מידע לרופאים ואנשי מקצוע
COMT
Catechol-O-Methyltransferase
קבוצה: גנים פרמקודינמיים
תפקיד
פזיולוגי: אנזים אחראי בעיקר
לפירוק הדופמין באונות
הקדמיות של המוח
גנוטיפים: Val / Val פירוק יתר של דופמין
Val / Met פירוק דופמין תקין
Met / Met הפחתה בפירוק דופמין
תרופות: אנטי פסיכוטיות, תרופות דופמינרגיות, COMT inhibitors, ECT, TMS, אופיאטים
קליניקה: תפקודים אקזקוטיביים, מצב רוח
דירוג רמת הראיות LOE: 2B
COMT הוא אנזים האחראי על פירוק הדופמין באונות הקדמיות של המוח. רמות הדופמין כאן הן קריטיות לזיכרון, לתשומת לב, לכושר שיפוט ולתפקודי ביצוע אחרים.98,99 שינוי
של חומצת אמינו ולין (Val) למתיונין (Met) מביאה להפחתת יכולתו של האנזים לפרק דופמין, מה שמביא להגברת פעילות הדופמין.100
גנוטיפ Val / Met מאפיין מטופלים עם רמות תקינות של פירוק דופמין, שכן יש להם אלל אחד לתפקוד מוגבר ואחד למופחת (Val / Met). 100-103
גנוטיפ Val / Val מטופלים עם גנוטיפ זה מציגים פעילות אנזימטית מוגברת וכפועל יוצא מכך פירוק מוגבר של דופמין. 100-103 לקיומו של גנוטיפ זה עלולות להיות השלכות התנהגויות בכל הנוגע לתפקודים קוגניטיביים, זיכרון, תשומת לב, מוטיבציה וכושר שיפוט.103, 104 בקרב מטופלים אלו הוכח במחקרים אנימליים והומאניים, כי תכשירים דופמינרגיים
משפרים את תפקוד הביצוע ואת זיכרון העבודה. בנוסף, הוכח כי COMT inhibitors מייצרות השפעה דו-שלבית זו על הקוגניציה בגנוטיפ זה, ועשויות להיות שימושיות מבחינה קלינית, בחולים עם ליקוי של התפקוד הביצועי.109-116
בנוסף להשפעות של ממריצים דופמינרגיים ואנטי פסיכוטיים, לגנוטיפ של ה-COMT יש השפעות על הרגישות לאופיואידים. מטופלים עם גנוטיפ Val / Val זקוקים
למינונים גבוהים יותר לשיכוך כאבים123
אסטרטגיות טיפוליות נוגדות דיכאון אלטרנטיביות כללו טיפול אלקטרו-קונבולסיבי (ECT) וגירוי מגנטי תוך גולגולתי (TMS) לחולי Val / Val. מחקרים קישרו את הגנוטיפ הזה לרגישות רבה יותר ל-ECT ולשיפור ציוני הדיכאון.124,125 בהתבסס על מחקרים אלה, ההערכה היא כי ECT או TMS עשויים להיות אסטרטגיה אפקטיבית בחולים אלו, באמצעות גירוי לשחרור הדופמין. הפעילות המוגברת של הגנוטיפ Val / Val יכולה לגרום למצב היפו-דופמינרגי. מחקרים בחולדות הראו כי TMS יכול להגביר את זרימת הדופמין בהשוואה לגירוי דמה.126 בנוסף, מחקרים בבני אדם הוכיחו כי TMS יכול להועיל לחולים הסובלים מדיכאון, על ידי העלאת רמות הדופמין בקליפת המוח הקדם חזיתית.127-131
גנוטיפ Met / Met מאפיין מטופלים עם הפחתה של פעילות האנזים ולפיכך הפחתה בפירוק דופמין. 100-103 תכשירים דופמינרגיים עלולים לייצר השפעה מזיקה על הקוגניציה בחולים אלו.105-108 חקרים קליניים אחרונים שבדקו את ההשפעות של תרופות אנטי-פסיכוטיות על תפקוד קוגניטיבי בסכיזופרניה והפרעה דו-קוטבית מצאו כי חולים עם גנוטיפ זה שיפרו ציונים במדידת תפקודי ביצוע, כמו גם הפחתה בתסמינים החיוביים בסכיזופרניה.117-122 בנוסף להשפעות של ממריצים דופמינרגיים ואנטי פסיכוטיים, לגנוטיפ של ה-COMT יש השפעות על הרגישות לאופיואידים. מטופלים עם גנוטיפ Met / Met יכולים להסתפק במינונים נמוכים יותר לשיכוך כאבים.123
ג'נומיינד (Genomind) היא הבדיקה הפרמקוגנטית (PGx) המתקדמת ביותר בפסיכיאטריה. היא בודקת 24 גנים, הקשורים לפירוק תרופות. קבלת תשובת הבדיקה בתוך 10 ימים מנטילת דגימת הרוק, בצורת דו"ח מעמיק ונוח לקריאה. הדו"ח מכיל מידע פרמקוגנטי על יותר מ-130 תכשירים פסיכיאטריים, והתאמתם הגנטית לנבדק. מחקרים שנערכו על הבדיקה הוכיחו את יתרונותיה בקיצור הזמן להשגת אפקט טיפולי ושיפור הההיענות לטיפול.
