Psychopharmacology. Supplementum最新文献

We review dystonia treatment results since 1981, including our own findings. Anticholinergics are still the most effective drugs, but less than 50% of patients continue with treatment. The authors recommend a combination of an anticholinergic, a benzodiazepine, and another drug (an antidopaminergic, carbamazepine, or fluperlapine) for the treatment of dystonia.

The potential mechanisms whereby GABA mimetics and the antimanic agent lithium stabilize dopaminergic transmission are discussed. Evidence is presented that GABA mimetics, and in particular progabide, affect dopamine-mediated events in the basal ganglia on at least three levels. First, they reduce dopamine neuron activity in both the basal and the activated states. Secondly, on a long-term basis, they antagonize the proliferation of striatal dopamine receptors subsequent to chronic neuroleptic treatment. Thirdly, they modulate the expression of dopamine receptor activation by acting distally to the dopaminergic synapse. Lithium and GABA mimetics have the last two properties in common. These effects may represent the biochemical basis for the therapeutic action of GABA mimetics in iatrogenic dyskinesias. Moreover, the similarity between the biochemical effects of GABA mimetics and lithium suggest that the former drugs may have a therapeutic potential in mania.

Dopamine-receptor blockade seems to be a prominent effect of neuroleptics. Blockade of other receptors might, however, contribute to the therapeutic effect. A series of neuroleptics have been tested for affinity to DA D-1 and D-2 receptors, serotonin receptors (S2), alpha-adrenoceptors (alpha 1), histamine receptors (H1), and muscarinic cholinergic receptors. According to the affinity to DA D-1 and D-2 receptors, neuroleptics can be divided into different groups. Thioxanthenes have affinity for both D-1 and D-2 receptors; phenothiazines have affinity for D-2 receptors and considerably lower affinity for D-1 receptors; and butyrophenones, diphenylbutylpiperidines, and benzamides have affinity only for D-2 receptors. Concerning affinity to other receptors the only consistent finding is affinity for S2 receptors. The clinical significance of these findings is speculative. In several behavioral tests the D-1/D-2 classification is also observed, and it is suggested that D-1-receptor activation is responsible for dyskinesia, and that thioxanthenes - due to their D-1 receptor blocking effect-induce less dyskinesia than other neuroleptics.

Animal models of persisting tardive dyskinesia have been developed in two species (rats and monkeys). Dyskinetic animals chronically treated with neuroleptics had significant decreases in glutamic acid decarboxylase and GABA in the substantia nigra, the medial globus pallidus, and the subthalamic nucleus, whereas animals without dyskinesias which had been treated similarly had a normal distribution of these biochemical parameters. These changes remained 2 months after neuroleptics were discontinued, and at that point there was a reduced turnover of striatal dopamine in the dyskinetic monkeys. These findings suggest that reduced GABA function in the substantia nigra may play a role in tardive dyskinesia.

Pharmacologic treatments which diminish central dopaminergic transmission improve symptoms of tardive dyskinesia (TD). These clinical data, supported by results from animal model studies, have provided a basis for the dopamine (DA) receptor hypersensitivity hypothesis of TD. Since its initial formulation, however, knowledge of the multiple effects of prolonged neuroleptic administration in mammalian CNS has greatly expanded. Clinical and animal model studies carried out independently now both suggest that GABA-mediated neuronal tracts of the basal ganglia are important, perhaps pivotal, in TD. Thus, we would extend the DA hypothesis of TD to include the idea that neuroleptic-induced DA receptor hypersensitivity in striatum results in GABA system hypofunction in striatal projection areas in those individuals who develop TD.

Neurochemical indices of dopaminergic function were assessed in basal ganglia of post-mortem brains of control subjects and schizophrenic patients who had been rated in life for the presence of movement disorder and neuroleptic intake. In schizophrenics who had been treated chronically with doses of neuroleptics, concentrations of dopamine D2 receptors were significantly increased above controls, whereas dopamine D1 receptors and dopamine metabolism were unchanged. Increased D2 receptors were also observed in basal ganglia of drug-free patients. Concentrations of dopamine D1 and D2 receptors in schizophrenics with movement disorder. Moreover, no relationship was found between dopamine receptor levels and the severity of movement disorder. Concentrations of the dopamine metabolite homovanillic acid were increased in the putamen and nucleus accumbens in a small number of patients with movement disorder compared with controls or patients without movement disorder. No changes were observed in markers of cholinergic and GABA-containing neurones. The present findings are not consistent with a "dopamine receptor hypersensitivity" concept of movement disorder in schizophrenia.

