Relationship between the plasma concentration of paliperidone and the clinical and drug-induced extrapyramidal symptoms in elderly patients with schizophrenia.

OBJECTIVE: We investigated the relationship between the plasma concentration of paliperidone (PAL) and clinical and drug-induced extrapyramidal symptoms (EPS) in elderly patients with schizophrenia. METHODS: In this study, 15 patients with schizophrenia receiving risperidone were switched to PAL and treated for 12 weeks. Their clinical symptoms were assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impression-Severity of Illness Scale. Their EPS were assessed using the Drug-induced EPS Scale, Abnormal Involuntary Movement Scale, and Barnes Akathisia Scale at baseline and 12 weeks. Plasma concentrations were measured by the liquid chromatography-mass spectrometry/mass spectrometry method. RESULTS: The results revealed that there were significant correlations between the plasma concentration of PAL and improved Positive and Negative Syndrome Scale total, negative, and general psychopathology scores (p<0.05). However, the efficacy did not improve linearly with plasma level. No significant correlations were found between the PAL plasma concentration and the mean change from baseline in the Drug-induced EPS Scale total score, Barnes Akathisia Scale, or Abnormal Involuntary Movement Scale. CONCLUSIONS: The results of this research suggested that, in elderly patients, although none of an increased plasma concentration of PAL, a worsening of EPS, or an increase in prolactin level occurs, linear clinical efficacy may not be obtained.

Study of the efficacy and safety of switching from risperidone to paliperidone in elderly patients with schizophrenia.

AIM: We investigated the clinical efficacy and safety of switching to paliperidone (PAL) in elderly schizophrenia patients receiving risperidone. METHODS: The subjects were 27 inpatients who had been diagnosed with schizophrenia according to the DSM-IV. The patient's clinical symptoms were assessed using the Positive and Negative Syndrome Scale and the Clinical Global Impression-Severity of Illness Scale, and their safety was assessed using the Drug-induced Extrapyramidal Symptoms Scale, bodyweight, body mass index, and laboratory tests. We also investigated patient satisfaction using the Drug Attitude Inventory, a subjective outcome measure. RESULTS: No significant differences in clinical symptom improvement efficacy were seen between the PAL-switching group and the control group. The mean changes from baseline on the Drug-induced Extrapyramidal Symptoms Scale total score, Drug Attitude Inventory score, and prolactin level were significantly greater in the PAL-switching group than in the control group. Furthermore, patients with PAL needed less biperiden, even though they had similar risperidone-equivalent daily dosages to the control group. CONCLUSIONS: The results of this study suggest that switching elderly patients from risperidone to PAL may result in superior safety and patient satisfaction, and may also make it possible to reduce the dosage of biperiden.

Clomipramine inhibits dynamin GTPase activity by L-α-phosphatidyl-L-serine stimulation.

Three dynamin isoforms play critical roles in clathrin-dependent endocytosis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via clathrin-dependent endocytosis. We previously reported that 3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine (clomipramine) inhibits the GTPase activity of dynamin 1, which is in mainly neuron. Therefore, we investigated whether clomipramine inhibits the activity of other dynamin isoforms in this study. We found that, similar to its inhibitory effect on dynamin 1, clomipramine inhibited the l-α-phosphatidyl-l-serine-stimulated GTPase activity of dynamin 2, which is expressed ubiquitously, and dynamin 3, which is expressed in the lung. Inhibition of GTPase activity raises the possibility that clomipramine can suppress SARS-CoV-2 entry into host cells.

Replacement of Arg-386 with Gly in dynamin 1 middle domain reduced GTPase activity and oligomer stability in the absence of lipids.

Dynamin plays an important role in membrane fission during endocytosis, and its middle domain is involved in the formation of functional oligomers. In this study, we found that replacement of Arg-386 with Gly in the middle domain region of dynamin 1 did not affect the intermolecular interactions of dynamin 1 in the presence of phosphatidylserine-liposomes. But, unexpectedly, this variant showed lower guanosine 5'-triphosphatase activity in the absence of phosphatidylserine-liposomes and enhanced monomer formation from oligomers. Our results indicate that GTPase activity in the absence of lipids is important in the dissociation of oligomer complexes, i.e., reduced basal dynamin 1 GTPase activity is associated with instability of dynamin oligomers.

Suppression of dynamin GTPase activity by sertraline leads to inhibition of dynamin-dependent endocytosis.

Dynamin (Dyn) 1 plays a role in recycling of synaptic vesicles, and thus in nervous system function. We previously showed that sertraline, a selective serotonin reuptake inhibitor (SSRI), is a mixed-type inhibitor of Dyn 1 with respect to both GTP and L-alpha-phosphatidyl-L-serine (PS) in vitro, and we suggested that it may regulate the neurotransmitter transport by modulating synaptic vesicle endocytosis via inhibition of Dyn 1 GTPase. Here, we investigated the effect of sertraline on endocytosis of marker proteins in human neuroblastoma SH-Sy5Y cells and HeLa cells. Sertraline inhibited endocytosis in both cell lines. Western blotting showed that SH-Sy5Y expresses Dyn 1 and Dyn 2, while HeLa expresses only Dyn 2. GTPase assay showed that sertraline inhibited Dyn 2 as well as Dyn 1. Therefore, the effect of sertraline on endocytosis was mediated by Dyn 2, at least in HeLa cells, as well as by Dyn 1 in cell lines that express it. Moreover, the inhibition mechanism of transferrin (Tf) uptake by sertraline differed from that in cells expressing Dyn 1 K44A, a GTP binding-defective variant, and sertraline did not interfere with the interaction between Dyn 1 and PS-liposomes.

Some selective serotonin reuptake inhibitors inhibit dynamin I guanosine triphosphatase (GTPase).

Neuronal dynamin I plays a critical role in the recycling of synaptic vesicles, and thus in nervous system function. We expressed and purified dynamin I to explore potentially clinically useful endocytosis inhibitors and to examine the mechanism of their action. We estimated the IC(50) of nineteen psychotropic drugs for dynamin I. The IC(50) values of two selective serotonin reuptake inhibitors (sertraline and fluvoxamine) were 7.3+/-1.0 and 14.7+/-1.6 microM, respectively. Kinetic analyses revealed that fluvoxamine is a noncompetitive inhibitor of dynamin I guanosine triphosphatase (GTPase) with respect to guanosine 5'-triphosphate (GTP) and a competitive inhibitor with respect to L-phosphatidylserine (PS). Fluvoxamine may compete with PS for binding to the pleckstrin homology domain of dynamin I. On the other hand, sertraline was a mixed type inhibitor with respect to both GTP and PS. Our results indicate that sertraline and fluvoxamine may regulate the transportation of neurotransmitters by modulating synaptic vesicle endocytosis via the inhibition of dynamin I GTPase.