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Effect of COMT val158met genotype on memory, attention, judgment and other executive functions.
http://www.ncbi.nlm.nih.gov/pubmed/26255563 [101]
http://www.ncbi.nlm.nih.gov/pubmed/20631684 [102]
http://www.ncbi.nlm.nih.gov/pubmed/18755576 [100]
“The gene encoding catechol-O-methyltransferase (COMT), an enzyme which regulates prefrontal cortex dopamine, contains a common functional single nucleotide polymorphism (val158met, rs4680G/A), which accounts for part of the interindividual variance in performance during working memory tasks and also predicts personality traits. We examined the relationship between the val158met
polymorphism and cognitive function as well as personality traits in 522 healthy individuals (mean age: 24.75 years, SD=5.84, mean years of education: 15.59, SD=2.65). COMT val158met genotype was
related in allele dosage fashion to performance in an executive function test, with the Met/Met carriers scoring highest.” [100]
http://www.ncbi.nlm.nih.gov/pubmed/17325717 [103]
“The catechol-O-methyltransferase (COMT) Val (158) Met polymorphism is hypothesized to affect executive function in patient and control populations. Twelve studies met inclusion criteria (total n=1910)
providing 10 samples each of patients and controls. In healthy controls, individuals with the Met/Met genotype performed better than those with the Val/Val genotype (d=0.29; 95% confidence interval (CI)
0.02-0.55; P=0.03).” [103]
http://www.ncbi.nlm.nih.gov/pubmed/26999687 [104]
has been associated with white-matter (WM) abnormalities and degenerative changes of cortical myelin in the cerebral cortex. Furthermore, findings suggested a role of the COMT gene in affecting both WM
and neuropsychological performances. We thus hypothesized that the COMT Val/ Met genotype would affect the association between cognitive functions and WM microstructure in a sample of schizophrenic
patients….Analysis indicated an association between cognitive functions and WM microstructure in the Val/Val group, but not in the Met carriers group. WM tracts include the corpus callosum, thalamic
radiations, corona radiata, forceps major and minor, superior and inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, corticospinal tract, and cingulum.” [104]
Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine.
http://www.ncbi.nlm.nih.gov/pubmed/20414144 [105]
“The results of this study extend earlier findings with the COMT genotypes to additional measures of cognition, and suggest that the presence of the Val allele is associated with poorer performance and
greater improvement with a stimulant drug.” [105]
COMT val158met moderation of dopaminergic drug effects on cognitive function: a critical review.
