Pharmacodynamic properties of lumateperone and its efficacy in acute bipolar depression: a mechanistic hypothesis based on data.

The treatment of bipolar depression is one of the most challenging needs in contemporary psychiatry. Currently, only quetiapine, olanzapine-fluoxetine combination, lurasidone, cariprazine, and recently lumateperone have been FDA-approved to treat this condition. The neurobiology of bipolar depression and the possible mechanistic targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of lumateperone fit into a previously developed model which was the first to be derived based on the strict combination of clinical and preclinical data. The authors performed a systematic review of the literature to identify the pharmacodynamic properties of lumateperone. The original model suggests that a constellation of effects on different receptors is necessary, but refinements, including the present study, suggest that the inhibition of the serotonin reuptake at the first level, the 5HT-2A blockade at the second level, and the norepinephrine alpha-1 receptors blockade at a third level in combination with D1 blockade contribute to the antidepressant effect in acute bipolar depression. The D2 blockade acts as a protective mechanism and reduces the risk of switching to mania/hypomania.

A systematic review of the real-world effectiveness and economic and humanistic outcomes of selected oral antipsychotics among patients with schizophrenia in the United States: Updating the evidence and gaps.

BACKGROUND: Schizophrenia is a chronic, relapsing, and burdensome psychiatric disorder affecting approximately 0.25%-0.6% of the US population. Oral antipsychotic treatment (OAT) remains the cornerstone for managing schizophrenia. However, nonadherence and high treatment failure lead to increased disease burden and medical spending. Cost-effective management of schizophrenia requires understanding the value of current therapies to facilitate better planning of management policies while addressing unmet needs. OBJECTIVE: To review existing evidence and gaps regarding real-world effectiveness and economic and humanistic outcomes of OATs, including asenapine, brexpiprazole, cariprazine, iloperidone, lumateperone, lurasidone, olanzapine/samidorphan, paliperidone, and quetiapine. METHODS: We conducted a literature search using PubMed, American Psychological Association PsycINFO (EBSCOhost), and the Cumulative Index of Nursing and Allied Health Literature from January 2010 to March 2022 as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English-language articles describing adults with schizophrenia receiving at least 1 of the selected OATs and reporting real-world effectiveness, direct or indirect costs, humanistic outcomes, behavioral outcomes, adherence/persistence patterns, or product switching were identified. RESULTS: We identified 25 studies from a total of 24,190 articles. Real-world effectiveness, cost, and adherence/persistence outcomes were reported for most OATs that were selected. Humanistic outcomes and product switching were reported only for lurasidone. Behavioral outcomes (eg, interpersonal relations and suicide ideation) were not reported for any OAT. The key economic outcomes across studies were incremental cost-effectiveness ratios, cost per quality-adjusted life-years, and health care costs. In studies that compared long-acting injectables (LAIs) with OATs, LAIs had a higher pharmacy and lower medical costs, while total health care cost was similar between LAIs and OATs. Indirect costs associated with presenteeism, absenteeism, or work productivity were not reported for any of the selected OATs. Overall, patients had poor adherence to OATs, ranging between 20% and 61% across studies. Product switching did not impact the all-cause health care costs before and after treatment. CONCLUSIONS: Our findings showed considerable gaps exist for evidence on behavioral outcomes, humanistic outcomes, medication switching, and adherence/persistence across OATs. Our findings also suggest an unmet need regarding treatment nonadherence and lack of persistence among patients receiving OATs. We identified a need for research addressing OATs' behavioral and humanistic outcomes and evaluating the impact of product switching in adults with schizophrenia in the United States, which could assist clinicians in promoting patient-centered care and help payers understand the total value of new antipsychotic drugs.

Therapeutic monitoring of antipsychotics with a focus on lurasidone and its dosing.

