Development Of New Antipsychotic Drugs Research Articles

Developmental and lesion models of schizophrenia in rodents

Animal modeling of schizophrenia is essential for understanding the neurobiological basis of the disease, as well as for the development of new antipsychotic drugs with improved therapeutic efficacy and safety profile. The review aims at summarizing the methodology and practical aspects of schizophrenia modeling based on dysontogenetic disturbances of the central nervous system in rats and mice. Environmental factors or the destruction of brain structures during prenatal or postnatal periods of development cause reorganization of neural networks, leading to irreversible changes in the function of the central nervous system, which usually appear after puberty. Developmental and lesion models of schizophrenia are widely regarded as the most appropriate due to their ability to reproduce characteristic behavioral and cognitive impairments with a delayed onset of symptoms, which is consistent with the clinical presentation of schizophrenia in humans.

Target Discovery Using Deep Learning-Based Molecular Docking and Predicted Protein Structures With AlphaFold for Novel Antipsychotics.

New drugs are needed to treat antipsychotic-resistant schizophrenia, especially those with clozapine-resistant schizophrenia. Atypical antipsychotics have predominantly 5-HT2A and dopaminergic antagonism, but also require investigation of other receptors. In this study, the binding affinities between clozapine, olanzapine, and quetiapine with neuropharmacological, immunological, and metabolic receptors were measured using GNINA (Deep Learning Based Molecular Docking) and AlphaFold (Predicted Protein Structures). Through this study, it was determined that these antipsychotics showed high binding affinity to a variety of receptors, such as CB2, 5-HT1BR, NPYR4, and CCR5. Cyclosporin A and everolimus which show high affinities with those receptors could be used for the development of new antipsychotic drugs based on these drugs. In the future, the method used in this study will be applied to the development of new antipsychotic drugs, including drug repositioning, and to the discovery of the pathophysiology of schizophrenia.

Understanding the Effects of Antipsychotics on Appetite Control.

Antipsychotic drugs (APDs) represent a cornerstone in the treatment of schizophrenia and other psychoses. The effectiveness of the first generation (typical) APDs are hampered by so-called extrapyramidal side effects, and they have gradually been replaced by second (atypical) and third-generation APDs, with less extrapyramidal side effects and, in some cases, improved efficacy. However, the use of many of the current APDs has been limited due to their propensity to stimulate appetite, weight gain, and increased risk for developing type 2 diabetes and cardiovascular disease in this patient group. The mechanisms behind the appetite-stimulating effects of the various APDs are not fully elucidated, partly because their diverse receptor binding profiles may affect different downstream pathways. It is critical to identify the molecular mechanisms underlying drug-induced hyperphagia, both because this may lead to the development of new APDs, with lower appetite-stimulating effects but also because such insight may provide new knowledge about appetite regulation in general. Hence, in this review, we discuss the receptor binding profile of various APDs in relation to the potential mechanisms by which they affect appetite.

«Золотой выстрел» в лечении и диагностике шизофрении: психиатры или нейробиологи?

