|תפקיד פזיולוגי:||חלבונים המשפיעים על ספיגה או חדירה של תרופות לתאי המטרה (במוח ובמעי)|
|גנוטיפים:||rs2032583 ו- rs1045642|
|תרופות:||אופיואידים, תרופות אנטי פסיכוטיות או תרופות נוגדות דיכאון|
|קליניקה:||חשיפה מוגברת אפשרית לאופיואידים ואנטי פסיכוטיים, כמו גם ל citalopram, escitalopram, paroxetine, venlafaxine, amitriptyline, nortriptyline ו- trimipramine.|
|דירוג רמת הראיות LOE:||2B [הסבר]|
ABCB1 P-glycoprotein (P-gp), המקודד על ידי הגן ABCB1 הוא משאבת זרימה האחראית על הובלת מספר תרופות ותרכובות אקסוגניות מחוץ לתא. בהתאם לרקמה, משאבות אלו יכולות להשפיע על ספיגת התרופות (למשל, רירית המעי), התפלגות (למשל מחסום דם – מוח) והפרשה (למשל, צינוריות פרוקסימליות בכליה).  בהקשר של תרופות פסיכיאטריות, שינוים גנטים מסוימים בגן יכולים להגביר את ספיגת המעיים וחדירות המוח לתרופות מסוימות. [215-219]
שינויים גנטיים בגן זה יש מעל 120 שינויים גנטיים, אך רק קומץ הראה תוקף ניבוי כלשהו לתגובה לנוגדי דיכאון.
rs2032583 ו- rs1045642 סקירה שנערכה לאחרונה על ידי Brückl and Uhr (2016) זיהתה ששני השינויים הללו קשורים באופן עקבי יותר ליעילות קלינית או לסיכון לתופעות לוואי לכמה תרופות נוגדות דיכאון, תרופות אנטי-פסיכוטיות או אופיואידים . כמה תרופות נוגדות דיכאון נפוצות המושפעות מגן ABCB1 כוללות citalopram, escitalopram, paroxetine, venlafaxine, amitriptyline, nortriptyline ו- trimipramine . [220-223] נראה שרוב האופיואידים רגישים לחדירות מוחית מוגברת בנוכחות גרסאות מסוימות של ABCB1. [216 , 224-228].
אנטי פסיכוטיות אטיפיות כמה מהתרופות האנטי-פסיכוטיות מהדור השני שרגישות ל- p-glycoprotein נקשרו בשיעורים גבוהים יותר של תופעות לוואי בגנים אלה [220, 229-233]. נתונים אלה מצביעים על כך שגרסאות גנטיות של ABCB1, המשפיעות על ספיגת התרופות וחדירת המוח, עשויות לשחק תפקיד בתגובת המטופל לתרופות המהוות מצע של חלבון זה.
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.
215. Hodges, L.M., et al., Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics, 2011. 21(3): p. 152-61.
216. Beer, B., et al., Association of polymorphisms in pharmacogenetic candidate genes (OPRD1, GAL, ABCB1, OPRM1) with opioid dependence in European population: a case-control study. PLoS One, 2013. 8(9): p. e75359.
219. Bruckl, T.M. and M. Uhr, ABCB1 genotyping in the treatment of depression. Pharmacogenomics, 2016. 17(18): p. 2039-2069.
220. Roberts, R.L., et al., A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics J, 2002. 2(3): p. 191-6.
221. de Klerk, O.L., et al., ABCB1 gene variants influence tolerance to selective serotonin reuptake inhibitors in a large sample of Dutch cases with major depressive disorder. Pharmacogenomics J, 2013. 13(4): p. 349-53.
222. Breitenstein, B., et al., Association of ABCB1 gene variants, plasma antidepressant concentration, and treatment response: Results from a randomized clinical study. J Psychiatr Res, 2016. 73: p. 86-95.
223. Breitenstein, B., et al., ABCB1 gene variants and antidepressant treatment outcome: A meta-analysis. Am J Med Genet B Neuropsychiatr Genet, 2015. 168b(4): p. 274-83.
224. Candiotti, K., et al., Single-nucleotide polymorphism C3435T in the ABCB1 gene is associated with opioid consumption in postoperative pain. Pain Med, 2013. 14(12): p. 1977-84.
225. Gong, X.-D., et al., Gene Polymorphisms of OPRM1 A118G and ABCB1 C3435T May Influence Opioid Requirements in Chinese Patients with Cancer Pain. Asian Pacific Journal of Cancer Prevention, 2013. 14(5): p. 2937-2943.
226. Lötsch, J., et al., Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers. Pharmacogenetics and Genomics, 2009. 19(6):p. 429-436.
227. Campa, D., et al., Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther, 2008. 83(4): p. 559-66.
228. Meineke, I., et al., Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6- glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. British Journal of Clinical Pharmacology, 2002. 54(6): p. 592-603.
