Lurasidone for the Treatment of Schizophrenia: Design, Development, and Place in Therapy.

This review aims to provide a comprehensive overview of the current literature on the drug design, development, and therapy of lurasidone for the treatment of schizophrenia. Lurasidone has antagonistic effects on the dopamine D2, 5-hydroxytryptamine (5-HT)2A, and 5-HT7 receptors and a partial agonistic effect on the 5-HT1A receptor with low affinities for muscarinic M1, histamine H1, and a1 adrenergic receptors. The receptor-binding profile of lurasidone is thought to be associated with fewer side effects such as anticholinergic effects, lipid abnormalities, hyperglycemia, and weight gain. Behavioral pharmacological studies have demonstrated that lurasidone exerts anxiolytic and antidepressive effects and improves cognitive function, which are associated with the modulation of 5-HT7 and 5-HT1A receptors. Literature search using PubMed was performed to find published studies of randomized controlled trials and recent meta-analyses regarding efficacy and safety, particularly metabolic side effects of lurasidone in schizophrenia. In short-term studies, the results of randomized placebo-controlled trials and meta-analyses have suggested that lurasidone was superior to placebo in improving total psychopathology, positive symptoms, negative symptoms, and general psychopathology in patients with acute schizophrenia. Regarding safety, lurasidone had minimal metabolic side effects, and was identified as one of the drugs with the most benign profiles for metabolic side effects. Long-term trials revealed that lurasidone had the preventive effects on relapse, with minimal effects on weight gain and other metabolic side effects. Furthermore, lurasidone improves cognitive and functional performance of patients with schizophrenia, especially in long-term treatment. Patients with schizophrenia require long-term treatment with antipsychotics for relapse prevention; thus, minimizing weight gain and other side effects is crucial. Lurasidone is suitable as one of the first-line antipsychotic drugs in the acute phase, and a switching strategy should be considered during the maintenance phase, to balance efficacy and adverse effects and achieve favorable outcomes in the long-term course of schizophrenia.

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.

Second-Generation Antipsychotic Long-Acting Injection Reduced the Time of Restrictive Interventions in Patients With Schizophrenia: Retrospective, A 4-Year Mirror-Image Study.

BACKGROUND: Whether second-generation antipsychotic long-acting injection (SGA-LAI) reduces psychotic symptoms at relapse compared with oral antipsychotics remains unclear. The present study investigated the effects of SGA-LAI on the time (in hours) of restrictive interventions in hospitalization by conducting a retrospective observational 4-year mirror-image study at a single medical center in Japan. METHOD: We performed a retrospective observational mirror-image study conducted between November 2013 and January 2018. Data were initially retrieved from 101 patients. The 38 patients with schizophrenia who met the inclusion criteria were enrolled in the analysis. The primary outcome was the time of restrictive interventions and the secondary outcomes included the number of hospitalizations (total, voluntary, and involuntary) and bed days compared 2 years before and after initiating SGA-LAI. The restrictive interventions were defined as seclusion and physical restraints. RESULTS: The mean time of restrictive interventions significantly decreased from 43.7 to 3.03 ( P = 0.021). The number of admissions and the total number of bed days in post-SGA-LAI fell from 1.03 to 0.61 ( P = 0.011) and 130 to 39.3 ( P = 0.003), respectively, compared with pre-SGA-LAI. In particular, the number of involuntary admissions was significantly reduced (0.50-0.26, P = 0.039). CONCLUSIONS: The findings indicate that SGA-LAI reduced the time of restrictive interventions and the number of involuntary admissions. Moreover, SGA-LAI may contribute to mild psychiatric symptoms during relapse.

Effects of benzodiazepine and orexin receptor antagonist on cognitive function revealed by auditory event-related potentials.

BACKGROUND: Cognitive decline after oral administration of sedatives, such as benzodiazepines, is a serious side effect. Suvorexant, an orexin receptor antagonist, has a favorable tolerability and a limited side-effect profile. AIM: The purpose of this study was to estimate the cognitive decline 1 day after oral medication with lormetazepam, a benzodiazepine, and suvorexant by comparing mismatch negativity (MMN) and P300 reflecting auditory discrimination function. METHODS: Sixty healthy subjects (42 males) were randomly assigned to three groups receiving suvorexant 20 mg, lormetazepam 2 mg, or placebo in this double-blind, randomized control study. Event-related potential recordings during an auditory oddball task and a digit symbol substitution test (DSST) were performed 1 day after oral administration. RESULTS: MMN, on the day after oral administration, was significantly attenuated in the lormetazepam group compared with the other two groups, but there was no difference between the suvorexant and placebo groups. No significant difference was found in P300 amplitudes and DSST scores among the three groups. CONCLUSION: These findings suggest that suvorexant, unlike benzodiazepine, is not associated with cognitive deficits, as revealed by MMN but not P300. This study shows a neurophysiological difference in the effects of suvorexant and benzodiazepine on cognitive function.