Dose-response relationships are not fully understood for antipsychotics. Especially in the case of multimodal antipsychotics, these relationships cannot be simplified to the level of dopaminergic receptor occupancy alone. In general, for most antipsychotics, there is no linear dose-response relationship. Reasons for this include, among others, pharmacokinetic factors affecting plasma levels. Based on meta-analyses, the doseresponse curve appears to be bell-shaped. However, in the case of some antipsychotics, it appears that even increasing the dose beyond the recommended range could yield further increases in efficacy. It should be stressed that this is an off-label procedure and cannot generally be recommended and there is not enough valid information for general conclusions for these antipsychotics either. Mini-invasive sampling and alternative matrices such as saliva or dry blood spots could open the way to more frequent monitoring of antipsychotics and a better understanding of doseresponse relationships.

Therapeutic monitoring of antipsychotics with a focus on lurasidone and its dosing.

Dose-response relationships are not fully understood for antipsychotics. Especially in the case of multimodal antipsychotics, these relationships cannot be simplified to the level of dopaminergic receptor occupancy alone. In general, for most antipsychotics, there is no linear dose-response relationship. Reasons for this include, among others, pharmacokinetic factors affecting plasma levels. Based on meta-analyses, the doseresponse curve appears to be bell-shaped. However, in the case of some antipsychotics, it appears that even increasing the dose beyond the recommended range could yield further increases in efficacy. It should be stressed that this is an off-label procedure and cannot generally be recommended and there is not enough valid information for general conclusions for these antipsychotics either. Mini-invasive sampling and alternative matrices such as saliva or dry blood spots could open the way to more frequent monitoring of antipsychotics and a better understanding of doseresponse relationships.

Umbrella Review: Association Between Antipsychotic Drugs and Metabolic Syndrome Hallmarks in Children and Adolescents.

OBJECTIVE: To summarize the available evidence on metabolic parameters indicating metabolic adverse effects and risk of metabolic syndrome in children and adolescents treated with antipsychotics, following a pre-specified protocol (PROSPERO ID 252336). METHOD: We searched PubMed, Embase and PsycINFO until May 14, 2021, to identify systematic reviews (SR), meta-analyses (MA) and network meta-analyses (NMA) examining symptoms associated to metabolic syndrome in patients <18 years of age who required treatment with oral antipsychotic drugs. Evidence from quantitative analyses for all outcomes related to anthropometric, glyco-metabolic, and blood pressure parameters (measured from baseline to intervention-end and/or follow-up, in subjects exposed to antipsychotics and placebo) was reported on the basis of their metrics (median difference [medianD], mean difference [MD], standardized mean difference [SMD], odds ratio [OR], risk ratio ([RR]). A qualitative synthesis was also made. A formal quality assessment of the included studies was carried out by using the AMSTAR 2. We also provided a hierarchical stratification of the evidence from meta-analyses based on the class of evidence. RESULTS: A total of 23 articles (13 MA, 4 NMA and 6 SR) were included for review. As compared with placebo, an increase in triglyceride levels was associated with olanzapine (medianD [95% CI]: 37 [12.27, 61.74] mg/dL; MD [95% CI]: 38.57 [21.44, 55.77] mg/dL) and quetiapine (medianD [95% CI]: 21.58 [95% CI]: 4.27, 38.31 mg/dL; MD [95% CI]: 34.87 [20.08, 49.67] mg/dL; SMD [95% CI]: 0.37 [0.06, 0.068]), whereas decreased triglyceride levels were found for lurasidone. Increased total cholesterol level was associated with asenapine (medianD [95% CI]: 9.1 [1.73, 16.44] mg/dL), quetiapine (medianD [95% CI]: 15.60 [7.30, 24.05] mg/dL; olanzapine (MD [95% CI] from 3.67 [1.43, 5.92] mg/dL to 20.47 [13.97, 26.94] mg/dL]; and lurasidone (medianD [95% CI]: 8.94 [1.27, 16.90] mg/dL). Change in glucose levels did not differ among antipsychotics or placebo. Lurasidone, molindone, and ziprasidone were the best tolerated in terms of weight gain. According to the AMSTAR 2 scoring system, 13 (56.5%) reviews were rated as very low quality. According to classes of evidence, most MA were level 4, especially because of their limited total sample size. CONCLUSION: By collating meta-analyses assessing biochemical markers of metabolic syndrome in antipsychotic-treated children, we conclude that olanzapine should not be the antipsychotic of choice in patients at risk for hypertriglyceridemia or hypercholesterolemia. Aripiprazole and lurasidone appear to be better tolerated in terms of metabolic adverse events. Insufficient meta-analytic data are available to provide a precise risk estimate of metabolic syndrome, and, overall, the quality of evidence is low. STUDY REGISTRATION INFORMATION: Association between the use of antipsychotic drugs and alterations of the parameters defining the Metabolic Syndrome (MetS) in children and adolescents: an umbrella review; https://www.crd.york.ac.uk/prospero/; CRD42021252336.