The available published data indicate that antagonism towards D2 receptors of dopamine is a «necessary condition» in the process of effective treatment of schizophrenia, but at the same time, this antagonism is insufficient to achieve a state of complete remission. These data serve as a powerful stimulus for the process of searching new treatments and synthesizing new drugs. The current status of the theory of neural networks demonstrates to the professional community that in order to effectively change the functioning of basic biological systems, a number of subtle changes in the central nervous system are required, which are possible with the use of certain substances. The influence of modulation of glutamate on these processes is currently a very «popular» direction both in neurobiology and in clinical psychiatry. At the same time, the role of the latter in the pathogenesis of a number of mental disorders remains unproven. In parallel with this direction, the mechanisms of serotonergic and cholinergic effects on the main components of the pathogenesis of mental disorders are being studied and used in the development of new antipsychotic drugs. Most antipsychotic drugs which belong to «new wave» exhibit an affinity for different types of receptors, which mediate the effect on several therapeutic targets. In practice, a large number of patients take certain drugs not only as monotherapy, but often combine them with other drugs. At the same time, the effectiveness of such therapeutical regimens is low. Therefore, in most modern protocols, monotherapy is still recommended. In recent years, there has been a growing body of research on pharmacotherapy augmentation strategies. The results of these studies demonstrate that augmentation preparations belonging to different pharmacological classes can be generally effective, not only in certain diseases, but also in certain types of patients. In attempts to create a model of «rational polypharmacy», it is very important to accurately define and target the therapy to «problematic symptoms», and it is also necessary to develop an optimal withdrawal strategy from the active therapy regimen. To date, the only existing «lifeline» is Clozapine, which, despite its many disadvantages, remains an effective therapeutic agent for resistant forms of schizophrenic spectrum disorders. New methods of drug synthesis, including «individual drug affinity» analysis and strategies based on the study of gene polymorphism, look promising in the context of antipsychotic drug development. It is unlikely that there will be a «golden shot» for the schizophrenic spectrum disorders in the coming decades, both in terms of diagnostics and treatment. There is a hope that some of the strategies currently being developed (polypharmacy, augmentation), along with new antipsychotic drugs entering the pharmaceutical market, will ultimately become the «shot» that the professional community, patients and their families are looking forward to.

Neuregulin-1 signalling and antipsychotic treatment

Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1-ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1-ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1-ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects.

Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia

Rare copy number variants (CNVs) play a prominent role in the etiology of schizophrenia and other neuropsychiatric disorders1. Substantial risk for schizophrenia is conferred by large (>500 kb) CNVs at several loci, including microdeletions at 1q21.1 2, 3q29 3, 15q13.3 2 and 22q11.2 4 and microduplication at 16p11.2 5. However, these CNVs collectively account for a small fraction (2-4%) of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy number gains at chromosome 7q36.3 with schizophrenia (P= 4.0×10-5, OR = 16.14 [3.06, ∞]). Microduplications with variable breakpoints occurred within a 362 kb region and were detected in 29 of 8,290 (0.35%) patients versus two of 7,431 (0.03%) controls in the combined sample (p-value= 5.7×10-7, odds ratio (OR) = 14.1 [3.5, 123.9]). All duplications overlapped or were located within 89 kb upstream of the vasoactive intestinal peptide receptor VIPR2. VIPR2 transcription and cyclic-AMP signaling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered VIP signaling in the pathogenesis of schizophrenia and suggest VIPR2 as a potential target for the development of novel antipsychotic drugs.

Group II mGluR agonist LY354740 and NAAG peptidase inhibitor effects on prepulse inhibition in PCP and d-amphetamine models of schizophrenia

Group II metabotropic glutamate receptor (mGluR) agonists represent a novel approach to the treatment of schizophrenia. Inasmuch as the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) activates these receptors, NAAG peptidase inhibitors conceptually represent a parallel path toward development of new antipsychotic drugs. While group II agonists are effective in several animal models of schizophrenia, they are reported to lack efficacy in moderating the effects of phencyclidine (PCP) on prepulse inhibition of acoustic startle in animal models of sensory processing deficits found in this disorder. The objective of this study was to re-examine the efficacy of a group II metabotropic glutamate agonist and NAAG peptidase inhibitors in prepulse inhibition models of schizophrenia across two strains of mice. The method used was an assay to determine the efficacy of these drugs in moderating the reduction in prepulse inhibition of acoustic startle in mice treated with PCP and D: -amphetamine. The group II agonist LY354740 (5 and 10 mg/kg) moderated the effects of PCP on prepulse inhibition of acoustic startle in DBA/2 but not C57BL/6 mice. In contrast, two NAAG peptidase inhibitors, ZJ43 (150 mg/kg) and 2-PMPA (50, 100, and 150 mg/kg), did not significantly affect the PCP-induced reduction in prepulse inhibition in either strain. These data demonstrate that the efficacy of group II agonists in this model of sensory motor processing is strain-specific in mice. The difference between the effects of the group II agonist and the peptidase inhibitors in the DBA/2 mice may relate to the difference in efficacy of NAAG and the agonist at mGluR2.

