The Role of Lurasidone in Managing Depressive Symptoms in People with Schizophrenia: A Review

Background: Schizophrenia is a severe mental disorder characterized by positive, negative, affective, and cognitive symptoms. Affective symptoms in patients with schizophrenia have traditionally been overlooked or even neglected because they are not considered as fundamental as positive and negative symptoms in the choice of medication. Methods: This paper aims to systematically evaluate the efficacy and safety of lurasidone in the treatment of depressive symptoms of schizophrenia. Results: Lurasidone appears to be particularly effective on the depressive symptomatology of schizophrenia while also alleviating the positive and negative symptoms associated with the illness. Conclusions: The efficacy of lurasidone in treating patients with first-episode psychosis who present with predominant depressive symptoms suggests that this medication may be a valuable treatment option not only for established cases of schizophrenia but also for individuals in the early stages of the illness. The good tolerability of lurasidone is an important factor that may positively influence treatment decisions.


Introduction
Schizophrenia is a severe mental disorder with a heterogeneous clinical presentation, characterized by different symptomatologic clusters named positive, negative, affective, and cognitive domains [1].There is considerable overlap between these different symptom domains, and the distinction between negative and affective symptoms (including depression and anxiety) can sometimes be clinically difficult.Both domains can negatively impact patients' level of functioning and quality of life; therefore, it is mandatory to early detect those symptoms and develop a targeted, individualized treatment plan for each patient [2].
Depressive symptoms in patients with schizophrenia have traditionally been overlooked or even neglected because they are not considered as fundamental as positive and negative symptoms in the choice of medication (typically, first-generation antipsychotics Brain Sci.2024, 14, 225 2 of 18 are more effective for positive symptoms, while second-generation antipsychotics are more effective for negative symptoms).
Due to the increasing prevalence of the Kraepelin dichotomy (i.e., distinction between psychotic "manic-depression" and "dementia praecox") in current diagnostic manuals and guidelines [3][4][5], as well as the dominance of the categorical diagnostic approach in clinical psychiatry [6][7][8], the relationship between psychotic and depressive symptoms of schizophrenia remains a diagnostic conundrum whose boundaries still seem unclear to many clinicians and researchers [9][10][11][12].
Several recent studies have attempted to clarify the predictive and prognostic role of depressive symptoms in patients with schizophrenia.The available data seem quite controversial, with some authors highlighting that the presence of depressive symptoms is associated with a good prognosis [13], while other studies have found a negative association between depressive symptoms and outcome in schizophrenia.In particular, several authors have reported that psychotic patients with depressive symptoms have earlier relapses, more frequent and longer hospitalizations, a poorer prognosis, and a worse outcome [14][15][16].
A higher prevalence rate of depression has been found in patients with schizophrenia compared with the general population, with estimates ranging from 7 to 65%.Patients with schizophrenia with a comorbid depressive disorder report poor quality of life, increased suicidal risk, poor medication adherence, higher rates of relapse and hospitalization, poor physical health, and worse long-term outcomes compared to people with schizophrenia without depressive symptoms.
More recently, studies focusing on the clinical high-risk and ultra-high-risk populations have found that patients with high sensitivity to stress and a tendency to develop negative depressive states are at higher risk of developing full-blown psychotic disorders [17][18][19].In addition, experience sampling studies have found that patients with schizophrenia spectrum disorders exhibit more negative affect in their daily lives, while laboratory studies have shown that these patients have a bias toward judging neutral stimuli as more negative.
Negative affect in patients with schizophrenia predicts poorer functional outcomes, more hospitalizations, reduced quality of life, increased need for psychiatric treatment, and more frequent suicide, even after controlling for negative, neurocognitive, and positive symptoms [20].
Negative symptoms of schizophrenia also play a critical role in determining poor outcomes, as they contribute significantly to poor psychosocial functioning and quality of life, are long-lasting, and place a significant burden on caregivers [21].In addition, these symptoms decrease patients' motivation to seek treatment and reduce treatment adherence [22].As a result, people with schizophrenia are often unemployed, single, poorly educated, and have few social contacts, which is reflected in their everyday difficulties.Their family members often feel stigmatized and may be exposed to social isolation [23].
