Effect of lemborexant on pharmacokinetics of clozapine: A potential drug-drug interaction mediated by time-dependent inhibition of CYP3A4.

Clozapine (CLZ) is extensively used for treatment-resistant schizophrenia (TRS) with caution to avoid serious adverse events such as agranulocytosis and drug-drug interactions (DDIs). In the current report, we present a case of a 35-year-old male non-smoking TRS patient whose steady-state plasma trough concentrations (Ctrough ) of CLZ and its active metabolite, N-desmethylclozapine (NDMC), were significantly increased after initiating oral administration of lemborexant (LEM), a dual orexin receptor antagonist, for the treatment of insomnia. The patient experienced oversedation with sleepiness and fatigue while maintaining high levels of Ctrough of CLZ. The increased concentrations of CLZ returned to normal ranges after the discontinuation of LEM dosing, implying a pharmacokinetic DDI between CLZ and LEM. To gain insight into possible mechanisms, we performed in vitro assays of CYP1A2- and CYP3A4-mediated CLZ metabolism by measuring the formations of NDMC and clozapine N-oxide (CNO). In accordance with previous studies, the incubation of CLZ with each enzyme resulted in the production of both metabolites. LEM had only a weak inhibitory effect on CYP1A2- and CYP3A4-mediated CLZ metabolism. However, the preincubation of LEM with CYP3A4 in the presence of NADPH showed a significant enhancement of inhibitory effects on CLZ metabolism with IC50 values for the formations of CNO and NDMC of 2.8 µM and 4.1 µM, respectively, suggesting that LEM exerts as a potent time-dependent inhibitor for CYP3A4. Taken together, the results of the current study indicate that co-medication of CLZ with LEM may lead to increase in exposure to CLZ and risks of CLZ-related adverse events.

Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study.

STUDY OBJECTIVES: We conducted a retrospective study to investigate the efficacy and safety of switching from other hypnotics, including benzodiazepines and Z-drugs, suvorexant, ramelteon, mirtazapine, trazodone, and antipsychotics, to lemborexant, a dual orexin receptor antagonist, for 3 months. METHODS: Clinical data obtained from the medical records of 61 patients treated at the Horikoshi Psychosomatic Clinic between December 2020 and February 2022 were analyzed, including the Athens Insomnia Scale, Epworth Sleepiness Scale, and Perceived Deficits Questionnaire-5. The primary outcome was the mean change in Athens Insomnia Scale score after 3 months. Secondary outcomes were the mean changes in the Epworth Sleepiness Scale and Perceived Deficits Questionnaire-5 scores over 3 months. We also compared pre- and post-diazepam equivalents. RESULTS: The mean Athens Insomnia Scale score decreased over 3 months after switching to lemborexant (1 mo: -2.98 ± 5.19, P < .001; 2 mo: -3.20 ± 5.64, P < .001; 3 mo: -3.38 ± 5.61, P < .001). Mean Epworth Sleepiness Scale score did not change from baseline to 1 month (-0.49 ± 3.41, P = 0.27), 2 months (0.082 ± 4.62, P = .89), or 3 months (-0.64 ± 4.80, P = .30). Mean Perceived Deficits Questionnaire-5 score did improve from baseline to 1 month (-1.17 ± 2.47, P = .004), 2 months (-1.05 ± 2.97, P = .029), and 3 months (-1.24 ± 3.06, P = .013). There was also a reduction in the total diazepam equivalent (baseline vs 3 mo: 14.0 ± 20.2 vs 11.3 ± 20.6, P < .001). CONCLUSIONS: Our study showed that, by switching to lemborexant from other hypnotics, the risks associated with benzodiazepines and Z-drugs may be reduced. CITATION: Horikoshi S, Miura I, Suzuki Y, et al. Switching to lemborexant for the management of insomnia in mental disorders: the SLIM study. J Clin Sleep Med. 2023;19(10):1753-1758.

Effect of Switching to Brexpiprazole on Plasma Homovanillic Acid Levels and Antipsychotic-Related Side Effects in Patients with Schizophrenia or Schizoaffective Disorder.