http://www.ncbi.nlm.nih.gov/pubmed/27241058 [106]
“The relationship between dopamine (DA) tone in the prefrontal cortex (PFC) and PFC-dependent cognitive functions (for example, working memory, selective attention, executive function) may be
described by an inverted-U-shaped function, in which both excessively high and low DA is associated with impairment. In the PFC, the COMT val158met single nucleotide polymorphism (rs4680) confers
differences in catechol-O-methyltransferase (COMT) efficacy and DA tone, and individuals homozygous for the Val allele display significantly reduced cortical DA. Many studies have investigated whether
val158met genotype moderates the effects of dopaminergic drugs on PFC-dependent cognitive functions. A review of 25 such studies suggests evidence for this pharmacogenetic effect is mixed for
stimulants and COMT inhibitors, which have greater effects on D1 receptors, and strong for antipsychotics, which have greater effects on D2 receptors. Overall, COMT val158met genotype
represents an enticing target for identifying individuals who are more likely to respond positively to dopaminergic drugs.” [106]
COMT val158met impact on methylphenidate response
https://www.ncbi.nlm.nih.gov/pubmed/29230023 [28]
Pooled-data revealed a statistically significant association between single nucleotide polymorphisms (SNPs) rs1800544 ADRA2A (odds ratio: 1.69; confidence interval: 1.12–2.55), rs4680 COMT (odds
ratio (OR): 1.40; confidence interval: 1.04–1.87), rs5569 SLC6A2 (odds ratio: 1.73; confidence interval: 1.26–2.37) and rs28386840 SLC6A2 (odds ratio: 2.93; confidence interval: 1.76–4.90), and, repeat
variants variable number tandem repeat (VNTR) 4 DRD4 (odds ratio: 1.66; confidence interval: 1.16–2.37) and VNTR 10 SLC6A3 (odds ratio: 0.74; confidence interval: 0.60–0.90). [28]
COMT Val66Met determines the direction of cognitive effects produced by COMT inhibition.
http://www.ncbi.nlm.nih.gov/pubmed/17063156 [110]
“We found significant drug effects on measures of executive function and verbal episodic memory…individuals with Val/Val genotypes improved, whereas individuals with Met/Met genotypes
worsened on tolcapone.” [110]
https://www.ncbi.nlm.nih.gov/pubmed/18536698 [113]
“Recent evidence suggests that prepulse inhibition (PPI) levels relate to executive function possibly by a prefrontal cortex (PFC) dopamine (DA) link. We explored the effects of enhanced PFC DA signaling by the nonstimulant catechol-O-methyltransferase (COMT) inhibitor tolcapone, on PPI and workingmemory of subjects homozygous for the Val (low PFC DA) and the Met (high PFC DA) alleles of the
COMT Val158Met polymorphism…These results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFC DA levels
according to an inverted U-shaped curve function.” [113]
https://www.ncbi.nlm.nih.gov/pubmed/22364739 [114]
“Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val (158) Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic
phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling
and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype…Depending on genotype, COMT inhibition can enhance or impair working memory and
increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders.” [114]
https://www.ncbi.nlm.nih.gov/pubmed/21521027 [116]
“It is widely accepted that abnormal prefrontal cortex biology resulting in deficient cognition is a primary problem in schizophrenia and that all currently available antipsychotics fail to improve cognitive and
negative symptoms originating from this deficit. Evidence from basic science has revealed the importance of prefrontal dopamine signaling for optimal prefrontal function. This article describes
succinctly the progress made so far, taking into account the mechanisms involved in catechol-Omethyltransferase (COMT)-induced modulation of prefrontal dopamine signaling, the impact of COMT
on cognitive function and the role of COMT gene polymorphisms. The potential role of the COMT inhibitor tolcapone to improve cognitive function in health and disease is also presented here. It will
soon be understood if tolcapone represents one of the first hypothesis-driven, biology-based, genotypespecific, targeted treatments of cognitive and negative symptoms of schizophrenia.” [116]
COMT Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis.