With new treatment approaches, the improved safety of modern antipsychotics, and the fulfillment of some of the unmet needs, the outcome of patients with schizophrenia is changing, and many can now achieve full recovery.This should be the goal of clinicians dealing with schizophrenia [24].The so-called third-generation antipsychotics, which include cariprazine, lurasidone, and brexpiprazole, have recently been introduced as monotherapy or adjuncts for the treatment of depressive and negative symptoms in patients with schizophrenia [25][26][27][28].Available studies suggest that they are particularly useful for these symptoms, have a relatively safe tolerability profile, and are well perceived by patients [29][30][31][32].In this paper, we aim to review the efficacy of lurasidone for the depressive symptoms of schizophrenia and try to identify the benefits and pitfalls of using lurasidone in clinical practice.Lurasidone is a benzisothiazole derivative approved by the US FDA for the treatment of schizophrenia, major depression, and depressive episodes associated with bipolar I disorder.Lurasidone is also approved by the EMA for the treatment of schizophrenia in adults and by Health Canada for the treatment of acute cases of schizophrenia and bipolar depression.Functionally, lurasidone is primarily an antagonist of D2 and 5-HT2A receptors.The D2 antagonism is associated with its Brain Sci.2024, 14, 225 3 of 18 efficacy in the treatment of schizophrenia, while the potent 5-HT2A antagonism improves the negative symptoms of schizophrenia and reduces extrapyramidal side effects and prolactin levels.In addition, lurasidone's unique profile includes potent 5-HT7 receptor antagonism associated with cognitive enhancement.Lurasidone's 5-HT1A receptor partial agonism explains its anxiolytic and antidepressant effects; the drug's binding affinity and antagonism at noradrenergic a2C receptors improve cognitive and motor function.Another positive aspect of lurasidone is its lack of antimuscarinic and anti-H1 histamine activity, which further reduces its side effects.Adverse effects such as akathisia, somnolence, and prolactin elevation are generally manageable with dose adjustment, and its modest noradrenergic alpha-1 antagonist activity (more than 20-fold less potent than its binding affinities at D2 and 5-HT2A receptors) implies a lower risk of postural hypotension and tachycardia.The pharmacodynamic profile of lurasidone is consistent with its efficacy in treating positive, negative, and depressive symptoms of schizophrenia while maintaining a relatively favorable tolerability profile.Nevertheless, the focus of research and attention on antipsychotics has been predominantly on their efficacy in treating positive and negative symptoms.In light of this, we conducted a comprehensive review of the available literature to systematically assess the efficacy of lurasidone in the treatment of depressive symptoms associated with schizophrenia.

Materials and Methods
Clinical trials evaluating the use of lurasidone for the treatment of depressive disorders in patients with schizophrenia spectrum disorders were identified using the following search terms: "schizophrenia", "schizoaffective disorder", "psychosis", "first episode of psychosis", "depressive symptoms", "affective symptoms", "pharmacological treatment", "atypical antipsychotics", "second-generation antipsychotics", and "lurasidone".Keywords were entered into PubMed, ISI Web of Knowledge, Scopus, and Medline databases and combined in order to identify relevant papers by making the search more restrictive or detailed.
The search strategy was limited to the period from inception to 31 December 2022.
The following criteria have been considered: (1) studies including patients with a diagnosis of schizophrenia, schizoaffective, or psychotic disorder; (2) the antipsychotic pharmacological treatment included lurasidone; (3) the primary or secondary outcomes considered in the study included affective/depressive symptoms.
Papers were excluded when antipsychotic pharmacological treatments included drugs different from lurasidone.Studies focused only on the efficacy of lurasidone on positive or negative symptoms without specific data on depressive/affective symptoms were excluded.
The following study designs were included: case reports/case series, open label studies, case/control studies, and randomized controlled trials (RCTs).Non-original research, such as systematic reviews, meta-analyses, and narrative reviews, was excluded.
