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Re: Which ADD med is most chemically similar to

Posted by BowTieBob on October 11, 2005, at 4:25:10

In reply to Re: Which ADD med is most chemically similar to BowTie Bob, posted by zeugma on October 7, 2005, at 18:15:10

> Good Morning Z,
>
> I always thought that clinical efficacy for Ritalin was a result of receptor sitmulation that induces the NE and dopamine effects. Also, Ritalin is comprised of 2 isomers, the d and l, with the d being the pharmacologically active one. It makes sense that if the 2 compete for the same receptor they may be some variation in efficacy. I am interested where you found the information about the dopamine transporter polymorphisms.
>
> Thanks.>>
>
> hi BTB,
>
> you are correct that Ritalin is composed of the d and l isomer and that the d isomer is responsible for clinical efficacy. Also, the dopamine and norepinephrine transporters terminate stimulation of postsynaptic receptors by their respective neurotransmitters, so transporter blockers such as Ritalin have powerful effects on neural signaling.
>
> It is most likely, from what you have written regarding the duration of Focalin XR and from the results of studies, that the l isomer may interfere with the duration of effect of Ritalin. I have taken Ritalin LA which is essentially the same mechanism as Focalin XR (bimodal release), and its duration of effect is perhaps 6-8 hours, while Focalin XR has a substantially longer effect (8- 10 hours). This is extremely important since few of us can afford to function for 6 hours a day.
>
> The pharmacogenomics of stimulant response is in its infancy, but this recent study gives the general idea:
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16123773&query_hl=3
>
> Neuropsychopharmacology. 2005 Aug 3; [Epub ahead of print]
>
>
> Association between Dopamine Transporter (DAT1) Genotype, Left-Sided Inattention, and an Enhanced Response to Methylphenidate in Attention-Deficit Hyperactivity Disorder.
>
> Bellgrove MA, Hawi Z, Kirley A, Fitzgerald M, Gill M, Robertson IH.
>
> [1] 1Department of Psychology and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland [2] 2Departments of Psychiatry and Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
>
> A polymorphism of the dopamine transporter gene (DAT1, 10-repeat) is associated with attention-deficit hyperactivity disorder (ADHD) and has been linked to an enhanced response to methylphenidate (MPH). One aspect of the attention deficit in ADHD includes a subtle inattention to left space, resembling that seen after right cerebral hemisphere damage. Since left-sided inattention in ADHD may resolve when treated with MPH, we asked whether left-sided inattention in ADHD was related to DAT1 genotype and the therapeutic efficacy of MPH. A total of 43 ADHD children and their parents were genotyped for the DAT1 3' variable number of tandem repeats polymorphism. The children performed the Landmark Test, a well-validated measure yielding a spatial attentional asymmetry index (leftward to rightward attentional bias). Parents rated their child's response to MPH retrospectively using a three-point scale (no, mediocre or very good response). Additionally, parents used a symptom checklist to rate behavior while on and off medication. A within-family control design determined whether asymmetry indices predicted biased transmission of 10-repeat parental DAT1 alleles and/or response to MPH. It was found that left-sided inattention predicted transmission of the 10-repeat allele from parents to probands and was associated with the severity of ADHD symptomatology. Children rated as achieving a very good response to MPH displayed left-sided inattention, while those rated as achieving a poorer response did not. Our results suggest a subgroup of children with ADHD for whom the 10-repeat DAT1 allele is associated with left-sided inattention. MPH may be most efficacious in this group because it ameliorates a DAT1-mediated hypodopaminergic state.Neuropsychopharmacology advance online publication, 3 August 2005; doi:10.1038/sj.npp.1300839.
>
> However, this partially contradicts an earlier study (which is the one I was thinking of in my previous post) in which the 10-repeat allele of the DAT1 was associated with poorer response:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12172219&query_hl=3
>
> Pharmacogenetics. 2002 Aug;12(6):497-9.
>
>
> Dopamine transporter gene and response to methylphenidate in attention-deficit/hyperactivity disorder.
>
> Roman T, Szobot C, Martins S, Biederman J, Rohde LA, Hutz MH.
>
> Department of Genetics, Federal University of Rio Grande do Sul, Brazil.
>