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.

Effect of oxytocin nasal spray on auditory automatic discrimination measured by mismatch negativity.

RATIONALE: As a treatment for cognitive dysfunction in schizophrenia, oxytocin nasal sprays potentially improve social cognition, facial expression recognition, and sense of smell. Mismatch negativity (MMN) is an event-related potential (ERP) reflecting auditory discrimination while MMN deficits reflect cognitive function decline in schizophrenia. OBJECTIVES: To determine whether oxytocin nasal spray affects auditory MMN METHODS: We measured ERPs in healthy subjects during an auditory oddball task, both before and after oxytocin nasal spray administration. Forty healthy subjects were randomly assigned to either the oxytocin or placebo group. ERPs were recorded during the oddball task for all subjects before and after a 24 international unit (IU) intranasal administration, and MMN was compared between the two groups. RESULTS: Participants who received oxytocin had significantly shorter MMN latencies than those who received a placebo. Oxytocin had no significant effect on the Change in MMN amplitude. CONCLUSIONS: The shortened MMN latencies that were observed after oxytocin nasal spray administration suggest that oxytocin may promote the comparison-decision stage.

Does Treatment Response With Antidementia Drugs After 6 Months in Alzheimer's Disease Predict Long-term Treatment Outcome?

BACKGROUND: Alzheimer's disease (AD) is a chronic, progressive disorder that causes declines in cognitive and physical functions. This condition places severe burdens on families and caregivers. Delaying progressive declines in cognitive function and reducing their burden are thus important. Relationships between early treatment response and subsequent outcomes of schizophrenia and major depressive disorder have been reported. We thus aimed to investigate the relationships between treatment response to antidementia drugs in AD after 6 months (M) and subsequent outcomes. METHODS: Eligible individuals comprised 194 patients diagnosed with presumed AD. Of these, 110 patients who received antidementia drugs for the first time and were assessed using the Mini-Mental State Examination (MMSE) at 6 M, 12 M, and 24 M were categorized as responders (n = 84) or nonresponders (n = 26). Responders were defined as showing a change in MMSE after 6 M the same as or lower than that in the natural course according to previously reported data. RESULTS: No significant differences in baseline characteristics (age, sex, education, or comorbidities) were seen between groups. Mean MMSE score at baseline was significantly lower in responders (18.0) than in nonresponders (20.7; P = 0.008). Mean change from baseline MMSE was significantly smaller in responders than in nonresponders at both 12 M (-0.46 vs -2.5; P = 0.04) and 24 M (-0.78 vs -4.4; P = 0.001). CONCLUSIONS: Treatment response with antidementia drugs after 6 M predicted better outcomes at 12 M and 24 M. Treatment response should be assessed every 6 M, and treatment should be reconsidered accordingly.

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.

Young patient with treatment-resistant schizophrenia drastically improved by combination of clozapine and maintenance electroconvulsive therapy: a case report.

Objectives: Although clozapine is considered the only effective pharmacological option for patients with treatment-resistant schizophrenia (TRS), around 30-40% of patients show clozapine resistance. Modified electroconvulsive therapy augmentation is reportedly clinically effective for clozapine-resistant schizophrenia, but few case reports have described the efficacy of combining clozapine and continuous/maintenance ECT for patients with TRS. Methods: We present the case of a young patient with TRS who was treated using combination therapy with clozapine and maintenance ECT (m-ECT). Results: The patient achieved drastic improvement under combination therapy with clozapine and m-ECT. Total Positive and Negative Syndrome Scale (PANSS) score fell markedly by 36 (from 108 to 72) using the combination of clozapine and m-ECT. Behaviors not reflected directly by PANSS score also improved. For example, the problem of being unable to take oral drugs stably because of delusions of poisoning was resolved. Furthermore, the patient maintained improvement under m-ECT, and long-term homestays became possible. Conclusion: Combination therapy with clozapine and m-ECT proved greatly effective in this case. Further clinical trials of this combination therapy for TRS are needed to confirm the effectiveness. Further studies are also expected to examine effective periods for this therapy.

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.