All selected papers were evaluated by two researchers (GS and AF).After evaluating the abstracts, the main data from the included papers were extracted: (1) authors and country; (2) study design; (3) sample size; (4) assessment tools; (5) main findings; (6) study limitations.
The systematic review has been conducted according to the PRISMA guidelines.

Results
2739 articles were identified; after removing duplicates, 331 articles were analyzed.After full-text analysis, 316 papers were excluded due to: lack of data on the effect of lurasidone on depressive symptoms; lack of pre-post assessment; and non-original data.Fifteen papers were finally included in the review (Figure 1).

Results
2739 articles were identified; after removing duplicates, 331 articles were analyzed.After full-text analysis, 316 papers were excluded due to: lack of data on the effect of lurasidone on depressive symptoms; lack of pre-post assessment; and non-original data.Fifteen papers were finally included in the review (Figure 1).In terms of study design, three case reports and one case series were found, while the remaining papers were either randomized controlled trials [33,34] or post hoc analyses [35][36][37] (Tables 1 and 2).Patient sample sizes ranged from one patient [38,39] (in the case reports by Oguchi et al. and Ricci et al.) to 1330 patients [40].
In seven experimental studies [34,37,[40][41][42][43][44], the efficacy of lurasidone in treating depressive symptoms in patients with schizophrenia has been evaluated against placebo treatment.In the remaining four experimental studies, the efficacy of lurasidone has been compared with risperidone, quetiapine extended releases, or different dosages of lurasidone.In terms of study design, three case reports and one case series were found, while the remaining papers were either randomized controlled trials [33,34] or post hoc analyses [35][36][37] (Tables 1 and 2).Patient sample sizes ranged from one patient [38,39] (in the case reports by Oguchi et al. and Ricci et al.) to 1330 patients [40].
In seven experimental studies [34,37,[40][41][42][43][44], the efficacy of lurasidone in treating depressive symptoms in patients with schizophrenia has been evaluated against placebo treatment.In the remaining four experimental studies, the efficacy of lurasidone has been compared with risperidone, quetiapine extended releases, or different dosages of lurasidone.
The majority of studies used validated instruments to assess the severity of depressive symptoms in patients with schizophrenia, including the Positive and Negative Syndrome Scale (PANSS), the Montgomery-Åsberg Depression Rating Scale (MADRAS), the Clinical Global Impression-Severity Scale (CGI-S), and the Calgary Depression Rating Scale.Only the study by Oguchi et al. [38] used a non-standardized assessment tool.In addition, most studies also used tools (such as the EQ-5D-3L) to assess quality of life [41] and satisfaction with the pharmacological treatment received (e.g., the Medication Satisfaction Questionnaire) [45].
Lurasidone was effective in improving depressive symptoms reported by patients with schizophrenia in all included studies [40,42,44,45], as well as positive and negative symptoms.In particular, Patel et al. [35] found a significant reduction in the severity of depressive symptoms as assessed by the MADRS at 12-month follow-up.All patients achieved a significant reduction of both positive and negative symptoms, with no significant adverse effects to be reported.
Four patients experienced their first cannabis-induced psychotic episode.

Unspecified
Lurasidone also appears to be effective in other symptom domains related to schizophrenia, such as depressive symptoms.

Case series
Brain Sci.2024, 14, 225 11 of 18 The efficacy of lurasidone on depressive symptoms has been confirmed at various doses.In particular, in a sample of 244 patients randomized to receive lurasidone 40 mg or lurasidone 80 mg, McEvoy et al. [44] found a significant reduction in depressive symptoms in all randomized groups.
In an open-label study by Correll et al. [42], lurasidone was also effective in improving depressive symptoms over the long term.The open-label phase of the study lasted nearly two years, and patients received flexible doses of lurasidone-ranging from 40 to 120 mgand reported significant improvements in depressive symptoms.