> This study aims to evaluate whether a previously reported association between homozygosity for the 10-repeat allele of the dopamine transporter gene (10/10) and poor response to methylphenidate (MPH) would be replicated in a sample of Brazilian attention deficit/hyperactivity disorder (ADHD) boys. In a blind naturalistic study, 50 male ADHD youths were treated with MPH. Efficacy of the medication was measured by means of the 10-item Conners Abbreviated Rating Scale (ABRS), and the Children's Global Assessment Scale (CGAS). While 75% (15/20) of the youths without 10/10 genotype demonstrated an improvement higher than 50% in the ABRS scores with MPH, only 47% (14/30) of the subjects with 10/10 genotype achieved the same level of improvement with medication (one-tailed P = 0.04). In addition, the group without this genotype had significantly higher increase in the CGAS scores than the other group (one-tailed P < 0.01). Our findings support an association between homozygosity for the 10-repeat allele at dopamine transporter gene locus and poor response to MPH.
>
> This is another recent study that indicated that homzygosity for the 10-repeat allele of the DAT1 is connected to MPH poor response:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15572278&query_hl=10
>
> Eur Neuropsychopharmacol. 2005 Jan;15(1):95-101.
>
> The homozygosity for 10-repeat allele at dopamine transporter gene and dopamine transporter density in Korean children with attention deficit hyperactivity disorder: relating to treatment response to methylphenidate.
>
> Cheon KA, Ryu YH, Kim JW, Cho DY.
>
> Department of Psychiatry, College of Medicine, Kwandong University, Myong-Ji Hospital, 697-24 Hwajung-Dong, Dukyang-ku 412-270, Koyang, Kyunggi-Do, Republic of Korea. kacheon@dreamwiz.com
>
> The symptoms of attention deficit hyperactivity disorder (ADHD) can be treated with methylphenidate (MPH), a potent blocker of dopamine transporter (DAT). The homozygosity of the 10-repeat allele at the DAT gene (DAT1) seems to be associated with a poor response to MPH in children with ADHD. In the present study, we investigated the association between DAT density using I-123-N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chlorophenyl)tropane [123I]IPT single photon emission computed tomography (SPECT)] and the homozygosity for 10-repeat allele at DAT1 and response to MPH in Korean children with ADHD. Eleven drug-naive children with ADHD were included in the study and treated with MPH for about 8 weeks. After the genotyping and SPECT were performed, we compared DAT density between ADHD children with and without the homozygosity for 10-repeat allele at DAT1 and investigated the correlation between the homozygosity for 10-repeat allele and response to MPH. ADHD children with 10/10 genotype (n=7) had a significantly greater increase of the DAT density in basal ganglia than the children without 10/10 genotype (n=4). We found that while only 28.6% (2/7) of the subject with 10/10 genotype showed good response to MPH treatment, 100% (4/4) of the subjects without 10/10 genotype showed good response to MPH treatment. Our findings support an association between homozygosity for 10-repeat allele at DAT1 and the DAT density assessed in vivo and correlation between the homozygosity for 10-repeat allele and poor response to MPH.
>
>
> All this is a difficult to take in! I would just say that Ritalin (apart problems with its duration of action) helped greatly with some ADHD symptoms, such as inability to perceive detail and poor focus, while it did not help organizational problems or my grossly impaired physical coordination (this may not be an ADHD symptom per se, but is certainly a symptom of something). Oddly, Provigil is the exact reverse of Ritalin and helps with the latter but not so much with the former. Provigil is also less anxiety-provoking for me and non-anorexiant, so I've spent most of the last year on Provigil rather than Ritalin. Provigil also combines better with nortriptyline, which I absolutely need to control narcoleptic symptoms, so it's the med for me for the time being.
>
>
> -z
>
> Good Morning Z,

Thanks for the great information. You certainly know where to look. I have been searching for a while! All this brings back memories of Biochemistry, Genetics, Physical Chemistry, etc. Love the stuff.

By the way, I do have ADD and do take Focalin XR along with some short acting Focalin to get me through a 12-14 hour day. I begin at 5:00 AM. It has really helped me focus and stay on task. But more importantly, it has helped in my family relationships, which is what originally prompted me to seek help.

Thanks, and have a great day.

BTB
>
>
>


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poster:BowTieBob thread:562267
URL: http://www.dr-bob.org/babble/20051010/msgs/565575.html