Novel pharmacological treatment alternatives for schizophrenia
Year: 2007
Type: dissertation
Abstract: Antipsychotic drugs are commonly divided into typical (first generation)\nand atypical (second generation) antipsychotic drugs. Clinically\neffective doses of typical antipsychotic drugs generate a striatal\ndopamine D2 receptor occupancy of about 70 80%, approaching a level\nthat is associated with a high risk of extrapyramidal side effects.\nTypical antipsychotic drugs are mostly effective against positive\nsymptoms, but have a more limited effect on and may even exacerbate\nnegative and cognitive symptoms. In contrast, some, but not all, atypical\nantipsychotic drugs are clinically effective at lower D2 receptor\noccupancy. Clozapine, which may be considered as the prototypical\natypical antipsychotic drug, thus displays only around 45% D2 receptor\noccupancy and generates virtually no extrapyramidal side effects.\nCompared with typical antipsychotic drugs, atypical antipsychotics have\nbeen found to improve not only positive symptoms, but also negative\nsymptoms and cognitive impairment. Several atypical antipsychotic drugs\nare, however, associated with other major side effects, such as for\nexample weight gain, diabetes, heavy sedation and even agranulocytosis.\nClozapine has a broad spectrum of receptor affinities and acts as an\nantagonist at several dopamine receptors (i.e. D2, D3 and D4 receptors),\nbut also at e.g. α1 and α2 adrenoceptors, 5-HT2A and 5-HT2C receptors,\nmuscarinic and histaminergic (H1) receptors. In contrast to a typical\nantipsychotic drug such as haloperidol most atypical antipsychotic drugs\nhave been found to increase dopamine in the medial prefrontal cortex of\nrodents. Moreover, most atypicals that generate improved cognitive\nfunction also enhance prefrontal glutamatergic transmission and increase\nextracellular levels of acetylcholine in the cerebral cortex. Since\ntreatment outcome is critically dependent on the degree of cognitive\nimpairment, the putative cognitive enhancing effects of antipsychotic\ndrugs are of considerable interest. Generally, the currently available\ndrugs for schizophrenia are insufficient in this regard. Therefore, the\ndevelopment of more effective and better tolerated antipsychotic drugs\nwith less side effects is highly warranted. This development may be\nfacilitated by evaluation of so-called augmentation strategies using\ncombinations of existing antipsychotics and other psychoactive drugs,\nsuch as for example antidepressants and various selective ligands for\nspecific neurotransmitter-related targets in the brain. In this thesis we\nhave experimentally evaluated several augmentation strategies employing a\ncombination of behavioral, biochemical and electrophysiological\ntechniques.\n\nOur results show that the addition of two antidepressant drugs,\nreboxetine or mianserin, significantly augment the antipsychotic-like\neffect induced by raclopride without affecting the raclopride-induced\ncatalepsy, concomitant with a preferentially increased prefrontal\ndopamine output. We have also shown that adjunctive treatment with the\nselective α2 adrenoceptor antagonist idazoxan when added to a typical\n(haloperidol) or an atypical (olanzapine) antipsychotic drug,\nsignificantly enhances the suppression of conditioned avoidance response\n(CAR) without increasing catalepsy and produces a substantial increase in\ndopamine output in the medial prefrontal cortex. Moreover, we have found\nthat galantamine, a cognitive enhancing drug used in Alzheimer s disease,\nfacilitates the excitability of VTA dopamine neurons via allosteric\npotentiation of nicotinic acetylcholine receptors of the α7 subtype, and\nthat galantamine through this mechanism, rather than through\nacetylcholine esterase inhibition, increases prefrontal dopamine outflow.\nSubsequently, we observed that addition of galantamine to raclopride can\nsignificantly enhance the raclopride-induced suppression of CAR without\nincreasing catalepsy, effects that could not be reproduced by adjunctive\ntreatment with donepezil, a selective acetylcholine esterase inhibitor.\nOur data support the view that increasing prefrontal dopamine and\nnoradrenaline output either by blocking the noradrenaline transporter or\nthe noradrenergic autoreceptor may represent viable strategies to augment\nthe efficacy of antipsychotic drugs without increasing extrapyramidal\nside effect liability. Our previous results also provide evidence that\nthis strategy may secondarily facilitate cortical glutamatergic\ntransmission and cognitive functioning, e.g. working memory. Our data\nfinally provide support for the adjunctive use of galantamine together\nwith antipsychotic drugs in schizophrenia, not only to improve cognition\nand negative symptoms, but also to potentially enhance the antipsychotic\neffect per se. By inference, these results support the development of\nselective allosteric potentiators of α7 nicotinic acetylcholine receptors\nfor the treatment of schizophrenia.
Source: Figshare
Author: Charlotte Wiker
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W1532804735