Effects of antipsychotic drugs on neurites relevant to schizophrenia treatment

Abstract

Although antipsychotic drugs are mainly used for treating schizophrenia, they are widely used for treating various psychiatric diseases in adults, the elderly, adolescents and even children. Today, about 1.2% of the worldwide population suffers from psychosis and related disorders, which translates to about 7.5 million subjects potentially targeted by antipsychotic drugs. Neurites project from the cell body of neurons and connect neurons to each other to form neural networks. Deficits in neurite outgrowth and integrity are implicated in psychiatric diseases including schizophrenia. Neurite deficits contribute to altered brain development, neural networking and connectivity as well as symptoms including psychosis and altered cognitive function. This review revealed that (1) antipsychotic drugs could have profound effects on neurites, synaptic spines and synapse, by which they may influence and regulate neural networking and plasticity; (2) antipsychotic drugs target not only neurotransmitter receptors but also intracellular signaling molecules regulating the signaling pathways responsible for neurite outgrowth and maintenance; (3) high doses and chronic administration of antipsychotic drugs may cause some loss of neurites, synaptic spines, or synapsis in the cortical structures. In addition, confounding effects causing neurite deficits may include elevated inflammatory cytokines and antipsychotic drug-induced metabolic side effects in patients on chronic antipsychotic therapy. Unraveling how antipsychotic drugs affect neurites and neural connectivity is essential for improving therapeutic outcomes and preventing aversive effects for patients on antipsychotic drug treatment.

Synapse Pathology in Schizophrenia: A Meta-analysis of Postsynaptic Elements in Postmortem Brain Studies

“…In particular, the use of antipsychotics has been suggested to influence synapse density. 82 , 83 Although some studies (10) did not/could not correct for medication use, 49 , 51 , 54 , 58 , 69 , 71 , 73 , 74 , 76 , 78 most studies included in our meta-analyses (18) found no association between medication use and the outcome measurement. 12 , 48 , 50 , 52 , 57 , 61–68 , 70 , 72 , 75 , 77 Thus, while our study shows a decrease in density of postsynaptic elements in SCZ, future research will need to address the contribution of these confounding factors.…”

The histone deacetylase complex MiDAC regulates a neurodevelopmental gene expression program to control neurite outgrowth

“…Here, we describe how the axon guidance ligands SLIT3 and NTN1 are transcriptionally controlled by an epigenetic regulator, the MiDAC complex. Finally, neurite outgrowth defects are observed in several neurodevelopmental disorders such as autism, epilepsy, fragile X-syndrome and psychiatric disorders (Gilbert & Man, 2017, Huang & Song, 2019, Krejci, Legartova et al, 2017, Wen, Cheng et al, 2017. However, the underlying molecular mechanisms remain unclear.…”

Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons

“…Notably, although both haloperidol and aripiprazole are able to diminish D2R-DISC1 complexes, haloperidol shows no effect on neuronal protection (Zheng et al, 2018). It suggests that complete blockade of D2R by antipsychotic drugs reduces D2R and DISC1 interaction, but may not protect neurites, which reflects their insufficiency for cognitive improvement (Huang and Song, 2019). It has been reported that there is increased D2R-DISC1 complex formation in the striatum of post-mortem schizophrenic brains (Su et al, 2014).…”