OBJECTIVE: Although switching antipsychotics is a common strategy in the treatment of schizophrenia, caution is needed because of the risk of worsening of psychosis, particularly when switching to a dopamine D2 partial agonist. Homovanillic acid (HVA), a dopamine metabolite, is thought to be a possible indicator of the response to antipsychotics. We examined the effects of switching to brexpiprazole monotherapy from other antipsychotics on plasma HVA levels and side effects during maintenance treatment of schizophrenia. METHODS: The antipsychotics of 37 Japanese patients with schizophrenia or schizoaffective disorder were switched to brexpiprazole for the improvement of side effects. We evaluated clinical symptoms and extrapyramidal symptoms (EPS) and took fasting blood samples at baseline and endpoint (eight weeks after completing the switch) to measure plasma levels of HVA, prolactin, and metabolic parameters. RESULTS: Switching to brexpiprazole significantly decreased the Drug-Induced Extrapyramidal Symptoms Scale total score (p=0.008), prolactin levels (p<0.001), body weight (p=0.046), and body-mass index (p=0.034), and increased HDL cholesterol (p=0.008). On the other hand, switching to brexpiprazole did not change plasma levels of HVA or Positive and Negative Syndrome Scale scores. CONCLUSION: Switching to brexpiprazole significantly improved EPS, high prolactin levels, and metabolic side effects without elevating plasma HVA levels. Brexpiprazole may stabilize dopaminergic neural transmission and could be a useful strategy to decrease the burden in patients with schizophrenia during the maintenance phase. Because of the small sample size, further studies with larger sample sizes are needed to confirm and extend our results.

Plasma levels of dopamine metabolite correlate with mismatch negativity in patients with schizophrenia.

AIM: Mismatch negativity (MMN) deficit is one of the most robust and replicable findings in schizophrenia, and primarily reflects deficient functioning of the N-methyl-D-aspartate (NMDA) receptor system. Although the dopamine receptor is known not to modulate MMN over the short term, it is unclear whether the dopamine system affects MMN in the long term. METHODS: We explored correlations between MMN and levels of plasma dopamine and serotonin metabolites in 18 patients with schizophrenia psychiatrically evaluated with the Positive and Negative Syndrome Scale (PANSS). RESULTS: A significant negative correlation exists between MMN amplitude and plasma levels of dopamine metabolites. Plasma serotonin metabolite levels were not correlated with MMN. The PANSS total score and Negative score also showed negative correlations with MMN amplitude. CONCLUSION: The usual strong therapeutic blockade of dopamine receptors applied in cases of schizophrenia may reduce MMN over the long term.

Low- and high-dose aripiprazole augmentation and plasma levels of homovanillic acid in major depressive disorder: A randomized, open-label study.

OBJECTIVE: This randomized controlled study evaluated the efficacy of low-dose (LD) and high-dose (HD) aripiprazole augmentation in major depressive disorder. Additionally, we examined the relationship between clinical response and changes in plasma homovanillic acid (pHVA) levels during aripiprazole augmentation. METHODS: Thirty-one patients with inadequate response to antidepressants were randomized to receive adjunctive treatment with LD (3 mg/day, n = 17) or HD (up to 12 mg/day, n = 14) aripiprazole for 6 weeks. We evaluated the Montgomery-Åsberg Depression Rating Scale (MADRS) and measured pHVA at baseline, Week 2, and end point. RESULTS: Both LD and HD aripiprazole significantly decreased MADRS score after 6 weeks, and the response rate was higher in HD aripiprazole group at end point. HD aripiprazole significantly decreased MADRS score at Week 2 compared with LD aripiprazole (p = .015). There was a significant difference in changes in pHVA between responders and nonresponders, showing pHVA decreased significantly in responders at Week 2 (p = .044). CONCLUSIONS: Increasing aripiprazole from the early period appeared useful for immediate response, although caution is needed when increasing the dose >6 mg/day. pHVA may be a possible indicator of the response to aripiprazole augmentation. Caution is needed in interpreting these findings because of the small sample size.

The Relationship between Mismatch Negativity and the COMTVal108/158Met Genotype in Schizophrenia.

