@Hip , I . Have met with the doctor and he gave me 1) methylfenilate in the morning, 2) ropinole in the night. I think the methylfenilate in the morning is overkill and opposite to what I need (maybe this is similar to
Amantadine ?). I think the ropinole could be helpful as it is a d2 agonist. I tried asking for tianeptine but he didnt listen. I will go to another neuro/psychiatrist. Amilsupride seems great and I have it here at home but I chickened out when I saw it rraises prolactin 8x and mine tested many times on the limit.
I think the study you want is PMID 15900211.
Thanks for the suggestions. I will add Amantadine to my "to try" list
)
I have gathered the following from studies i read, and came up with this text. I think I can't say that this SNP is surely not linked to my problem. It probably pays a big role. It has even been patented as a marker for antidepressive/antypsychotic responsiveness (see NOTE at the end). I am also doubtful I had epileptic fits. They were probably extrapyramidal reactions (accute dystonic storm/seizures) to metoclopramide. I was drugged 2 years on phenobarbital for possibly no good reason.
Dystonia is a movement disorder characterized by involuntary, sustained muscle contractions that result in twisting and repetitive movements or abnormal postures [PMID 16914406]. Dystonia can be classified by the age of onset, body distribution, and etiology. Classification by etiology separates the spectrum of dystonia into primary and secondary categories. Secondary dystonia is associated with a known acquired causes or additional neurologic signs, such as muscle weakness, spasticity, ataxia, ocular motility abnormalities, retinal abnormalities, cognitive impairment, or
seizures. Secondary dystonia typically arises from a specific underlying condition, such as exposure to dopamine receptor-blocking drugs [PMID 14509661].
The rs1800497 SNP, or Taq1A, C>T,was considered a silent mutation located 10 kb from DRD2 gene, in the 3’ untranslated region. However recently the identification of a novel gene in the neighboring forward-strand region of DRD2 gene, named ANKK1 gene, showed that the rs1800497 SNP is located in exon 8 of the ANKK1 gene [PMID 15146457].
The rs1800497 Taq1A, alelle A1, (TT) , is associated with a reduced number of dopamine binding sites in the brain [PMID 9672901], up to 30% less [PMID 22848508], which is the result of an increased activity of striatal Aromatic Amino Acid Decarboxylase enzyme [2005, PMID 15900211]
Aromatic Amino Acid Decarboxylase enzyme catalyzes several different decarboxylation reactions:[
http://www.hmdb.ca/proteins/HMDBP00278]
L-DOPA to dopamine - a neurotransmitter
5-HTP to serotonin (5-HT) - a neurotransmitter
L-histidine to histamine - a neurotransmitter
phenylalanine to phenethylamine - trace amine neurotransmitter
L-tyrosine to tyramine - trace amine neurotransmitter
tryptophan to tryptamine - trace amine neurotransmitter
It is known that extrapyramidal adverse effects are associated with increased drug occupancy of the dopamine 2 receptors (DRD2). The
A1 allele of the DRD2/ANKK1, rs1800497, is associated with decreased striatal DRD2 density. Results strongly suggested that A1+ variants of the DRD2/ANKK1 Taq1A allele do confer an associated risk for akathisia in patients who were treated with SGAs [2013, DRD2/ANKK1 Taq1A (rs 1800497 C>T)
genotypes are associated with susceptibility to second generation antipsychotic-induced akathisia]. It has thus been suggested that DRD2 polymorphisms can be usedas a pretreatment marker for response to DRD2antagonists at therapeutic doses, and that A1 (+) or Del(-) subjects are highly sensitive to DRD2 antagonists, expressed as either treatment responders or non-responders vulnerable to extrapyramidal symptoms.[2007, PMID 17362435]
In one study of 64 cases, the risk of ExtraPyramidal Symptoms with SSRIs, seems to be associated, with the presence of the A1 allele of DRD2 Taq1A polymorphism. [PMID 16633151]
DRD2 TaqIA polymorphism has been reported to be associated with an increased risk for developing motor fluctuations but not hallucinations in Parkinson's disease. [PMID 11425949][PMID 14732464]
Metoclopramide is a dopamine-2 receptor antagonist used for various gastrointestinal disorders. The anti-emetic action of metoclopramide is the result of its antagonist activity at D2 receptors in the chemoreceptor trigger zone in the central nervous system; this action prevents the nausea and vomiting triggered by most stimuli [Rang HP, Dale MM, Ritter JM, et al. Pharmacology. 5th ed. Edinburgh: Churchill Livingstone; 2003.].
