Patient-Doctor Interaction: one of the hallmarks of clinical medicine

· TGI - Biomarkers, TGI - Health

A rotating animation of the human brain showin...

A rotating animation of the human brain showing the left frontal lobe in red within a semitransparent skull. The anterior cingulate cortex (ACC) is sometimes also included in the frontal lobe. Other authors include the ACC as a part of limbic lobe. (Photo credit: Wikipedia)

Placebo treatments have been shown to lead to clinical improvement in a broad spectrum of disorders. Although advances have been made in understanding the neurobiology of placebo, here the authors of this work made efforts:

– to demonstrate genetic modulation of true placebo effects

– to demonstrate a relationship between different levels of placebo treatment and COMT genotype.

{ COMT is  a catechol-O-methyltransferase: The O in the name stands for oxygen. COMT is one of several enzymes that degrade catecholamines such as dopamineepinephrine, and norepinephrine. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene. As the regulation of catecholamines is impaired in a number of medical conditions, several pharmaceutical drugs target COMT to alter its activity and therefore the availability of catecholamines}

{ The COMT protein is coded by the gene COMT. The gene is associated with allelic variants. The best-studied is Val158Met. Others are rs737865 andrs165599 that have been studied, e.g., for association with personality traits.}

{ A functional single-nucleotide polymorphism (a common normal variant) of the gene for catechol-O-methyltransferase results in a valine to methionine mutation at position 158 (Val158Met) rs4680. The Val variant catabolizes dopamine at up to four times the rate of its methionine counterpart, however the Met variant is less expressed in the brain, resulting in a 40% decrease in functional enzyme activity. The lower rates of catabolisis for the Met allele results in higher synaptic dopamine levels following neurotransmitter release, ultimately increasing dopaminergic stimulation of the post-synaptic neuron.

COMT has been implicated in multiple disorders i.e. major depressive disorder, Parkinson’s and pain, might be deemed as a weakness in its candidacy for a placebo response marker. However the authors in the current study argue that its wide association with disease and drug treatments might be why it is such a powerful potential target for modulating placebo effects.

Given the preferential role of COMT – in prefrontal dopamine degradation – the Val158Met polymorphism is thought to exert its effects

– on cognition by modulating dopamine signaling in the frontal lobes.(cognitive tasks broadly related to executive function, such as set shifting, response inhibition, abstract thought, and the acquisition of rules or task structure). Biol. Psychiatry 58 (11): 901–7.doi:10.1016/j.biopsych.2005.05.010PMID 16043133.

– on emotional processing, as they seem to influence the interaction between prefrontal and limbic regions. Research conducted at the Section of Neurobiology of Psychosis, Institute of Psychiatry, King’s College London has demonstrated an effect of COMT both in patients with bipolar disorder and in their relatives. Psychol Med 41 (4): 779–88.doi:10.1017/S0033291710001431PMID 20667170.

– has a pleiotropic effect on emotional processing.

Psychol Med 41 (4): 1–10. doi:10.1017/S0033291710001431PMID 20667170. and Int. J. Neuropsychopharmacol. 12 (3): 371–81.doi:10.1017/S1461145708009395PMID 18796186.

The polymorphism has been shown to affect ratings of subjective well-being. When women were measured with experience sample monitoring, which is similar to mood assessment as response to beeping watch, the met/met form confers double the subjective mental sensation of well-being from a wide variety of daily events. The ability to experience reward increased with the number of ‘Met’ alleles. Also, the effect of different genotype was greater for events that were felt as more pleasant. The effect size of genotypic moderation was quite large: Subjects with the val/val genotype generated almost similar amounts of subjective well-being from a ‘very pleasant event’ as met/met subjects did from a ‘bit pleasant event’. Genetic variation with functional impact on cortical dopamine tone has a strong influence on reward experience in the flow of daily life. Persons with the met/met phenotype describe events as very pleasant or pleasant with twice the numeric amplitude of those absent the met/met genetic polymorphism. Neuropsychopharmacology 33 (13): 3030–6. doi:10.1038/sj.npp.1301520PMID 17687265.}

The present study suggests the hypothesis that the COMT val158met polymorphism is a potential genetic marker of placebo response.

Also that IBS (Irritable Bowel Syndrome) patients

– homozygous for the COMT val158met methionine allele (met/met) were the most responsive to placebo treatment.

– heterozygous (val/met) patients showed an intermediate response, and

– homozygous valine (val/val) patients showed essentially no placebo mediated symptom improvement.

The article says that “Indeed several studies that examine the effect of amphetamine or tolcapone relative to a placebo treatment have observed that met/met subjects tend to be unresponsive or worsen relative to placebo response when treated with these drugs, suggesting there is an optimum level of dopamine associated with placebo effect. Identifying biological characteristics of placebo responders and non-responders could be key to managing underlying placebogenic factors to benefit patients by delivering personalized medicine, for example by adjusting the dose of medication in accordance to the subject’s placebo susceptibility or selecting a different class of drugs for the individualized patient.”

The placebo treatment is especially thought to influence the experience and perception of subjective symptoms such as depressed mood and pain, rather than directly modifying disease pathophysiology.

The power of the patient-doctor interaction to enhance healing is one of the hallmarks of clinical medicine, and increasingly resources are devoted to teaching clinicians how to communicate warmth and caring to their patients (Annals of internal medicine 114: 482–489.; Family medicine 43: 99–105).

The findings reinforce this healing benefit for met/met patients and raise an interesting question. Despite their best efforts, many a warm and caring physician has had patients that seemed to derive minimum benefit from their empathic attentions.

val/val patients are less influenced by the placebo treatment, regardless of whether it is delivered in an augmented or limited context, potentially shed some light on this clinical challenge.

Role models (senior doctors) who transparently shared their personal experiences of doctoring were more effective in helping students learn relationship skills that in turn benefit the patients (e.g., met/met patients). (Family medicine 43: 99–105).



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