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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 8 of 8. This is the beginning of the thread.
Posted by JohnX on March 16, 2001, at 0:33:05
Just thought I'd drum up some quick thoughts
or links on TD causes.My primary understanding of what causes TD particularly in the older neuroleptics (anti-psychotics), is that chronic D2 antagonism in the nigrostriatal pathway will cause spawning of new D2 receptors to couteract this. Sometimes when the neuroleptic is removed, the body is unable to "undue" the D2 receptors it has spawned, and this can cause the hyperkinetic movement disorders in TD.
Are there other know hypothesis/causes for TD?
-John
Posted by steve on March 16, 2001, at 1:33:46
In reply to Causes of Tardive Dykinesia, posted by JohnX on March 16, 2001, at 0:33:05
>
> Just thought I'd drum up some quick thoughts
> or links on TD causes.
>
> My primary understanding of what causes TD particularly in the older neuroleptics (anti-psychotics), is that chronic D2 antagonism in the nigrostriatal pathway will cause spawning of new D2 receptors to couteract this. Sometimes when the neuroleptic is removed, the body is unable to "undue" the D2 receptors it has spawned, and this can cause the hyperkinetic movement disorders in TD.
>
> Are there other know hypothesis/causes for TD?
>
> -JohnMy understanding is that your hypersensitivity theory is generally regarded as being outdated. Otherwise they wouldn't be looking into antioxidants as a prophylactic. The damage does seem to be structural, as D2 agonists don't cause it.
S.
Posted by Sunnely on March 16, 2001, at 20:51:36
In reply to Causes of Tardive Dykinesia, posted by JohnX on March 16, 2001, at 0:33:05
Hi John,
At present the EXACT cause(s) of TD remains unknown. Having said that, the following are some of the hypotheses as to the pathophysiology of the TD. However, all have inconsistencies and limitations. (This is hypothesis you stated.)
1. The theory of hypersensitivity of DA postsynaptic receptors (D2) which occurs after persistent receptor blockade in the basal ganglia, where nigrostriatal pathway ends. Eventually, there is an increase in the number of dopamine receptors leading to TD.
Supporting this hypothesis: 1. Induction of TD by dopamine blockers (e.g., neuroleptics), 2. Reversal of TD by dopamine depleters (e.g., reserpine, tetrabenazine) or dopamine blockers (e.g., neuroleptics), 3. Unmasked by increasing dosages of neuroleptics, 4. Apperance of similar choreiform movements in other syndromes clearly related to dopamine excess such as the levodopa dyskinesias seen in Parkinson's disease, 5. Exacerbation by anticholinergics, and 6. Improvement with cholinesterase inhibitors (e.g., physostigmine).
Inconsistencies: 1. Some dopamine agonists such as bromocriptine, may amelorate rather than worsen TD (attributed by some researchers to "downregulation" of the receptors), 2. Several postmortem studies have not demonstrated an increase in haloperidol-binding receptors in TD, 3. PET studies failed to demonstrate an increased striatal density of dopamine (D2) receptors in patients with TD, 4. In animal studies, chronic neuroleptic treatment causes an increase in dopamine receptor density, but that the increase is compensated for readily by a decrease in dopamine synthesis, 5. It does not account adequately for the time course of onset of TD nor for its persistence afer neuroleptics are discontinued, and 6. Radiographic, CSF (cerebrospinal fluid), and endocrine studies have produced highly variable results.
2. The GABA-ergic Hypoactivity Hypothesis of TD. This hypothesis states that TD may be related to reduced activity in a subgroup of GABA neurons in the striatum.
3. Excitotoxic Mechanisms Hypothesis of TD. This hypothesis is similar to GABA-ergic hypothesis but indicates that there is degeneration of nigrostriatal GABA-containing neurons caused by excitotoxicity by EAA (excitatory amino acids), primarily glutamate. Huntington's disease, a model of excitotoxic injury of the striatum has similarity to TD.
4. Noradrenergic Dysfunction Hypothesis of TD. Aside from dopamine, norepinephrine have been described in several different movement disorders (e.g., Huntington's disease, Parkinson's disease, autosomal dominant torsion dystonia, and Tourette's syndrome).