Metoclopramide can cause or worsen extrapyramidal symptoms (EPS)/drug-induced movement disorders (DIMD). Tardive dyskinesia and Parkinsonism is generally seen after long-term use,whereas dystonia and akathisia can occur after a single dose of metoclopramide.[PMID 18926476]. Metoclopramide's extrapyramidal symptoms generally manifest as acute dystonic reactions within the initial 24–48 hours of use. The risk of these reactions is increased at higher doses and in pediatric patients and adults <30 years of age. [
http://www.nejm.org/doi/full/10.1056/NEJMicm1412207], [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261495/]
Acute dystonic reactions, the most common type of extrapyramidal symptom associated with metoclopramide, occur in approximately 0.2% of patients (1 in 500) treated with 30 to 40 mg of metoclopramide per day [PMID 1298936]. Symptoms include involuntary limb movements, facial grimacing, torticollis, oculogyric crisis, rhythmic protrusion of the tongue, bulbar type of speech, trismus, opisthotonus (tetanus-like reactions), and, rarely, stridor and dyspnea, which possibly result from laryngospasm. [
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261495/]
The most rapid treatment of an acute dystonic reaction caused by metoclopramide is the intravenous or intramuscular administration of anticholinergics.[
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4261495/]
Metoclopramide-induced acutedystonic reaction, may occur in patients carrying a CYP2D6 genetic polymorphism. [PMID 16702617] Author's of a previous study felt that if there is a case of dystonic reaction to metoclopramide, this drug should not be administered to other members of the family. [PMID 1298936]
Dexamethasone is one of the few CYP2D6 inducers and at the same time it significantly increases D2 receptor binding in the limbic system of rats [PMID 15520493]
The common link between all these meds is that they were all neuroleptics in one way or another, some by inducing serotonergic pathways,others by directly blocking dopamine. This has led to Extrapyramidal symptoms/drug induced movement disorders, be it accute dystonic reactions to metoclopramide or sleep myoclonus, dystonic reactions, from other neuroleptics. All of the medications to which I had adverse side effects are heavily metabolised by CYP2D6, which I also have polymorphisms for. The one medication which made me feel great, Dexamethasone, is a CYP2D6 inducer, one of the few known, and is known to increase D2 receptor density in rats. I have found a few people who felt good on dexamethasone, which they tried for some reason unrelated to fatigue, and they were put on a prodopaminergic and felt great, when before all the ADs had failed (of course this is all anectodal...)
What the neurologists told me at the time about having epileptic convulsions, which happened after metoclopramide, was severely wrong, in fact they were not epileptic patterns but rather Drug Induced Movement Disorders.
The likely culprits for my Extrapyramidal issues with these medications have been an impaired metabolism of the drugs used coupled with a problem in the dopaminergic pathway (maybe underactivation, maybe in the mesolimbic pathway), resulting of CYP2D6 and Taq1A A1, respectively.
Note: interesting related patent
http://www.google.com/patents/US20070026402
Genetic marker of response to atypical antipsychotics and antidepressants methods
The invention provides methods of identifying candidate psychiatric patients, or patients with movement disorder, for treatment with receptor site or increases density of D2 dopamine receptors. The method comprises determining a patient's DRD2 genotype. Patients having the Taq1A (A1) allele (A1+ allelic status) are candidates for treatment with high dose, high binding antipsychotics and/or SSRIs that influence D2 receptor density. Patients lacking the Taq1A allele (A1− allelic status) are candidates for treatment with low dose, low binding atypical antipsychotics, and are not likely to respond well to these SSRIs.