Lurasidone as add-on to fluoxetine in obsessive-compulsive disorder with comorbid restrictive anorexia: a case report.

Obsessive-compulsive disorder (OCD) is a pervasive disabling disorder that may overlap with other psychiatric conditions, including anorexia nervosa. Recent guidelines recommend low doses of second-generation antipsychotics as add-on therapy to selective serotonin reuptake inhibitors (SSRIs) for those patients presenting OCD who display residual symptomatology. Here we report a clinical case of a 45-years-old woman affected by severe OCD in comorbidity with anorexia nervosa, restrictive type (AN-r), treated with fluoxetine (titrated up to 40 mg/day) in augmentation with low doses of lurasidone (37 mg/day). At baseline and during a 6 months-follow-up we administered Clinical Global Impression-Severity, Symptom Checklist-90 items, Y-BOCS-II (Yale-Brown Obsessive Compulsive Scale) and EDI-3 (Eating Disorder Inventory). After 1 month of augmentation treatment, a clinically significant response was observed on obsessive symptoms at Y-BOCS-II (≥35% Y-BOCS reduction) and eating symptomatology at EDI-3. Full remission was reported after 3 months (Y-BOCS scoring ≤14) ( P  < 0.01). Further longitudinal and real-world effectiveness studies should be implemented to confirm these novel results, to investigate the potential of lurasidone as add-on strategy to SSRI in poor responder OCD patients, including treatment-resistant-OCD (tr-OCD), as well as in improving eating disorder symptomatology, whereas there is comorbidity with AN-r.

Effectiveness of atypical antipsychotics for unipolar and bipolar depression in adolescents and young adults: A systematic review and meta-analysis.

BACKGROUND: Antipsychotic medications are increasingly used for difficult-to-treat depression in young people. However, the evidence-base for this is unclear. Our aim was to assess the evidence for the efficacy of atypical antipsychotics in treating unipolar and bipolar depression in adolescents and young adults. METHOD: We conducted a comprehensive systematic review and meta-analysis of randomized-control-trial studies (RCTs) of antipsychotic medications for 10- to 25-year-olds with unipolar and bipolar depression. The primary outcome of interest was change in depressive symptoms from baseline to trial endpoint. RESULTS: No studies were identified that evaluated the use of antipsychotics in the treatment of unipolar depression. However, we identified four studies, of quetiapine, lurasidone and olanzapine/fluoxetine combination, comprising a total of 866 randomized patients, that evaluated treatment of bipolar depression. All studies used the Children's Depression Rating Scale-Revised (CDRS-R). Our meta-analysis revealed the weighted mean difference (WMD) was -4.58 (95 % CI, -6.59 to -2.57) between antipsychotic and placebo-treated groups. Response and remission rates were also significantly in favor of antipsychotic treatment. LIMITATIONS: There were few studies, several did not address risk-of-bias domains and there was a lack of non-industry sponsored studies. CONCLUSION: There is an absence of evidence for the use of antipsychotic medications in treatment of youth unipolar depression, and no recommendations can be made. There is some evidence for the efficacy of antipsychotics, specifically lurasidone and olanzapine/fluoxetine combination, in the treatment of young people with bipolar depression. However, this evidence is limited and more studies investigating the use of these medications in young people are needed.