A recent case report by Ricci et al. [46] highlighted the efficacy of lurasidone in the treatment of first-episode psychosis patients with prevalent depressive symptoms.The authors reported a significant improvement in clinical domains and level of functioning associated with the good tolerability of the drug.Moreover, Ricci et al. [39] described in a case series the use of lurasidone in treating depressive symptoms in patients with schizophrenia and cannabis.In a case series on patients with treatment-resistant schizophrenia receiving clozapine by Olivola et al. [47], all patients received lurasidone as add-on treatment and therefore achieved a significant reduction of both positive and negative symptoms, with no significant adverse effects.
The presence of side effects has been specifically evaluated only in the study by Olivola et al. [47] using the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale (UKU-SERS), while another study included the evaluation of the levels of satisfaction with medication using the Medication Satisfaction Questionnaire [45].

Discussion
Schizophrenia is a severe mental disorder characterized by heterogeneous clinical dimensions, positive and negative symptoms, and disorganized behaviors.The heterogeneous symptom constellations involve cognitive, behavioral, and emotional symptoms, but no single symptom can be considered pathognomonic for the disorder.For many decades, the presence of depressive symptoms in patients with schizophrenia has been overlooked, although it is a common clinical feature in patients with schizophrenia.In particular, depressive symptoms can cause severe impairment in patients with schizophrenia, not only because they usually increase suicide risk but also because they reduce social functioning and quality of life [48,49].
Therefore, it is essential to address and appropriately treat the heterogeneity of the clinical presentation of patients with schizophrenia.Moreover, patients with schizophrenia present comorbid psychiatric disorders, including the increased prevalence of anxiety, depressive and substance use disorders, and high suicidality rates.Depressive symptoms as well as full-mood episodes are common in schizophrenia but should be present for only a relatively brief period.Depressive symptoms show a modal prevalence of about 25%, and they may occur in all phases of schizophrenia.
Depressive symptoms during a psychotic episode may be related to multiple factors, adding complexity to the diagnostic process.Depressive symptoms in schizophrenia may be induced by several clinical factors, including medication side effects, the presence of physical illnesses, etc.; thus, it is important to highlight the temporal course of the onset of depressive symptoms, either in the prodromal phase (acute dysphoria or depressive symptoms overlapping with negative ones) or during the full-blown illness (i.e., depressive presentations with or without acute psychotic symptoms) [50].Depressive symptoms seemed to be part of schizophrenia.Patients with schizophrenia-regardless of genderpresent depressive symptoms frequently, and these symptoms do not appear to be simply a by-product of age, neuroleptics, family history, negative symptoms, or movement disorder.
Overall, in line with the Kraepelinian dichotomy, depressive symptoms have traditionally been considered nosologically distinct from those of schizophrenia, although recent evidence tends to challenge such assumptions by demonstrating the potential limitations of a strictly categorical approach [51].Recently, the need for a more dimensional approach has been argued, as depression in schizophrenia is not only an artifactual comorbidity but may be a real element of psychotic symptomatology, as clinical patterns may emerge with different hierarchical orders [52].
However, the management of depressive symptoms in patients with schizophrenia is currently an area of concern, particularly in relation to their pharmacological treatment [53].In the Supplementary Materials, two clinical cases based on ordinary clinical practice have been reported as an example of using lurasidone for managing depressive symptoms in patients with schizophrenia (Supplementary Materials Table S1).
Vakalopoulos and Fitzroy [54] proposed a new nosological approach to psychosis based on the pharmacological differences associated with depressive and negative symptom dimensions (again based on a relative monoaminergic-muscarinic imbalance in signaling).Dondé et al. [55] critically reviewed recent international guidelines for the treatment of depressive symptoms in people with schizophrenia, highlighting the need for more specific and targeted approaches that take into account the complex interplay of different symptom clusters.Mulholland and Cooper [56] have previously highlighted the importance of treating depressive symptoms in the context of schizophrenia with specific pharmacological agents, emphasizing their crucial impact on overall functioning and well-being.In a recent meta-analysis, Gregory et al. [57] concluded that despite the therapeutic potential of antidepressants for the treatment of depression in schizophrenia, the currently available literature does not clearly confirm the usefulness of this strategy.