Mismatch negativity (MMN) is a component of auditory event-related potentials that reflects automatic change detection in the brain, showing qualities of endophenotypes in schizophrenia. MMN deficiency is one of the robust findings in patients, and it reflects both cognitive and functional decline. Catechol-o-methyltransferase (COMT) is a key enzyme involved in regulating dopamine transmission within the prefrontal cortex. A preliminary study suggested that the COMTVal108/158Met genotype (rs4680) is related to cognitive function in schizophrenia. Both the COMTVal108/158Met genotype and MMN are related to cognitive function, but no studies have reported on the relationship between MMN and the COMTVal108/158Met genotype in schizophrenia. This study therefore examined the relationship between COMTVal108/158Met genotype and MMN. The duration of MMN was measured, and the COMTVal108/158Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism in 49 Japanese schizophrenia patients (Val/Val, n = 21; Met carriers, n = 28). Amplitude and latency of MMN were compared between Val/Val and Met carriers.

COMT Val 108/158 Met polymorphism and treatment response to aripiprazole in patients with acute schizophrenia.

INTRODUCTION: The COMT Val 108/158 Met polymorphism (rs4680) may affect treatment response to antipsychotics, as well as metabolism and dynamics of neurotransmitters during the treatment of schizophrenia. We investigated the effects of the COMT Val 108/158 Met polymorphism on treatment response to aripiprazole and plasma monoamine metabolite levels in patients with acute schizophrenia. MATERIALS AND METHODS: Forty patients with schizophrenia were treated with aripiprazole for 6 weeks. We measured Positive and Negative Syndrome Scale (PANSS) and plasma levels of homovanillic acid (HVA) and plasma MHPG (3-methoxy-4-hydroxyphenethyleneglycol) at baseline and endpoint. The COMT Val 108/158 Met polymorphism was genotyped with the polymerase chain reaction and restriction fragment length polymorphism. RESULTS: There were significant genotype-time interactions on PANSS total and general psychopathology scores, with Met/Met genotype showing greater improvement. The response rate to aripiprazole did not differ between COMT Val 108/158 Met genotype groups. We found a significant time effect on plasma MHPG levels, but no time effect on plasma HVA levels or time-genotype interactions in the plasma levels of HVA and MHPG. Although the responder rate did not differ among the 3 genotype groups. CONCLUSION: Our results suggest that individuals with the Met/Met genotype had greater improvement in PANSS score after the treatment with aripiprazole. On the other hand, the Val 108/158 Met polymorphism may not induce changes in plasma levels of monoamine metabolites during aripiprazole treatment. Because of the small sample size, further studies are needed to confirm and to extend our results.

DNA methylation of ANKK1 and response to aripiprazole in patients with acute schizophrenia: A preliminary study.

Epigenetic modification including DNA methylation may affect pathophysiology and the response to antipsychotic drugs in patients with schizophrenia. The objective of the present study was to investigate the effect of the DNA methylation of ANKK1 (ankyrin repeat and kinase domain containing 1) on the response to aripiprazole and plasma levels of monoamine metabolites in antipsychotic-free acute schizophrenia patients. The subjects were 34 Japanese patients with schizophrenia who had been treated with aripiprazole for 6 weeks. Comprehensive DNA methylation of ANKK1 was determined using a next-generation sequencer. DNA methylation levels at CpG site 387 of ANKK1 were higher in responders to treatment with aripiprazole and correlated with the changes in Positive and Negative Syndrome Scale scores, although the associations did not remain significant after Bonferroni correction. In responders, methylation at all CpG sites was significantly correlated with plasma levels of homovanillic acid (r = 0.587, p = 0.035) and 3-methoxy-4hydroxyphenylglycol (r = 0.684, p = 0.010) at baseline. Despite our non-significant results after multiple correction, our preliminary findings suggest that methylation levels at CpG site 387 of ANKK1 may be associated with treatment response to aripiprazole. Furthermore, methylation of ANKK1 may affect dopaminergic neural transmission in the treatment of schizophrenia, and may influence treatment response. Caution is needed in interpreting these findings because of the small sample size, and further studies are needed to confirm and expand our preliminary results.

