Novel antipsychotics in development haldol for dementia – Psychotropic Drugs

The improvement of the secondary negative symptoms, and the symptoms of depression often associated with schizophrenia, has been an important feature of the atypical antipsychotics. Such pharmacological features may reside in the actions of the haldol for dementia atypical antipsychotics on 5-HT2 receptors in addition to their actions on dopamine receptors. For example, all these drugs have a high affinity for 5-HT2A and 2C receptors, and to a lesser extent 5-HT6 and 5-HT7 receptors. For these reasons, several compounds have been developed with a high affinity for haldol for dementia 5-HT2 receptors. Of these, pipamerone, a highly selective 5-HT2/D2 antagonist, has been shown to have an anti-autistic, disinhibiting and resocializing effect and a low frequency of extrapyramidal haldol for dementia side effects. By contrast, MDL 100 907, a compound largely lacking D2 antagonism but a potent 5-HT2A antagonist, while showing promising antipsychotic properties in pre-clinical studies, was not found to be as effective as haloperidol in haldol for dementia the treatment of schizophrenia. Similarly, the D4/5-HT2A antagonist fananserin lacked clinical efficacy despite a promising experimental haldol for dementia profile. It is not without interest that several selective D4 antagonists haldol for dementia have failed to show clinical efficacy in the treatment of haldol for dementia schizophrenia despite the evidence that some typical (e.G. Haloperidol) and atypical (e.G. Clozapine) agents increase the density of these receptors following chronic treatment. Thus it would appear that the 5-HT2A antagonism, together with D2 antagonism, may contribute to the atypical profile of the new antipsychotics haldol for dementia but the 5-HT2A antagonism alone would not appear to confer antipsychotic effects. Adrenergic receptors and antipsychotic action

While most schizophrenia research has focused on the importance of haldol for dementia dopamine, there is evidence that hyperactivity of the noradrenergic system also haldol for dementia occurs in these patients. There is clinical evidence that the alpha-2 adrenoceptor antagonists can improve memory in schizophrenic patients and haldol for dementia that atypical antipsychotics are more effective than typical neuroleptics in haldol for dementia normalizing the cognitive deficits in these patients presumably due to haldol for dementia their actions on alpha-2 receptors. There is also evidence that both alpha-1 adrenoceptors and 5-HT2A receptor stimulation of the prefrontal cortex can cause cortical haldol for dementia dysfunction. As many of the atypical antipsychotics are antagonists of both haldol for dementia alpha-1 and 5-HT2A receptors, such actions could help to explain the improved cognitive function haldol for dementia seen with these drugs. So far such clinical and experimental findings have not been haldol for dementia extended to the development of novel antipsychotics with a view haldol for dementia to enhancing their improved cognitive action. Glutamatergic receptors and antipsychotic action

Recent experimental and clinical evidence suggests that the glutamatergic system haldol for dementia plays a vital role in the pathophysiology of schizophrenia and haldol for dementia may also contribute to the efficacy of atypical antipsychotics. In post-mortem schizophrenic brains, messenger RNA expression of the main glutamate receptor subtypes has haldol for dementia shown that the kainate and AMPA metabotropic receptors, and subtypes of the NMDA ionotropic receptor, are decreased. Most studies have concentrated on the NMDA receptors where it haldol for dementia has been shown that atypical antipsychotics such as clozapine decrease haldol for dementia some subtypes of this receptor: the densities of the kainate and AMPA receptors have been haldol for dementia shown to increase. Such findings underpin the application of drugs which activate the haldol for dementia NMDA receptors as possible novel antipsychotics. Thus glycine and D-serine, as NMDA receptor agonists, have been studied for their potential antipsychotic effects. High doses of glycine (30-60 g/day) have been shown to improve the negative symptoms in schizophrenia. D-serine, a full agonist at the NMDA receptor glycine site, was also reported to improve the negative symptoms, psychosis and cognitive function of schizophrenic patients while D-cycloserine, a partial agonist of the glycine site, was also shown to improve the negative symptoms when added haldol for dementia to conventional neuroleptics without improving the cognitive function. These preliminary clinical findings would support the possible value of haldol for dementia drugs that enhance glycine receptor function at least in the haldol for dementia treatment of the negative symptoms of schizophrenia.