5. Toxic Free Radicals in the Basal Ganglia Hypothesis. Free radicals are substances that contain an odd number of electrons which are highly reactive and are byproducts of many in vivo reactions. The most important free radicals in biology and medicine include molecular oxygen, superoxide, hydroxyl radical and most transition metals. This hypothesis states that nigrostriatal damage may result from abnormal production of cytotoxic free radicals during increased metabolism of catecholamines especially dopamine and norepinephrine (induced by neuroleptics). This theory also hypothesized that free radicals and their cytotoxic effects are responsible for aging. It has been shown that there is a significant loss of cells with age in areas of human brain that contain high concentrations of dopamine (especially in substantia nigra and locus coeruleus). Free radicals such as molecular oxygen and hydroxyl radicals cause celllular destruction and membrane destabilization and have been implicated in other movement disorders such as Parkinson's disease, manganese-induced encephalopathy, and Hallervorden-Spatz disease. This is the basis for the suggestion that free radicals and anti-oxidants may be effective in Parkinson's disease. This is also the basis for the trial of Vitamin E (an anti-oxidant) in TD. (Vitamin E does not always work for TD. It appears that the milder and earlier stage of TD is more responsive to Vitamin E but not the advanced and later stage.) Free radicals are also the basis for the hypothesis that increased iron concentration in the basal ganglia might lead to hypersensitivity of dopamine (D2) receptors (supporting the supersensitivity hypothesis of TD). Iron is essential for the production of the hydroxyl radicals, the most damaging of all free radicals.
6. Loss of Nigrostrial Cholinergic Neurons Hypothesis. This hypothesis is based on the well-established inhibitory action of dopamine (D2) receptors on striatal cholinergic neurons. This hypothesis proposed that TD is not the consequence of dopamine receptor proliferation, but results from damage or destruction of striatal cholinergic interneurons. This is caused by prolonged overactivation of cholinergic neurons, which occurs when they are released from dopaminergic inhibition following neuroleptic administration. Cholinergic neurons comprise 2-3% of the neuronal population of the striatum.
+++++++++++++++++++++++++++++++++++++++
>
> Just thought I'd drum up some quick thoughts
> or links on TD causes.
>
> My primary understanding of what causes TD particularly in the older neuroleptics (anti-psychotics), is that chronic D2 antagonism in the nigrostriatal pathway will cause spawning of new D2 receptors to couteract this. Sometimes when the neuroleptic is removed, the body is unable to "undue" the D2 receptors it has spawned, and this can cause the hyperkinetic movement disorders in TD.
>
> Are there other know hypothesis/causes for TD?
>
> -John
Posted by JohnX on March 17, 2001, at 7:27:52
In reply to Causes of Tardive Dykinesia, posted by JohnX on March 16, 2001, at 0:33:05
Thanks for the information!-John
Posted by Chris A. on March 17, 2001, at 12:06:55
In reply to Re: Causes of Tardive Dykinesia » JohnX, posted by Sunnely on March 16, 2001, at 20:51:36
Would adding other antioxidants other than E and C make sense at this time? My consultant already had me taking 2000 IU of E daily. I am not interested in taking more pills, but if there is chance they will help I am willing. Thanks for the info.Chris A.
Posted by pat123 on March 17, 2001, at 12:31:51
In reply to Is it premature to pile on the antioxidants?, posted by Chris A. on March 17, 2001, at 12:06:55
>
> Would adding other antioxidants other than E and C make sense at this time? My consultant already had me taking 2000 IU of E daily. I am not interested in taking more pills, but if there is chance they will help I am willing. Thanks for the info.
>
> Chris A.
Would adding more of something that is cancer protective, anti-aging, and anti free radical ?
Yes, of course ! You need biologicals,ie plant
based stuff. You can just eat more veggies. I juice. C needs bioflavinoids to be effective.Pat
Posted by Chris A. on March 17, 2001, at 13:12:13
In reply to Re: Is it premature to pile on the antioxidants?, posted by pat123 on March 17, 2001, at 12:31:51
Thanks for the encouragement.
Currently Crunching Carrots,
Chris A.
Posted by pat123 on March 17, 2001, at 17:50:53
In reply to Re: Is it premature to pile on the antioxidants? » pat123, posted by Chris A. on March 17, 2001, at 13:12:13
> Thanks for the encouragement.
>
> Currently Crunching Carrots,
>
> Chris A.My fav is broccoli; I was just reading a paper on the bio and isoflavinoids in it. Cauliflower or any while veggie is good, too. I have trouble with the fruits so I juice them. Carrot juice is good, too.
Pat
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