Antipsychotic drugs prevent the motor hyperactivity induced by psychotomimetic MK-801 in zebrafish ( Danio rerio)

Glutamate N-methyl- d-aspartate (NMDA) receptor antagonists, such as dizocilpine (MK-801), elicit schizophrenia-like symptoms in humans and a behavioral syndrome in rodents, characterized by hyperlocomotion and stereotyped actions, which is antagonized by antipsychotic drugs. Animal models of schizophrenia have been established and used for the development of new antipsychotic drugs. In this work we characterized the behavioral effects of MK-801 and investigated the effect of typical and atypical antipsychotic treatments on locomotor activity as well on the hyperlocomotion induced by MK-801 in zebrafish. MK-801 (20 μM) increased the locomotor behavior as measured by the number of line crossings, distance traveled, and the mean speed in the tank test after 15, 30, and 60 min of exposure. All tested antipsychotics counteracted MK-801-induced hyperactivity on all parameters analyzed and at doses that, given alone, had no effect on spontaneous locomotor activity. The results suggest a similar profile between typical and atypical antipsychotics in the reversal of locomotor disorders induced by MK-801. Moreover, an anxiolytic effect was verified at 30 and 60 min of MK-801 exposure, which was not reversed by antipsychotics tested in this work. In addition, olanzapine, which alone caused an anxiolytic response, when given with MK-801 potentiated the latter's effect on anxiety. In this work we demonstrated the value of the zebrafish, a simple to use animal model, in developing some behavioral features observed in schizophrenia, which may indicate a new approach for drug screening.

S20-03 Determination of drug concentrations in serum and dopamine receptor occupancy in brain for optimal antipsychotic drug therapy

Evidence has been given that antipsychotic effects of dopamine receptor antagonists are associated with 60 and 80% striatal dopamine D2 and D3 receptor occupancy. Receptor occupancy correlates well with concentrations of the antipsychotic drugs in serum or plasma, much better than the dose. The latter is consistent with weak correlations between antipsychotic dose and serum concentrations and explained by the high interindividual variabilities in drug metabolism. Using positron emission tomography (PET) for in vivo determination of dopamine receptor occupancy in conjunction with drug concentration measurements “therapeutic windows” could be calculated for the atypical antipsychotic drugs amisulpride, risperidone and ziprasidone. On the other hand, analysis of drug concentrations in serum of schizophrenic patients who were treated with these drugs and who had responded to the medication confirmed the PET derived target levels and with some modifications also those of aripiprazole and clozapine. In vivo characterisation of dopamine receptor occupancy and measurement of blood levels should therefore be part of the clinical trials during the development of new antipsychotic drugs. They provide most relevant information for the later use of therapeutic drug monitoring to optimise the treatment of individual patients.

Decrease in parvalbumin‐expressing neurons in the hippocampus and increased phencyclidine‐induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia

Treatment of rats with methylazoxymethanol (MAM) on gestational day (GD)17 disrupts corticolimbic development in the offspring (MAM-GD17 rats) and leads to abnormalities in adult MAM-GD17 rats resembling those described in schizophrenic patients. The underlying changes in specific cortical and limbic cell populations remain to be characterised. In schizophrenia, decreases in inhibitory gamma-aminobutyric acid (GABA)-containing interneurons that express the calcium-binding protein parvalbumin have been reported in the prefrontal cortex and hippocampus. In this study we analysed the expression of parvalbumin (PV), calretinin (CR) and calbindin (CB) in the prefrontal cortex and hippocampus of MAM-GD17 rats. Exposure in utero to MAM led to a significant decrease in the number of neurons expressing PV in the hippocampus, but not the prefrontal cortex. Neurons expressing CR or CB were not affected in either structure. The neurochemical changes in MAM-GD17 rats were accompagnied by increased hyperlocomotion after administration of phencyclidine (PCP), analogous to the hypersensitivity of schizophrenic patients to PCP. Therefore, the developmental MAM-GD17 model reproduces key neurochemical and behavioural features that reflect cortical and subcortical dysfunction in schizophrenia, and could be a useful tool in the development of new antipsychotic drugs.