Dopamine antagonists are effective in suppressing hyperkinetic symptoms in patients with tardive dyskinesia, spontaneous oral dyskinesia, Huntington's chorea, and Gilles de la Tourette's syndrome. These neuroleptics have no curative effect upon the conditions and may even aggravate symptoms in the long term. In many cases a single neuroleptic drug may lose its effect. A more lasting effect may be obtained by combining drugs with pre- and postsynaptic antidopamine effects.

Tardive dyskinesia (TD) occurs in predisposed individuals receiving neuroleptic treatment, but prior to the onset of symptoms it is not possible to predict who is at risk for this disorder. If the time course for evolving symptoms, perhaps mediated through dopamine hypersensitivity, could be identified, treatment interventions could be initiated. Eight male Cebus monkeys (15-18 years old) were tested with the dopamine agonists apomorphine, d-amphetamine, bromocriptine, and pergolide before, during, and after 3 months of treatment with haloperidol 0.25 mg/kg daily PO. This treatment cycle was repeated four times. Apomorphine and amphetamine produced moderate buccolinguo-masticatory (BLM) signs. Bromocriptine and pergolide produced very few BLMs. Initially haloperidol suppressed dopamine agonist-induced BLMs, but tolerance to the effect developed and was replaced by a potentiation of apomorphine-induced BLMs. Markedly increased apomorphine- and amphetamine-induced BLMs were seen following the first 3 months of haloperidol medication (behavioral hypersensitivity), but this gradually decreased to near-baseline levels, even with re-exposure to neuroleptics in the four treatment cycles. Bromocriptine and pergolide produced no signs of BLM behavioral hypersensitivity. These findings suggest that long-term neuroleptic treatment in nonhuman primates induces dynamic compensatory CNS changes, which may not fully explain the pathogenesis of TD on the basis of dopamine hypersensitivity.

The long-term prognosis of tardive dyskinesia (TD) has been insufficiently studied. Symptoms are reversible in many patients, but an irreversible course is widely believed to be the expected outcome. This pessimistic view has led to the assumption that neuroleptics should not be used in patients with TD because these drugs will produce an inevitable aggravation of TD. To clarify this issue, 27 patients were serially evaluated over 5 years for changes in neuroleptic treatment, TD, and mental status. Ten patients were able to discontinue medications; 15 required continued low-dose neuroleptic therapy [average 223 mg/day chlorpromazine (CPZ) equivalents], and two needed high doses (1000-2000 mg/day CPZ equivalents) to control psychosis. The majority of patients improved by more than 50% in both treated and untreated groups. In 8 of 27 patients (29.6%) TD resolved; in 1 patient TD increased by 25%. Younger patients improved the most. Prognosis was most favorable if neuroleptics were discontinued, but improvement was still possible with low to moderate doses (less than 600 mg/day CPZ equivalents). The large majority of patients with schizophrenia or schizoaffective illness relapsed, and required continued drug treatment. TD must be evaluated over several years to monitor the resolving/persisting course. Control of psychosis and improvement of TD during low-dose neuroleptic treatment suggest the antipsychotic and neurological effects of neuroleptics may involve different thresholds or mechanisms of action.

The continuing concern about tardive dyskinesia (TD) has stimulated a broad search for therapies for this disorder. Since neuroleptic drugs are thought to be the etiological agents, acting presumably through dopamine receptor blockade, nondopaminergic drugs have been the focus of recent study. However, no uniformly safe and effective drug treatment has been identified. Augmentation of cholinergic function is theoretically attractive, but further research is needed to develop practical and effective compounds. GABA drugs do not consistently suppress TD. The effect of benzodiazepines in TD is unclear, but these agents may be of some temporary benefit in patients with distressing symptoms. Lithium, serotonergic compounds, and numerous neuropeptides all fail to have any consistent effect in TD. Early reports of benefit with alpha- and beta-noradrenergic agents are interesting but require further study. Many other drug types have been tried without benefit. For the majority of patients, it may be best to give no drug treatment. Any drug that is capable of suppressing TD may aggravate the disorder in the long term. The potential for a spontaneous gradual remission of TD is an argument in favor of a patient, nonaggressive, and cautiously optimistic approach to this disorder.