Low Dose Alpha-Methyl-Para-Tyrosine (AMPT) in the Treatment of Dystonia and Dyskinesia

There is evidence of two functional pools of dopamine within the dopaminergic cell. 9 These pools, the cytosolic pool (or newly synthesized pool) and vesicular pool (stored pool) are often distinguished by their different response to the dopamine-depleting drugs. 10 The primary effect of AMPT is to limit the amount of newly synthesized dopamine formed in the cytosol by lowering the production of dopamine via direct inhibition of tyrosine hydroxylase. Reserpine and Tetrabenezine prevent the uptake of dopamine into vesicular stores, which ultimately results in a loss of cellular dopamine. 11

The dosages of AMPT recommended for most clinical trials and the treatment of pheochromocytoma range from 1000 to 3000mg/day, which substantially reduce catacholamine biosynthesis (36% to 80%). 12 We propose that the clinical effect of low doses of AMPT is to modify neuroleptic-related increases in cytosolic dopamine by direct inhibition of tyrosine hydroxylase. By affecting the fluctuations that occur in dopamine production, AMPT provides a therapeutic benefit not available with the use of other dopaminergic medications.

Under physiological conditions, the activity of tyrosine hydroxylase is regulated by phosphorylation at Ser31 (Serine31) or Ser40. 13 Phosphorylated tyrosine hydroxylase has enhanced efficacy in dopamine synthesis. Various stimuli, including N-methyl-D-aspartic (NMDA) receptor stimulation, 14 nicotine, 15 and histamine, 16 have been shown to affect the activity of tyrosine hydroxylase through phosphorylation at these serine residues. 17 Antipsychotics such as thioridazine or clozapine increase tyrosine hydroxylase activity, 18 likely through increases of phosphorylation of tyrosine hydroxylase at Ser31 or Ser40 via dopamine-2 (D2) receptors. 19 These increases in tyrosine hydroxylase phosphorylation occur following administration in both naive animals 20 and in animals that have been chronically administered antipsychotics for 2 weeks. 19 Therefore, neuroleptic treatment has the potential to cause transient upregulation of dopamine levels which may be more than necessary for normal execution of motoric function and, as a result, cause dystonia or dyskinesia.

Since AMPT acts directly on tyrosine hydroxylase, and probably bypasses phosphorylation effects caused by antipsychotics, it is possible that low dose AMPT might have a special benefit in tardive dyskinesia. We report three cases in which the use of AMPT (at 1 gram per day or less) had efficacy in the treatment of movement disorders, which was superior to previous treatments.

Reserpine, one of the early drugs which lowered dopamine activity, never attained wide clinical use because of significant side effects. 22 This clinic formerly used reserpine as an adjunctive to neuroleptics for treating the episodic psychotic symptoms commonly seen in the developmentally disabled population. Reserpine sometimes lowered the intensity and frequency of such psychotic reactions but also caused side effects of sedation, sluggishness, and depression. In the mid-1980s, AMPT was substituted for reserpine. Currently, 30 clinic outpatients are receiving AMPT, with only one receiving more than 1000mg/day. The majority had a long history of severe violence related to psychosis. The rest had various conditions including episodes of nonviolent psychosis, autistic impulsivity, violence related to nicotine craving, and movement disorders. Nearly all of these current patients have failed attempts to titrate down the AMPT.

Since the dose of AMPT is low, the side effects listed in the manufacturer’s description, such as crystalluria, diarrhea, anxiety, and depression, have not been seen. All of the individuals who received AMPT at this clinic were also receiving antipsychotics, and a number of patients have demonstrated side effects, such as prolactin elevations and pseudo-Parkinson movement disorders. Since AMPT blocks dopamine synthesis, treatment of movement side effects requires restitution of dopamine using l -dopa or l -tyrosine. This clinic’s protocol to treat movement side effects stops the AMPT and gives four doses of clinic-supplied l -tyrosine (1000mg every 12 hours). Symptoms generally clear quickly after the first dose of l -tyrosine. Use of the combination of AMPT and reserpine in eight patients demonstrated no increased benefit but did produce increased movement side effects, including two cases of neuroleptic malignant syndrome.

The delayed motoric side effects of neuroleptics are classified as tardive disorders. Tardive dyskinesia and tardive dystonia are observed in roughly 25% of patients treated with neuroleptics. 23 The basal ganglia plays a primary role in motoric function, and within it, the nigrostriatal dopamine pathway has a major part in volitional aspects of the initiation of movement. It is thought that imbalance of D2 receptor expression in the basal ganglia is induced by chronic neuroleptics. 23 Neuroleptic-induced increases in tyrosine hydroxylase phosphorylation were first described in both the nigrostriatal and mesolimbic systems in vivo by Salvatore et al. 20 This study also showed that haloperidol elevated phosphorylation at Ser19 in the striatum, a site recently shown to affect the ability of Ser40 to phosphorylate. 24 Because phosphorylation of tyrosine hydroxylase at Ser31 or Ser40 can increase dopamine biosynthesis, the neuroleptic-induced increases in Ser31 or Ser40 would be expected to elevate levels of dopamine in dopamine pathways. Recently, it has been shown that D2 receptors play a role in the neuroleptic-induced increase in tyrosine hydroxylase phosphorylation at Ser31 and Ser40 in the striatum. 25 Because tyrosine hydroxylase phosphorylation increases from a single administration of neuroleptics either in naïve animals or in animals undergoing chronic neuroleptic administration, a hyperdopaminergic tone in the basal ganglia could be the end result of the use of neuroleptics and may predispose certain individuals to tardive dyskinesia or tardive dystonia. The use of AMPT would bypass the increase in phosphorylation caused by neuroleptics, and perhaps restore a functionally normal level of dopamine.

Although none of the reported cases is completely stable, the use of AMPT did provide some therapeutic control of neuroleptic-induced motor dysfunctions. The apparent capacity of low-dose AMPT to provide therapeutic benefits suggests that dopamine activity can be stabilized by manipulating the activity of tyrosine hydroxylase and its effect on the cytosolic dopamine storage pool. The effect of antipsychotic use on the activity of tyrosine hydroxylase may be a contributor to the phenomenon of tardive movement disorders. Therapy with AMPT seems to offer a way to offset the presumed increases in dopamine function that occur with the use of antipsychotics which contribute to the tardive movement disorder.

Received August 17, 2005; accepted October 31, 2005. Dr. Ankenman is affiliated with the Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky. Dr. Salvatore is affiliated with Madison County Hospital, London, Ohio. Address correspondence to Dr. Ankenman, 306 Whitney-Hendrickson Building, 800 Rose Street, Lexington, KY 40536; [email protected] (e-mail).