229. Hattori, S., et al., Associations of ABCB1 gene polymorphisms with aripiprazole-induced autonomic nervous system dysfunction in schizophrenia. Schizophr Res, 2017.
230. van der Weide, K., et al., Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population. Pharmacogenomics J, 2017. 17(5): p. 471-478.
231. Kuzman, M.R., et al., Association study of MDR1 and 5-HT2C genetic polymorphisms and antipsychotic-induced metabolic disturbances in female patients with schizophrenia. Pharmacogenomics J, 2011. 11(1): p. 35-44.
232. Kuzman, M.R., et al., The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychoticinduced weight gain in female schizophrenic patients. Psychiatry Res, 2008. 160(3): p. 308-15.
233. Vijayan, N.N., et al., Antipsychotic drug dosage and therapeutic response in schizophrenia is influenced by ABCB1 genotypes: a study from a south Indian perspective. Pharmacogenomics, 2012. 13(10): p. 1119-27.
Literature Summary: ATP Binding Cassette Subfamily B Member 1 (ABCB1)
Variants of the ABCB1 gene alter
increase absorption and brain permeability of certain drugs
“P-gp is expressed… in the plasma membrane of cells in barrier and elimination organs, where it has protective and excretory functions. It plays an important role in first-pass elimination of orally administered drugs to limit their bioavailability by effluxing drugs from the lumen-facing epithelia of the small intestine and colon, and from the bile-facing canaliculi of the liver… It restricts the permeability of drugs into ‘sanctuary’ organs from the apical or serosal side of blood-tissue barriers (e.g. blood-brain, blood-cerebral spinal fluid, blood-placenta, blood-testis barriers) … A great number of studies have been carried out to establish the role of ABCB1 genetics in various phenotypes such as P-gp expression, function, drug response, and disease susceptibility.” 
ABCA7 C3435T is associated with nortriptyline-induced postural hypotension in patients treated for major depression.
“A single nucleotide polymorphism (SNP) of ABCB1 (3435C>T) was recently correlated with expression levels and in vivo function of P-gp. We examined this SNP in patients with major depression enrolled in a randomized antidepressant treatment trial of nortriptyline and fluoxetine, and observed a significant association
between nortriptyline-induced postural hypotension and 3435C>T (chi(2) = 6.78, df = 2, P = 0.034). Our results suggest that homozygosity for 3435T alleles of ABCB1 is a risk factor for occurrence of nortriptyline-induced postural hypotension (OR = 1.37, P = 0.042, 95% CI 1.01-1.86).”
ABCB1 rs2032583 influences response to SSRIs.
“In this meta-analysis, we systematically summarized 16 pharmacogenetic studies focused on the association of ABCB1 variants and antidepressant treatment outcome in patients with MD (overall n = 2695). We investigated the association of treatment outcome and six ABCB1 single nucleotide polymorphisms SNPs)….SNP rs2032583 showed a nominally significant association across all studies (P = 0.035, SNP was studied in a total of 2,037 patients) and a significant Bonferroni-corrected association among inpatients (P = 1.5 × 10(-05), n = 485).”
Single-nucleotide polymorphism C3435T in the ABCB1 gene is associated with opioid consumption in postoperative pain.
“Based on a mixed linear model, the ABCB1 three genotypes showed a statistically significant effect on opioid consumption (F = 4.20, P = 0.017). There was a statistically significant difference in opioid consumption
among the ABCB1 three genotypes in the 0-6 hours (P = 0.031, 95% confidence interval [CI] CC 14.7-24.8 mg and TT 5.2-14.6 mg) and 6-12 hours (P = 0.009, 95% CI CC 5.6-13.8 mg and TT 1.2 mg-5.1 mg) postoperative period. There were no significant statistical differences in opioid consumption among the ABCB1 three genotypes in the 12-24 hours (P = 0.302) and 24-48 hours (P = 0.763) postoperative period. The TT genotype had significantly lower levels of cumulative opioid consumption compared with the CC genotype in first 24 hours after surgery (P = 0.029). 
Gene polymorphisms of OPRM1 A118G and ABCB1 C3435T may influence opioid requirements in Chinese patients with cancer pain.
“Significant higher 24h-opioid doses were observed in patients with GG (P=0.0004) and AG + GG (P=0.005) genotypes than the AA carriers. The dominant mutant 118G allele tended to be associated with progressively increasing 24h-opioid doses (P=0.001). Compared with CC/CT, patients with ABCB1 TT genotype received higher 24h- and weight-surface area-adjusted-24h- opioids doses (P=0.057 and 0.028, respectively).” 
Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers.