Cognitive Effects of Lurasidone and Cariprazine: A Mini Systematic Review.

Cognitive deficits are associated with schizophrenia and show a progressive worsening, often being unresponsive to treatment. New antipsychotic molecules acting as antagonist at the serotoninergic 5-hydroxytryptamine receptor 7 (e.g. lurasidone) or partial agonists at dopamine D3 receptor (e.g. cariprazine) could have an impact on cognition in this patient group. The aim of the systematic review is to explore the efficacy of lurasidone and cariprazine in improving cognition in both animal models and human studies. The following terms: (lurasidone AND cognit*) OR (cariprazine AND cognit*) were searched in Web of Science from inception to December 2021. We included all studies that assessed changes in cognitive function after treatment with cariprazine or lurasidone. Of 201 selected articles, 36 were included. Twenty-four articles used animal models (rats, mice and marmosets), five evaluating the effects of cariprazine and 19 the effects of lurasidone. Twelve articles were clinical studies (cariprazine n = 2; lurasidone n = 10). In both animal and human studies lurasidone showed a greater efficacy on cognitive performance compared to placebo, quetiapine, ziprasidone or treatmentas- usual. Cariprazine was superior to other antipsychotics in improving cognitive functions in both animal and human studies. The cognitive effect of lurasidone could be explained by its potent antagonism at the 5-HT7 receptors combined with partial agonism at 5-HT1A receptors. The pro-cognitive effect of cariprazine is probably explained by its very high affinity for D3 receptors. Head-to-head studies comparing lurasidone and cariprazine are needed to establish the "first-choice" treatment for cognitive dysfunction associated with schizophrenia.

Antidepressant efficacy of cariprazine in bipolar disorder and the role of its pharmacodynamic properties: A hypothesis based on data.

The treatment of bipolar depression is one of the most challenging needs in contemporary psychiatry. Currently, only quetiapine, olanzapine-fluoxetine combination, lurasidone, cariprazine, and recently lumateperone have been FDA-approved to treat this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of cariprazine fit into a previously developed model which was the first to be derived based on the strict combination of clinical and preclinical data. The authors performed a systematic review of the literature to identify the pharmacodynamic properties of cariprazine. The original model suggests that a constellation of effects on different receptors is necessary and that serotonin reuptake inhibition does not appear to play a significant role in acute bipolar depression. On the contrary, norepinephrine activity seems to be necessary. Probably the early antidepressant effect can be achieved through an agonistic activity at 5HT-1A and antagonism at alpha1 noradrenergic and 5-HT2A receptors, but the presence of a norepinephrine reuptake inhibition appears essential to sustain it. Overall, the properties of cariprazine fit well the proposed model and add to its validity. A point that needs further clarification is norepinephrine reuptake inhibition which is not yet fully studied for cariprazine.

Narrative review of the advances in the pharmacotherapeutic management of juvenile-onset schizophrenia.

INTRODUCTION: Schizophrenia usually begins with prodromal symptoms in adolescence. In 39% of patients, onset of psychotic symptoms occurs prior to age 19. Advances in the treatment of psychosis with medications over the last decade are reviewed in this paper. AREAS COVERED: Understanding how to prescribe antipsychotics early in schizophrenia requires an understanding of the pathophysiology of the disease. The current structure of the dopamine hypothesis is reviewed. Risperidone, paliperidone, olanzapine, quetiapine, and aripiprazole have become established treatments prior to 2012. Since 2012, lurasidone (2017) and brexpiprazole (2022) have also been approved. Lurasidone was approved based on placebo-controlled studies, but brexpiprazole has been approved on the bases of open safety trials. In comparative trials, aripiprazole was better tolerated and less likely to cause hyperprolactinemia and metabolic abnormalities. EXPERT OPINION: Antipsychotics can induce adaptive changes in the brain that predispose patients to future problems such as tardive dyskinesia and supersensitivity psychosis. When pathophysiology of schizophrenia, and a clear understanding of the pharmacology of existing antipsychotics are included in the evidence-based analysis, use of partial agonists, which are less likely to induce adaptive changes in the brain and less likely to induce metabolic and prolactin side effects, become the preferred agents.

