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Saturday, October 13, 2007

Treatment Resistant Depression and Genes

A lot of exciting new developments are taken place with treatment resistant depression. A lot of candidate genes are under study to clarify an individual vulnerable to non response to antidepressants. Since most antidepressants exert their effect through functional modification of monoamine neurotransmitters a lot of genetic research has focused on processes accompanying neurotransmission.

Dr Shock's opinion is that we will not find a gene for treatment resistant depression (TRD) as we we will not find a gene for depression. Both terms are to complex, but we will be able to discover genes contributing to TRD. TRD can result from pharmacokinetic factors as well as farmacodynamic factors. Research can unravel different genes for different mechanism for TRD

Dr Francisco Moreno has written an introduction about the role of gene factors in TRD on PsychiatricTimes

The following gene polymorphismen were analyzed with showing a difference between depressed patients responding to antidepressants and those not responding:
1. Serotonin transporter genes (5-HTTLPR and intron (STin2))
2. Norepinephrine transporter gene (NET)

Why did this not lead to genetic testing to predict TRD?
1. Conflicting results for the various racial groups, research from Asia differed from that in Europe for these genes.
2. Other pharmacodynamically related genes (e.g. circadian systems, immunological systems, neurotrophic factors)also showed significant differences but subsequent inconsistent replications have been reported.

Patients with a TRD had a larger number of risk genotypes than treatment responders, who in turn had a greater number of risk genotypes than the healthy controls. This finding supports a model in which the additive small effects of multile risk genes explain depression and treatment resistance

Beside this overview of the research on genes and TRD he suggests the following 4 principles when confronted with TRD:

1. Diagnosis. Establishing an accurate diagnosis is essential, identifying co morbidity and specific features that might predict a specific response can facilitate treatment. In the future hopefully selection of treatment can be based on genetic predictors of efficacy, safety and tolerability.

2. Dosage. What dosage will ensure the greatest likelihood of response. Genotyping of drug-metabolizing genes can help. Pharmacokinetic factors are of importance in antidepressant treatment. Genotyping of metabolizing enzymes are available and more accessible to clinicians.

3. Duration. Take time for the antidepressant to become fully operative. Don't switch every now and then.

4. Drug. What has helped before or a relative with depression, what has been tried, were prior treatments optimal.

Dr Shock enjoyed this article. He recognizes these aspects of the treatment of TRD. On his unit these principles are implemented as follows:

1. Drug free observation on inpatient depression unit for diagnoses.

2. Treatment with tricyclic antidepressants with weekly plasma level control for adequate dosing

3. Average inpatient stay of 40 days

4. Clear extensive treatment algorithm for depression

Related article on this blog:
9 steps for treatment resistant depression

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