http://www.ncbi.nlm.nih.gov/pubmed/26745992 [117]
“Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (total=1416). Met/Met
individuals were significantly more likely to respond than Val-carriers (P=.039, OR Met/Met=1.37, 95% CI: 1.02-1.85). Met/Met patients also experienced significantly greater improvement in positive
symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024-0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly
more likely to respond relative to Val-carriers (P=.0098, OR Met/Met=1.54, 95% CI: 1.11-2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65).” [117]
[COMT genetic variation and clinical response to antipsychotic drug treatment: A Meta-analysis].
https://www.ncbi.nlm.nih.gov/pubmed/26164511 [118]
Nine studies included 868 participants who met inclusion criteria. Significant association was found between the COMT Val108/158Met gene polymorphism and antipsychotic drug efficacy. Evaluating the
therapeutic efficacy through general symptoms: Met vs Val, RR=1.18, 95% CI: 1.04-1.35, P=0.013; Met/Met vs Val/Val, RR=1.40, 95% CI: 1.08-1.82, P=0.010. Evaluating the therapeutic efficacy through
negative symptoms: Met vs Val, RR=1.24, 95% CI: 1.05-1.46, P=0.013; Met/Met vs Val/Val, RR=1.60, 95% CI: 1.04-2.46, P=0.031.COMT Val108/158Met gene polymorphism is significantly associated with
antipsychotic drug efficacy, and Met gene is a dominant gene which displays a better response to antipsychotic drugs. [118]
COMT (Val(158/108) Met) genotype moderates the impact of antipsychotic medication on verbal IQ in twins with schizophrenia.
https://www.ncbi.nlm.nih.gov/pubmed/21233783 [119]
“In this study, we aimed to assess the moderating effects of the catechol-O-methyl transferase (COMT) (Val (158/108) Met) genotype on antipsychotic medication-induced changes in the cognitive
performance of patients with chronic schizophrenia. The sample consisted of 85 monozygotic and 53ability was measured using the Wechsler Adult Intelligence Scale-third edition. We used structural
equation modelling to estimate main and interaction effects of the COMT status and antipsychotic medication dose on verbal intelligence quotient (VIQ) and performance intelligence quotient
scores…Our results show that the verbal abilities of Val homozygotes of the COMT gene are cognitively impaired by higher doses of antipsychotic medication. This association is reversed in Met carriers.
These data are consistent with an earlier study that found evidence of moderating effects of antipsychotic medication on N-back and verbal fluency tasks.” [119]
Antipsychotic medications and cognitive functioning in bipolar disorder: moderating effects of COMT Val108/158 Met genotype.
https://www.ncbi.nlm.nih.gov/pubmed/23421957 [120]
“There is a negative association between the use of antipsychotics and cognitive functioning in bipolar patients, which may be mediated by altered dopamine signaling in selected brain areas, and moderation thereof by genetic sequence variation such as COMT Val108/158Met. The interaction between antipsychotic drug use and the COMT Val108/158Met genotype on two-year cognitive functioning in
bipolar patients was examined…The negative effects of antipsychotics on cognitive functioning in bipolar disorder may be moderated by the COMT Val 108/158 Met genotype, with a negative effect of
Val allele load. If replicated, the results may be indicative of pharmacogenetic interactions in bipolar disorder.” [120]
COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia.
https://www.ncbi.nlm.nih.gov/pubmed/17123785 [121]
“Preliminary evidence suggests that a single nucleotide polymorphism (SNP), the val108/158met SNP, within the gene that codes for catechol-O-methyltransferase (COMT), a key enzyme involved in
regulating dopamine (DA) transmission within the prefrontal cortex (PFC), is related to cognitive function in schizophrenia and cognitive improvement with atypical antipsychotic drugs (APDs)… Consistent with several previous studies, an association between COMT genotype and tests of executive function and working memory was identified at baseline. In addition, a novel interaction between genotype and
improvement on tests of attention and verbal fluency was identified. Specifically, met homozygous and Val/ Met heterozygous patients demonstrated significantly greater improvement than Val homozygous
patients following 6 months of treatment with clozapine. The results are discussed in relation to previous cross-sectional studies and prospective investigations of the associations between COMT genotype,
cognition, and cognitive improvement with atypical APDs in schizophrenia.” [121]
Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications.