Lurasidone Augmentation of Clozapine in Refractory Schizophrenia: A Case Series.

PURPOSE: Clozapine represents the criterion standard therapy for patients with treatment-resistant schizophrenia. Unfortunately, a significant percentage of such patients are also partial responders to clozapine. Consequently, several augmentation strategies have been proposed with various and sometimes controversial efficacy. Among these add-on treatments, lurasidone has been recently introduced and could represent a potential option, especially for the additional positive effect on cognitive symptoms. METHODS: This case series aims to determine possible advantages of lurasidone augmentation in four patients treated with clozapine, who were diagnosed with treatment-resistant schizophrenia. Positive and Negative Syndrome Scales were used to evaluate psychopathology, the Udvalg for Kliniske Undersøgelser scale for tolerability and safety. FINDING: All patients achieved a significant reduction of both positive and negative symptoms, with no significant adverse effects to be reported. IMPLICATIONS: Our observation suggests that lurasidone can lead to clinically significant improvements in psychopathology with a good tolerability profile when added to clozapine.

Lurasidone in first-episode psychosis with predominant depressive symptoms: a case report.

Lurasidone is an atypical antipsychotic approved for the treatment of schizophrenia and bipolar depression. It seems to have an antidepressant effect due to 5-HT7 as well as 5-HT2A and 5-HT1a receptor affinity. Here we present a case of a 19-year-old male patient with first-episode psychosis (FEP) and predominant depressive symptoms. Remarkable clinical and functional improvement was observed 3 months after the beginning of lurasidone treatment. The patient's depressive symptoms disappear with a dramatic reduction of psychotic ones, with good tolerance of the drug and without adverse effects. Lurasidone seems to be a promising treatment option for FEP with predominant depressive symptoms.

Reproductive Safety of Lurasidone and Quetiapine: Update from the National Pregnancy Registry for Psychiatric Medications.

Background: Second-generation antipsychotics (SGAs), also called atypical antipsychotics, are common therapies for women with a spectrum of psychiatric disorders. No systematically ascertained human reproductive safety data are available for lurasidone, and prospective data for quetiapine are limited, making decisions regarding use of these medications during pregnancy complicated. Materials and Methods: The National Pregnancy Registry for Psychiatric Medications is a prospective cohort study designed to collect reproductive safety data relative to SGAs. Pregnant women aged 18-45 years, with psychiatric illness and prenatal psychotropic medication exposure completed three phone interviews during pregnancy and the postpartum period. Cases of presumed malformations are abstracted from medical records for adjudication by a teratologist blinded to medication exposure. Results: Of 2,293 women enrolled at the time of analysis, 134 in the lurasidone group, 264 in the quetiapine group, and 886 controls completed the postpartum interview and were therefore eligible for inclusion. Dropped or lost-to-follow-up participants (13%) and those currently pregnant were excluded. Participants were predominantly White, college-educated, and married (lurasidone = 88.1%, 76.9%, 77.6%; quetiapine = 89.8%, 71.2%, 75.0%; controls = 92.7%, 86.7%, 89.1%). Absolute risks of major malformations were 2.19% (lurasidone), 1.85% (quetiapine), and 1.77% (controls). Odds ratios comparing lurasidone and quetiapine with controls were 1.24 (95% confidence interval [CI] = 0.36-4.32) and 1.04 (95% CI = 0.38-2.85), respectively. Conclusions: No specific patterns of malformations were observed in infants exposed to the medications of interest. Lurasidone and quetiapine did not appear to be major teratogens, but further information is needed to refine risk estimates. Food and Drug Administration guidance underscores the importance of pregnancy registries. Clinical trial number: NCT01246765.

A case of postpsychotic depression improved by switching antipsychotic monotherapy.

