactivation) of extra sites so that receptors as a group are more fully occupied with neurotransmitters by percentage.  The cycle of culling old receptor sites and growing new brain cells (neuroplasticity) takes about four to six weeks.  This downregulation of sites is also responsible for discontinuation syndromes when an SRI is stopped too quickly.

By binding to the transporter proteins, these drugs slow the rate at which serotonin, dopamine and norepinephrine are inactivated and taken up by monoamine oxidases, increasing the total availability and lengthening the time they are bound to their receptor sites, hence the name 'reuptake inhibitor'.  

The newest drugs, levomilnacipran, escitalopram, venlafaxine and the older fluoxetine, sertraline and clomipramine all have very high affinities only for the SERT and NET transporters.  Older drugs are generally not nearly as selective.

The earliest drugs, the monoamine oxidase inhibitors, or MAOIs still are among the most effective drugs for depression, but monoamine oxidase has many more roles in the central nervous system, resulting in a very high number of common and dangerous side effects when these drugs inhibit the release of MAO.  They are considered a last-line drug treatment.

The second generation of antidepressants, the tricyclics and tetracyclics were derived from accidental discoveries that early antihistamines had appreciable antidepressant properties.  It was common for patients to report depressed mood after discontinuing drugs like diphenhydramine, chlorpheniramine, brompheniramine and doxylamine.  These second generation drugs remain effective but have many side effects that are problematic but not dangerous, like dry mouth, tiredness, urinary retention, hypotension and anxiety.  It's worth noting that the over-the-counter antihistamine brompheniramine lead to the first SSRI created, zimelidine whose success was soon overshadowed by a blockbuster analog called Prozac (fluoxetine).  Fluoxetine's unmatched success and eye-popping sales numbers were a complete sea change for the pharmaceutical industry.

 

As the specificity of newly approved drugs continues to increase, side effect profiles become a shadow of what they once were.  New discoveries that will likely guide pharmacology into a scientific merger with genetically based biopharmaceuticals are discoveries of genetic markers (genotypes) that predict depression and by cross-referencing with a database containing which treatments worked for which DNA samples, a custom-tailored drug could eventually be created for each patient.  Oncology currently is building and using such a database to better dictate treatment for cancer, and is seeing significant advantages to using this method. 

Patient-specific biopharmaceuticals are essentially the ultimate goal in psychiatry,  but this idealism is darkened by the cost of these drugs.  The newest typical SRI, levomilnacipran costs over $1000US for a thirty day supply.  Monoclonal and familial antibody shots for immunotherapy and chemotherapy are often in excess of $3000US each.  Without reforms in pharmaceuticals and insurance benefits these new gene-based therapies may be well out of reach for all except the wealthiest. 

This writer is of the opinion that the total in lost work-hours due to mental illness well justifies lower costs and more inclusive insurance plans.