“In a multicenter study conducted in tertiary care outpatient pain centers, 352 patients (156 men and 196 women, aged 58.5+/- 14.6 years) treated for 1-600 months (63.4 +/- 92.4 months) with various opioids for pain of various origins were included. Genotyping was performed for all the variants reportedly modulating pain in well-defined cohorts. Association analyses focused on opioid dosing, the actual 24-h pain score on a 0-10 rating scale and the occurrence of side effects… Daily opioid doses ranged from 4 to 1750 mg oral morphine equivalents (133.4 +/- 203.2 mg) and significantly decreased in a gene dose-dependent manner with the P-glycoprotein variant ABCB1 3435C>T.” 
Association of ABCB1/MDR1 and OPRM1gene polymorphisms with morphine pain relief.
“…univariate analysis with a recessive model allowed us to detect a significant difference in morphine response between the two genotype groups: patients sharing C/C and C/T alleles proved to be moderate responders (ΔNRS = 2.73), whereas T/T carriers were good responders (ΔNRS = 4.39). The biological plausibility of such an association relies on the assumption that a function membrane transporter determines an effect drug flux from the cell, reducing morphine absorption, permeability of the blood-brain barrier, and thus bioavailability of morphine for brain receptors. Therefore, these findings lead to the conclusion that the ABCB1/MDR1 gene may play a relevant role in morphine pharmacokinetics as well.” 
Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patient after short-term infusion of morphine.
“The homozygous mutant genotype (TT) coincided with the highest maximum CSF concentrations of [morphine] (P<0.001, nonparametric rank test), which is consistent with previously published data indicating that the TT genotype is associated with lower expression of P-glycoprotein. This would be compatible with high CSF concentrations due to decreased efflux of [morphine] across the blood-brain barrier.” 
Associations of ABCB1 gene polymorphisms with aripiprazole-induced autonomic nervous system dysfunction in schizophrenia.
“Our study revealed that the T allele of rs1045642, C allele of rs2235048, and T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) are associated with decreased sympathetic activity in patients with schizophrenia treated with aripiprazole. Previous studies have reported that the rs1045642 T variantwas associated with a lower level of intestinal MDR1 expression and affected the plasma aripiprazole levels.” 
Genetic risk factors for clozapine-induced neutropenia and agranulocytosis in a Dutch psychiatric population.
“When comparing neutropenia patients with controls, again the risk of having neutropenia was about threefold higher in patients with the ABCB1 3435TT genotype; the ABCB1 3435TT genotype was more frequent in neutropenia patients (34% versus 20% in controls) and the wild-type ABCB1 3435CC genotype was more frequent in controls (31% versus 18% in neutropenia patients; P=0.05).” 
Association study of MDR1 and 5-HT2C genetic polymorphisms and antipsychotic-induced metabolic disturbances in female patients with schizophrenia.
“…among olanzapine-treated patients, statistically significant glucose level increase was obtained in association with C3435T genotype as well, with the greatest increase among patients without the C3435 allele
(mean±s.d. baseline C vs no C: 4.70±0.47 vs 5.09±0.72 increased to 5.07±0.79 vs 5.80± 2.26, F=5.062, d.f.=1, P=0.028” 
The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients.
“Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >or=7% group [patients gaining more than 7% of
their initial weight]. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >or=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >or=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain.” 
Antipsychotic drug dosage and therapeutic response in schizophrenia is influenced by ABCB1 genotypes.
“A strong allelic, genotypic and haplotypic association, was observed, which was predictive of good responseto antipsychotics. Individuals carrying the favorable homozygous genotypes of rs1045642 and rs2032582
displayed better response with increased dosage while those carrying risk genotype manifested refractoriness on increased dosage.” 
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.
Effect of COMT val158met genotype on memory, attention, judgment and other executive functions.
“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.” 
“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).” 
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.” 
Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine.
“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.” 
COMT val158met moderation of dopaminergic drug effects on cognitive function: a critical review.
“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.” 
COMT val158met impact on methylphenidate response
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). 
COMT Val66Met determines the direction of cognitive effects produced by COMT inhibition.
“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.” 
“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.” 
“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.” 
“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.” 
COMT Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis.
“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).” 
[COMT genetic variation and clinical response to antipsychotic drug treatment: A Meta-analysis].
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. 
COMT (Val(158/108) Met) genotype moderates the impact of antipsychotic medication on verbal IQ in twins with schizophrenia.
“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.” 
Antipsychotic medications and cognitive functioning in bipolar disorder: moderating effects of COMT Val108/158 Met genotype.
“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.” 
COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia.
“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.” 
Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications.
“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.” 
Pain polymorphisms and opioids: An evidence based review.
“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.”
Influence of Val108/158Met COMT Gene Polymorphism on the Efficacy of Modified Electroconvulsive Therapy in Patients with Treatment Resistant Depression.
“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).”
Catechol-O-methyltransferase (COMT) polymorphisms predict treatment response in electroconvulsive therapy.
“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.”