Hashimoto encephalopathy with high plasma monoamine metabolite levels: a case report.

Hashimoto encephalopathy (HE) is believed to be an immune-mediated disorder associated with Hashimoto's thyroiditis. It was suggested that neuropsychiatric symptoms, the presence of antithyroid antibody, and good response to steroids were important for the diagnosis of HE. It has been reported that homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), which are monoamine metabolites of dopamine and noradrenaline, respectively, are the possible biomarkers of neuropsychiatric diseases. We report a case of Hashimoto encephalopathy, in which we longitudinally measured the plasma levels of monoamine metabolites. A 52-year-old woman developed acute psychosis, and was admitted to the psychiatric ward of our hospital due to psychotic state, 6 days after a traffic accident. An extensive evaluation showed no remarkable findings, except an increase in antithyroglobulin antibodies. Plasma levels of HVA and MHPG were extremely high at 66.5 and 41.8 ng/mL, respectively. On day 16, 50 mg/day oral prednisolone was administered, which improved her psychotic symptoms. Plasma levels of HVA and MHPG decreased to 7.2 and 9.9 ng/mL, respectively, on day 19. After the temporary worsening of psychosis and increase in plasma levels of HVA and MHPG, the dosage of prednisolone was tapered and low-dose risperidone was started. Her psychiatric symptoms gradually improved and plasma monoamine metabolite levels decreased again (HVA: 17.9 ng/mL; MHPG: 7.7 ng/mL). Although autoimmune mechanism has been suggested to be involved in HE, neural mechanism and pathogenesis of HE remain unknown. Our findings suggest that monoaminergic neural activity might be associated with psychotic symptoms in patients with HE and plasma levels of monoamine metabolites might be useful as state markers.

Associations between five-factor model of the Positive and Negative Syndrome Scale and plasma levels of monoamine metabolite in patients with schizophrenia.

The five-factor model of the Positive and Negative Syndrome Scale (PANSS) for schizophrenia symptoms is the most common multiple-factor model used in analyses; its use may improve evaluation of symptoms in schizophrenia patients. Plasma monoamine metabolite levels are possible indicators of clinical symptoms or response to antipsychotics in schizophrenia. We investigated the association between five-factor model components and plasma monoamine metabolites levels to explore the model's biological basis. Plasma levels of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography in 65 Japanese patients with schizophrenia. Significant negative correlation between plasma 5-HIAA levels and the depression/anxiety component was found. Furthermore, significant positive correlation was found between plasma MHPG levels and the excitement component. Plasma HVA levels were not correlated with any five-factor model component. These results suggest that the five-factor model of the PANSS may have a biological basis, and may be useful for elucidating the psychopathology of schizophrenia. Assessment using the five-factor model may enable understanding of monoaminergic dysfunction, possibly allowing more appropriate medication selection. Further studies of a larger number of first-episode schizophrenia patients are needed to confirm and extend these results.

Effects of Shakuyaku-Kanzo-to on Extrapyramidal Symptoms During Antipsychotic Treatment: A Randomized, Open-Label Study.

Extrapyramidal symptoms (EPS) are common adverse effects of antipsychotic treatment. This study examined the effects of the traditional Japanese herbal medicine (kampo) shakuyaku-kanzo-to on EPS during antipsychotic treatment. Twenty-two Japanese patients with psychiatric disorders who had developed EPS during antipsychotic treatment were randomly allocated to receive either shakuyaku-kanzo-to (7.5 g/d) or biperiden (3 mg/d) for 2 weeks. Extrapyramidal symptoms were evaluated using the Drug-Induced Extrapyramidal Symptom Scale (DIEPSS) and the Barnes Akathisia Rating Scale. Plasma levels of the monoamine metabolite homovanillic acid and serum prolactin levels were measured to investigate the mechanisms of action of shakuyaku-kanzo-to. Twenty of the 22 patients completed the study (10 patients in the shakuyaku-kanzo-to group and 10 patients in the biperiden group). There was a time effect on the Drug-Induced Extrapyramidal Symptom Scale total score (P < 0.01), suggesting that both shakuyaku-kanzo-to and biperiden decreased EPS. Notably, there was a time × drug interaction in dystonia, suggesting that shakuyaku-kanzo-to had a greater effect on dystonia compared with biperiden. No significant changes were observed in plasma homovanillic acid or serum prolactin levels after 2 weeks of treatment in either group. The effects of shakuyaku-kanzo-to on abnormal muscle tonus and dopamine D2 receptors may have contributed to improve EPS. These results suggest that shakuyaku-kanzo-to may be useful in decreasing EPS, especially dystonia, in patients undergoing treatment with antipsychotic agents.