Cholecystokinin as a target for neuropsychiatric drugs

Cholecystokinin (CKK) has gained in importance in research for several reasons. Recent evidence suggests that CCK is implicated in the regulation of anxiety. Animal studies support human findings that CCK induces anxiety-like behaviors through CCK(B) receptors. Presently available CCK antagonists do not seem to be potent anxiolytic and antipanic drugs. Animal and human studies have also been conducted on the role of CCK in schizophrenia. The obvious neuroanatomical association between dopamine and CCK continues to stimulate research directed towards the development of new antipsychotic drugs. In spite of considerable effort made in this area, it is rather doubtful that CCK agonists or antagonists can be potent antipsychotic drugs. Of particular relevance are findings implicating CCK in anxiogenic processes associated with drug dependence and withdrawal. The most important avenue for CCK seems to be addictive disorders. Considering the therapeutic potential of these compounds, further developments in this field can be anticipated.

The Importance of Side Effects in the Development of New Antipsychotic Drugs

The Importance of Side Effects in the Development of New Antipsychotic Drugs

Understanding the Mechanism of Action of Atypical Antipsychotic Drugs

The thrust of development of new antipsychotic drugs has been to identify new compounds that have enhanced antipsychotic efficacy and have lesser side-effects than standard neuroleptic compounds. Drug development strategies no longer concentrate on D2 receptor antagonism but aim to produce novel compounds. The following have been pursued: (a) selective dopamine receptor antagonists; (b) serotonin receptor agonists and antagonists (5-HT1a,e'5-HT2,5-HT3) or mixed 5-HT2-D2 receptor antagonist; (c) selective dopamine agonists or partial agonists; and (d) sigma-site and excitatory amino-acid antagonists. Such compounds are at various stages of development. The only drug which has truly distinguished itself as 'atypical' is clozapine. Its mechanism of action is unknown and the search for it, in large part, has been the impetus for development of the compounds listed above.

Pressure-induced disorders in neurotransmission and spontaneous behavior in rats: An animal model of psychosis

Disorders in neurotransmission and spontaneous behavior in rats exposed to a high pressure helium-oxygen mixture that shows interesting parallels with the dopaminergic hypothesis of schizophrenia at both the biochemical and the therapeutic responding levels are reviewed. Furthermore, as human subjects exposed to a very high pressure have shown psychotic episodes, we conclude that the pressure-induced disorders in neurotransmission and spontaneous behavior in rats could constitute a valid animal model of schizophreniform psychosis and a useful tool for both the investigation of the biological mechanisms underlying schizophrenia and the development of new antipsychotic drugs.

Dopamine receptor subtypes: implications for development of new antipsychotic drugs

Since the discovery that l-DOPA could alleviate the symptoms of Parkinson's disease, it has been assumed that the striatum is the site of action of the dopamine formed from l-DOPA. However, for the past 15 years, evidence has accumulated to suggest that dopamine is also released by the dendrites of dopamine neurons in the substantia nigra and D1 dopamine receptors in this region of the brain appear to play an important role in the actions of l-DOPA. Activation of D1 receptors in the substantia nigra may, in part, explain some of the synergistic effects of D1 and D2 agonists in animal models for Parkinson's disease. These effects are discussed in light of recent studies suggesting that dopamine, acting on D1 and D2 dopamine receptor subtypes, activates distinct efferent pathways from the striatum. Clinical studies suggest that these findings may have important implications for the treatment of Parkinson's disease.