AIM: Postpsychotic depression is challenging to differentiate, yet it is clinically frequent, puts patients at risk for suicide, and affects their mental capacity. Treatment with antipsychotics for postpsychotic depression is desirable; however, there is no consensus on which antipsychotics are optimal. CASE PRESENTATION: We report the case of a young male patient with schizophrenia in his 20s who developed postpsychotic depression, including despair, overwhelming loss, humiliation, and suicidal ideation during treatment with paliperidone. As a result, we switched his medication to lurasidone, which relieved his depressive symptoms without any symptom relapse and his social functioning improved. CONCLUSION: Postpsychotic depression has more psychic characteristics than behavioral. According to various international guidelines for the pharmacological treatment of schizophrenia, antipsychotics should be administered for depressive symptoms of schizophrenia. As evidenced in this case report, lurasidone may be a practical alternative for improving postpsychotic depression.

Sleep Disturbance, Irritability, and Response to Lurasidone Treatment in Children and Adolescents with Bipolar Depression.

BACKGROUND: The presence of mixed (subsyndromal hypomanic) symptoms may influence treatment outcomes in pediatric bipolar depression. This post-hoc analysis investigated "bridge" symptoms that have cross-sectional and predictive associations with depressive and manic symptom clusters in youth with bipolar depression. METHODS: The moderating effects of these bridge symptoms on the response to flexibly dosed lurasidone 20-80 mg/d compared to placebo treatment was analyzed in children and adolescents with bipolar I depression in a six-week, placebo-controlled, double-blind study followed by a 2-year, openlabel extension study of lurasidone. RESULTS: Sleep disturbances, assessed by "difficulty with sleep" (Children's Depression Rating Scale, Revised [CDRS-R] item 4) and "decreased need for sleep" (Young Mania Rating Scale [YMRS] item 4), and "irritability" (CDRS-R item-8, YMRS item 5) were identified as "bridge" symptoms and found to have replicable causal associations with depressive (CDRS-R total) and manic symptom clusters (YMRS total) at baseline and week-6. A greater improvement in overall depression severity at week 6 with lurasidone (vs. placebo) treatment was observed in the presence (vs. absence) of decreased need for sleep at study baseline, mediated in part by significant reductions from study baseline in decreased need for sleep and manic symptom severity. The absence of sleep disturbance and irritability in patients at open-label extension study baseline was associated with higher rates of sustained recovery (symptomatic and functional remission) over 6 months compared to patients with those symptoms at baseline (68% vs. 50%, Number Needed to Treat=6). CONCLUSION: Our findings suggest that sleep disturbance and irritability are cardinal symptoms that "bridge" between depressive and manic symptom clusters and influence treatment outcomes in youth with bipolar depression.

Lurasidone use in Cannabis-Induced Psychosis: A Novel Therapeutic Strategy and Clinical Considerations in Four Cases Report.

BACKGROUND: Lurasidone is an atypical antipsychotic approved for the acute and maintenance treatment of schizophrenia. Recently, lurasidone was also extended FDA approval for adults with major depressive episodes associated with bipolar I disorder (bipolar depression), as either a monotherapy or as adjunctive therapy with lithium or valproate. The use of low doses of atypical antipsychotics is an essential component of early intervention in psychosis, but little has yet been studied on first episode cannabis-induced psychosis. For its particular performance and tolerability, lurasidone is becoming an important option for the treatment of first-episode psychosis in youth. Case presentation four patients experiencing first cannabis-induced psychotic episode were treated with lurasidone. In all patients, there was an improvement in the clinical picture of psychosis. The recovery was positive, not only with the remission of positive and negative symptoms, but also regarding disruptive behaviour, with the return of functioning. All the patients were treated with lurasidone, with a target dose of 74-128 mg/day. No significant side effects were reported. CONCLUSION: There are non-controlled studies for the use of lurasidone in first episode psychosis cannabis induced. These findings suggest that lurasidone is an atypical antipsychotic beneficial in this clinical picture. Treatment with medium-high doses of lurasidone could be effective and tolerable in this phase of the disorder. Randomized control trials with longer follow-up are recommended to confirm these positive results.