Impacts of age on plasma monoamine metabolite concentrations in a large cohort of healthy individuals.

The measurement of plasma concentrations of monoamine metabolites is a useful method for inferring the dynamics of monoamine metabolites in the brain. To clarify effects of age and sex on plasma monoamine metabolites levels, we used high-performance liquid chromatography to measure plasma levels of homovanillic acid (HVA), free and total 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) in healthy men and women of various ages (n=214). In all plasma monoamine metabolites, there were significant differences across the age groups, and multiple comparisons revealed that older subjects had higher levels than younger subjects. Moreover, significant positive correlations were found between age and plasma levels of HVA, free MHPG, total MHPG, and 5-HIAA. On the other hand, plasma concentrations of monoamine metabolites were not influenced by sex, except for total MHPG for which the plasma levels were significantly higher in men than in women. Age-related changes in monoamine oxidase and renal function might affect our results. This large cohort survey provides further evidence to be cautiously aware of age effects when regarding plasma monoamine metabolites levels as reflections of central activity.

Near-infrared spectroscopy and plasma homovanillic acid levels in bipolar disorder: a case report.

Misdiagnosis of bipolar disorder is a serious, but not unusual problem for patients. Nevertheless, there are few biomarkers for distinguishing unipolar and bipolar disorder. Near-infrared spectroscopy (NIRS) is a noninvasive and useful method for the measurement of hemoglobin concentration changes in the cortical surface area, which enables the assessment of brain function. We measured NIRS and plasma monoamine metabolite levels in a patient with bipolar disorder. A 22-year-old man was admitted due to major depression. At admission, NIRS findings showed oxygenated hemoglobin reincrease in the posttask period, which is characteristic of schizophrenia. After treatment with paroxetine, he became manic with psychotic symptoms. His plasma level of homovanillic acid just before the manic switch was ten times higher than that just after paroxetine initiation. Treatment with lithium and antipsychotics was successful, and plasma homovanillic acid decreased after treatment. In this case, the NIRS findings may predict a possible risk of a manic switch, which is likely induced by paroxetine. NIRS may be able to help distinguish unipolar and bipolar disorder in clinical settings.

Switching antipsychotics to aripiprazole or blonanserin and plasma monoamine metabolites levels in patients with schizophrenia.

OBJECTIVE: Blonanserin is a novel atypical antipsychotic drug that has efficacy equal to risperidone. We investigated the effects of aripiprazole and blonanserin on clinical symptoms and plasma levels of homovanillic acid (pHVA) and 3-methoxy-4hydroxyphenylglycol in the switching strategy of schizophrenia. METHODS: Twenty two Japanese patients with schizophrenia were enrolled into this open study. The antipsychotics of all patients were switched to aripiprazole or blonanserin for the improvement of clinical symptoms or side effects. Plasma monoamine metabolites levels were analyzed with high-performance liquid chromatography. RESULTS: There were no significant effects for time (p = 0.346) or time × group interaction (p = 0.27) on the changes of positive and negative syndrome scale (PANSS) total score, although blonanserin decreased PANSS scores. We observed negative correlation between pHVA at baseline and the change in PANSS total score (rs = -0.450, p = 0.046). We also found positive correlation between the changes in pHVA and the changes in PANSS total (rs = 0.536, p = 0.015) and positive (rs = 0.572, p = 0.008) scores. CONCLUSIONS: There were no differences between blonanserin and aripiprazole in the improvement of clinical symptoms. Our results suggest that pHVA may be useful indicator for the switching strategy to aripiprazole or blonanserin in schizophrenia.