Tardive dyskinesia

This syndrome was first described by Schonecker within 5 years of the introduction of the neuroleptics. It comprises involuntary movements of the tongue, lips and face (such as protrusion or twisting of the tongue, lip smacking, puffing of the cheeks, sucking of the lips and chewing) often combined with abnormal involuntary movements of the trunk and limbs, termed choreiform or choreoathetoid movements. Despite the association of tardive dyskinesia with the introduction of neuroleptics, it is evident that 5-15% of elderly people who have never received neuroleptics also show an orofacial dyskinesia, the prevalence rate of the condition in schizophrenic patients on neuroleptics being variously reported to be between 0.5 and 56% (mean of 20%).

Factors predisposing a patient to tardive dyskinesia include age, sex (female patients show a greater prevalence), presence of brain damage, early susceptibility to drug-induced extrapyramidal side effects and the presence of a primary affective disorder. In patients with such predisposing factors, the presence of neuroleptics may precipitate the onset of the syndrome. In addition, the schizophrenic illness itself may be a risk factor as there is evidence from clinical reports published long before the advent of neuroleptics that abnormal movements similar to tardive dyskinesia occurred. Recent evidence further suggests that schizophrenic patients with pronounced negative symptoms (e.g. blunting of affect and social withdrawal) are more likely to develop the syndrome than those with primarily positive symptoms (hallucinations, delusions, etc.). Clearly the somewhat simplistic view advanced some years ago that tardive dyskinesia was due to dopamine receptor supersensitivity resulting from prolonged dopamine receptor blockade by a neuroleptic is now redundant. Table 11.8 summarizes the risk factors for tardive dyskinesia.

Despite the diversity of drugs which have been tried for the treatment of tardive dyskinesia, no satisfactory drug therapy exists to date. In some cases the short-acting reserpine analogue tetrabenazine has been used with limited success. More recently, some success has been claimed for the calcium channel blockers verapamil and diltiazem, and for the antioxidant alpha-tocopherol (vitamin E), but double-blind controlled studies are still needed to validate the efficacy of such treatments. Clearly, since neuroleptics may precipitate this syndrome, it is essential that such drugs be prescribed only when clearly indicated, at a minimum effective dose and for only as long as their beneficial effects are clearly needed. Concurrent anticholinergic drug administration leads to a worsening of the symptoms of tardive dyskinesia, and the possibility of the syndrome arising is much greater in patients over the age of 50.

Akathisia, considered to be one of the leading causes of non-compliance with typical neuroleptics, is not thought to be linked to dopamine receptor

Table 11.8. Tardive dyskinesia: risk factors

• Duration of treatment

• Organicity

• Extrapyramidal side effects

Antiparkinsonian medications

• Drug-free intervals

• Neuroleptic: dose, potency function. Treatment with propranolol or a benzodiazepine, which may be effective, would suggest a disorder of the sympathetic or GABAergic systems. There is no evidence that a sedative antipsychotic is beneficial in the symptomatic relief of akathisia.

Recently it has been found that haloperidol and several putative atypical neuroleptics such as rimcazole, BMY14802 and HR 375 have a high affinity for sigma receptors in the mammalian brain. It is now established that the sigma receptors (see p. 453) are different from the phencyclidine receptors which are located in the ion channel of the NMDA receptor complex. Drugs like N-allylnormetazocine (NANM) and (+) pentazocine for example, bind specifically to sigma sites but not to the phencyclidine sites thereby enabling the two receptor sites to be distinguished. However, it must be emphasized that not all neuroleptics have an affinity for the sigma receptors and furthermore drugs such as rimcazole and BMY 14802 have questionable antipsychotic activity. Nevertheless it is possible that some atypical neuroleptics may owe some of their therapeutic activity to their action on sigma receptors. The possible significance of sigma receptors to the action of different classes of psychotropic drugs is discussed in Chapter 19.

It may be concluded that despite the importance of the dopamine hypothesis of schizophrenia in serving to unify the mechanism of action of both typical and atypical neuroleptics, it is apparent that some serotonin receptor subtypes, and glutamate receptors of the NMDA subtype, may also play a crucial role.

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