https://www.ncbi.nlm.nih.gov/pubmed/15522252 [122]
“The gene encoding catechol-O-methyltransferase (COMT), an enzyme that regulates prefrontal cortex dopamine, contains a common functional polymorphism (Val (108/158) Met) that influences prefrontal
cortex function in an allelic dose-dependent manner. A recent study reported that the COMT Val (108/158) Met polymorphism influences cognitive- and physiologic-related prefrontal cortex responses
to antipsychotic treatment. The present study tested the effects of several COMT polymorphisms on the cognitive response to antipsychotic medication in patients with schizophrenia…These results support
other data suggesting that the COMT Val (108/158) Met polymorphism might be an important factor in the cognitive response to antipsychotic medication.” [122]
Pain polymorphisms and opioids: An evidence based review.
https://www.ncbi.nlm.nih.gov/pubmed/30592275 [123]
“It has been shown that the Val158Met polymorphism, a common genetic variant in Caucasian populations, influences the activity of the COMT enzyme. This enzyme, which metabolizes dopamine,
adrenaline and noradrenaline, is an important modulator of dopaminergic and noradrenergic neurotransmission, known to play a role in pain… In human studies, COMT genotype affects the
efficacy of opioids in acute and chronic pain in different settings (e.g. migraines, fibromyalgia, musculoskeletal pain and cancer pain). Low COMT activity increases opioid receptors and enhances
opioid analgesia and adverse effects in cancer pains.”[123]
Influence of Val108/158Met COMT Gene Polymorphism on the Efficacy of Modified Electroconvulsive Therapy in Patients with Treatment Resistant Depression.
https://www.ncbi.nlm.nih.gov/pubmed/?term=25388840 [124]
“In this double-blinded control study, we tested the efficacy of modified electroconvulsive therapy (MECT) in patients with treatment resistant depression (TRD) using the Hamilton Depression Rating
Scale for Depression (HAMD). The total scores of HAMD were found to be significantly decreased after the treatment. The genotyping of catechol-O-methyltransferase (COMT) was carried out with
polymerase chain reaction-based testing. Our results demonstrated that frequency of mutant COMT alleles in TRD patients was significantly higher than that of the controls indicating a correlation of the
enzyme genotype to the occurrence of TRD. Moreover, the patients homozygous for wild-type COMT gene (G/G) were evidenced to be more sensitive to MECT treatment than those with an heterozygous
mutant genotype (A/G).”[124]
Catechol-O-methyltransferase (COMT) polymorphisms predict treatment response in electroconvulsive therapy.
https://www.ncbi.nlm.nih.gov/pubmed/17700596 [125]
“Several lines of evidence suggest that catechol-O-methyltransferase (COMT) may be associated with treatment response in depression. We conducted a study on 119 patients with treatment-refractory
depression admitted consecutively for electroconvulsive therapy (ECT). The COMT high/high genotype leads to a higher enzyme activity and thus lowers dopaminergic activity in the prefrontal cortex. In the
present sample, those homozygous to high-active allele of COMT responded significantly more frequently to ECT.” [125]
אין במידע ו/או בתכנים המופיעים במאמר משום מתן עצה רפואית, חוות דעת מקצועית, תחליף להתייעצות עם מומחה או מתן אבחנה בנוגע לטיפול במצב רפואי מסויים. לשם קבלת ייעוץ אישי יש לפנות להתייעצות עם רופא בתחום המומחיות המתאים. מבלי לגרוע מכלליות האמור, כל הסתמכות על התכנים המופיעים במאמר ופעולה על פיהם נעשים על אחריותך הבלעדית והמלאה ולא תהיה לך כל תביעה ו/או טענה ו/או דרישה כנגד כותבי ומפרסמי המאמר או מי מטעמם, בגין נזקים הנובעים משימוש במידע הכלול במאמר זה.
