How the COMT Gene Impacts Mental Health Treatment

What does the COMT enzyme do?

COMT (catechol-O-methyltransferase) is a central enzyme that breaks down catecholamines including dopamine, norepinephrine, and epinephrine.

COMT plays a vital role in regulating dopamine signaling in the prefrontal cortex where dopamine transporters are relatively sparse.¹ Dopamine levels here are critical for memory, attention, judgment, and other executive functions.^2,3

COMT gene mutations and dopamine

Val158met (rs4680) is a common single nucleotide polymorphism in the COMT gene which results in a change of one amino acid in the protein from a valine (Val) to a methionine (Met). The met allele is associated with approximately 40% lower enzymatic activity, leading to increased dopamine activity. Interestingly:

• The heterozygous genotype (Val/Met) is considered as the normal level of dopamine degradation or clinically non-actionable.
• Individuals with the Val/Val genotype display elevated COMT enzyme activity and thus reduced dopamine levels.
• Individuals with the Met/Met genotype have reduced COMT enzyme activity and thus elevated dopamine levels. ^1,4-7

What is the clinical significance of COMT gene mutations?

Clinical studies have shown that the COMT Val/Val genotype may have behavioral consequences regarding cognitive function, memory, attention, motivation and judgment.^7,8

In Val/Val (high-activity) patients, dopaminergic agents have been shown to improve executive function and working memory to a greater degree in both animal and human studies. However, these agents may produce a deleterious effect on cognition in Met/Met (low-activity) patients. Another class of drugs known as COMT inhibitors have also been shown to produce this biphasic effect on cognition in Val/Val versus Met/Met individuals.^9-13

COMT and schizophrenia

Recent clinical studies investigating the effects of antipsychotic medications on cognitive function in schizophrenia and bipolar disorder found that patients with the Met/Met genotype had improved scores on measures of executive function (as well as positive symptoms of schizophrenia) when compared with their Val/Met and Val/Val counterparts.^14-20

COMT and depression treatment

Alternative antidepressant therapeutic strategies include electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS), which may be modulated by COMT genotype.

Studies have shown an association with COMT Val/Val genotype with greater sensitivity to ECT and improvements in depressive scores.²¹ There is also evidence COMT genotype may differentially impact executive function in tDCS therapy.^22-24 TMS, similar to other neurostimulation techniques, has been shown to increase dopamine in the prefrontal cortex,^25-30 but data evaluating the effect of COMT on TMS response has been limited.

COMT pharmacogenomics

Genomind’s pharmacogenetic testing focuses on COMT as it relates to dopamine in the prefrontal cortex (PFC) because there is a relative lack of dopamine transporter proteins in the PFC. The activity of these transporters can be up or down-regulated to balance the activity of enzymes. The relative lack of dopamine transporters in the PFC means that dopamine levels in the PFC are largely determined by activity of the COMT enzyme.

If clinically indicated, patients that display the COMT Val/Val genotype may benefit from agents that increase synaptic dopamine. For example, Val/Val patients showed improved cognition in response to amphetamine while Met/Met patients did not.¹⁰

Met/Met patients have higher than average dopamine levels, and a number of studies indicate that those patients tend to have superior executive function skills as compared to Val/Met and Val/Val patients.⁷ Met/Met patients may show impairments in cognition in response to dopamine agonists, since synaptic dopamine is already elevated at baseline.

COMT case study

Genomid has collected several case studies that support the clinical utility of the COMT Val158Met genotype. One example is a 15-yr old male patient with a long history of medication failures. The patient presented chronic progressive depression, amotivation and suicidal thinking. Genetic testing revealed that the patient was Val/Val for the COMT enzyme. Thus, his amotivation and fatigue may have been related to reduced dopamine levels. He was started on dextroamphetamine/amphetamine (e.g., Adderall) to increase synaptic dopamine levels. His symptoms greatly improved, and he demonstrated increased motivation and energy, the ability to engage in extracurricular activities, and cessation of suicidal thinking.

This case is just one example of how COMT genotype results can provide key information to aid in the treatment of your patients.

Learn about the other genes included on the Genomind pharmacogenetic panel, and register to order today.

References

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