Several compounds that act as positive modulators of the AMPA haldol for dementia receptors have also been studied. Of these, CX516 was shown to improve the attention, memory and distractability of patients together with a significant improvement haldol for dementia of cognitive function. Thus it would appear that agonists of the glycine site haldol for dementia on the NMDA receptor, and modulators of the AMPA receptors, may prove to be novel antipsycho-tics in the future. Sigma receptors and antipsychotic action

Since the discovery that the psychotomimetic benzomorphans act on sigma haldol for dementia receptors in the brain, while some antipsychotics such as haloperidol and remoxipride act as haldol for dementia sigma receptor antagonists, attention has been directed towards the development of sigma receptor haldol for dementia antagonists as potential antipsychotic agents (see p. 453). Several sigma antagonists have been clinically tested over the past haldol for dementia 17 years. However, most trials to date involve few patients, few studies have been replicated and many of the first haldol for dementia sigma agents to be tested were also antagonists of 5-HT2 receptors (e.G. Rimcazole, tiosperone). Of the more specific sigma antagonists, panamesine (EMD 57445) has been the subject of three trials involving a small haldol for dementia number of patients. Panamesine was found to exert acute antipsychotic effects at least haldol for dementia in some patients. Eliprodil (SL 820715) is also a sigma ligand but in addition has NMDA haldol for dementia antagonistic properties which could limit its efficacy. In an open trial, eliprodil was shown to improve the negative symptoms in a haldol for dementia small number of patients. A potent selective sigma antagonist, SR-31742, is also currently undergoing clinical trials in schizophrenia, the results of which may provide conclusive evidence regarding the haldol for dementia antipsychotic potential of such drugs. Thus it would appear that there is some evidence that haldol for dementia sigma antagonists may have antipsychotic potential but more detailed clinical haldol for dementia studies are required to substantiate this. GABAergic receptors and antipsychotic action

Experimental studies have demonstrated that the GABA-A receptors have an inhibitory action on the dopaminergic system haldol for dementia while the GABA-B receptors have an indirect stimulatory action on these receptors. Thus it would be anticipated that GABA-A receptor agonists might be of some value in the haldol for dementia treatment of schizophrenia. Of the drugs available, the benzodiazepines have been reasonably well studied and shown to haldol for dementia be beneficial in the treatment of both positive and negative haldol for dementia symptoms. However, such drugs are limited by their abuse potential and because haldol for dementia tolerance develops to their therapeutic effects. Valproate acts as a gabamimetic by inhibiting the metabolizing enzyme haldol for dementia GABA transaminase thereby enhancing central gabaergic tone. The evidence for the efficacy of valproate has been reviewed haldol for dementia and suggests that valproate is of limited value as the haldol for dementia sole therapy for the treatment of schizophrenia but could be haldol for dementia an effective drug for adjunctive treatment. Thus anticonvulsants with gabaergic properties may be promising candidates for haldol for dementia the future.

There is evidence that schizophrenic patients have a deficiency in haldol for dementia omega 3 fatty acids in their neuronal membranes while clozapine haldol for dementia has been shown to increase the concentration of such fatty haldol for dementia acids in red blood cell membranes, thereby suggesting that atypical antipsychotics may contribute to the normalization haldol for dementia of neuronal membrane function by increasing their polyunsaturated fatty acid haldol for dementia content. This forms the basis of the membrane hypothesis of schizophrenia. Two open studies in which fish oils rich in omega haldol for dementia 3 fatty acids were given over a period of 6 haldol for dementia weeks showed an improvement in both positive and negative symptoms haldol for dementia and a marked reduction in the abnormal voluntary movement scores; there was a strong correlation between the clinical improvement and haldol for dementia the increase in the omega 3 fatty acids in the haldol for dementia red blood cell membranes. These studies have been extended to show a marked and haldol for dementia sustained response to treatment over a 1-year period. Thus omega 3 fatty acids may provide an important and haldol for dementia novel approach to the development of antipsychotics in the future.