X hits on this document

Word document

The usefulness and use of second-generation - page 31 / 81





31 / 81

have been reasonably well studied and have been shown to be beneficial in the treatment of both positive and negative symptoms [216].   However, such drugs are limited by their abuse potential and because tolerance of their therapeutic effects develops.  Valproate acts as a GABAmimetic by inhibiting the metabolizing enzyme GABA transaminase, thereby enhancing central GABAergic tone. The evidence for the efficacy of valproate has been reviewed [217]: it is suggested that the drug is of limited value as sole therapy for the treatment of schizophrenia, but it could be an effective medication for adjunctive treatment. Thus, anticonvulsant drugs with GABAergic properties may be promising candidates for the future.

Polyunsaturated fatty acids and antipsychotic action

There is evidence that patients with schizophrenia have a deficiency in omega- 3 fatty acids in their neuronal membranes [218];  clozapine has been shown to increase the concentration of such fatty acids in red blood cell membranes, suggesting that the SGAMs may contribute to the normalization of neuronal membrane function by increasing their polyunsaturated fatty acid content. This forms the basis of the phospholipid and membrane hypotheses of schizophrenia [219].   Two open studies in which fish oils rich in omega-3 fatty acids were given over a period of 6 weeks showed an improvement in both positive and negative symptoms and a marked reduction in the Abnormal Voluntary Movement scores; there was a strong correlation between the clinical improvement and the increase in the omega-3 fatty acids in the red blood cell membranes [220].   These studies have been extended to show a marked and sustained response to treatment over a 1-year period [221].  However, recently two well-designed, controlled, double-blind studies were reported, with differing results.  Fenton et al. [222] added omega-3 fatty acids or a placebo to the antipsychotic regimens of 87 patients with schizophrenia and schizoaffective disorder for 16 weeks and found no difference between adjunctive treatments.  Emsley et al. [223] added omega-3 fatty acids or a placebo to the existing antipsychotic treatments of 40 patients with schizophrenia for 12 weeks and found that the patients taking omega-3 fatty acid  had significantly reduced PANSS positive and negative scores.  Thus, omega-3 fatty acids may provide an important and novel approach to the development of antipsychotic drugs in the future.

Dopamine-receptor partial agonists

The need to develop novel antipsychotic drugs that have improved therapeutic action and reduced side-effects has stimulated an interest in dopamine receptor full antagonists and partial agonists.  This approach has been stimulated by the observation that dopaminergic neurons have autoreceptors that are sensitive to the inhibitory action of dopamine [224].  In support of the view that dopamine agonists and partial agonists exert antipsychotic action [225,226], studies have shown that apomorphine and N-propyl-norapomorphine have modest activity; more recently, the partial agonist preclamol [(-)-3PPP] has also been shown to have some therapeutic activity.  The potential advantage of partial dopamine agonists lies in the fact that their activity can vary from that of a full agonist to that of an antagonist depending on their intrinsic activity and the local concentration of dopamine at the receptor sites.  Despite the extensive experimental and clinical studies undertaken on preclamol, recent work has  demonstrated that tachyphylaxis occurs in response to the action of the drug following its chronic

Document info
Document views308
Page views308
Page last viewedSat Jan 21 04:47:39 UTC 2017