Lurasidone showed specific activity in improving depressive symptoms in people with schizophrenia [43].This is an important finding, as depressive symptoms are often difficult to manage in people with schizophrenia and can have a significant impact on their overall well-being.It is noteworthy that lurasidone appears to be effective not only in treating depressive symptoms but also in alleviating both positive and negative symptoms associated with schizophrenia.This broader effect on the range of symptoms is a positive feature, as it suggests that the drug may provide holistic benefits to individuals with this complex disorder.McEvoy et al.'s [44] finding that different doses of lurasidone, specifically 40 mg and 80 mg, were effective in reducing depressive symptoms suggests that the drug's efficacy may be dose-dependent and may guide clinicians in tailoring treatment to individual patient needs.In addition, the efficacy of lurasidone in treating patients with first-episode psychosis who present with predominant depressive symptoms suggests that lurasidone may be a valuable treatment option not only for established cases of schizophrenia but also for individuals in the early stages of the illness.The good tolerability of lurasidone is an important factor that may positively influence treatment decisions.
In four studies, the efficacy of lurasidone in treating depressive symptoms has been compared with risperidone or quetiapine treatment, showing the superiority of lurasidone treatment.These data are very relevant since risperidone has been specifically evaluated in several studies for improving depressive symptoms in patients with schizophrenia [58,59].In particular, patients receiving risperidone-compared with those treated with haloperidol-reported a significant reduction in depressive symptoms.Therefore, it is extremely important to have found that lurasidone-an innovative third-generation antipsychotic-is effective in treating depressive symptoms in patients with schizophrenia.Such data are particularly relevant since lurasidone has a safe tolerability profile and is well perceived by patients [29][30][31][32].However, in the future, it should be of interest to conduct realworld studies aiming to assess and compare the effectiveness of various third-generation antipsychotics (including brexpiprazole and cariprazine) in ordinary clinical practice.It was out of the scope of the present review to include and evaluate studies considering the impact of other antipsychotics on affective symptoms in patients with schizophrenia.
Moreover, another important finding-which deserves further rigorous studies-is related to the use of lurasidone for managing people with treatment-resistant schizophrenia receiving clozapine.Evidence for using lurasidone for managing depressive symptoms in such a complex target group of patients with schizophrenia is quite limited, based on the case series published by Olivola et al. [47].However, it is necessary to highlight that up to 30% of patients with schizophrenia experience minimal to no symptomatic response from antipsychotic treatment.The only approved pharmacotherapy for treatment-resistant schizophrenia is clozapine, which must be carefully managed due to its side effects and safety concerns.Furthermore, half of patients with treatment-resistant schizophrenia are intolerant or resistant to clozapine.It appears clearly that using innovative antipsychotic drugs, such as lurasidone, the complex management plan of patients can be personalized and should be useful to improve the long-term prognosis of affected patients.Furthermore, lurasidone is effective in treating depressive symptoms in cannabis-induced psychotic disorders.Among psychoactive substances, cannabis represented the most commonly used ones worldwide, with one in four adults reporting to have assumed cannabis at least once during their lifetime.Several reasons have been identified for using cannabis, such as the effects of relaxation, euphoria, and sociability.However, several studies have confirmed that cannabis use is associated, in the long term, with the risk of developing full-blown psychosis.The documented psychotomimetic effects are largely attributable to THC, the main psychoactive compound in cannabis, which acts on the central nervous system by primarily binding to the CB 1 cannabinoid receptors.The availability in the illegal market of high-potency forms of cannabis has represented a growing concern for the potential adverse effects on mental health.Cannabis use is related to an earlier onset of psychotic illness, and a psychotic breakdown may occur almost three years earlier in cannabis users compared to non-users.Cannabis use may influence the expression of prodromal symptoms and progression to psychosis in individuals at high risk due to the complex interplay among personal, genetic, and social variables, defining the individual's liability to develop a full-blown psychotic disorder.The incidence of cannabis-induced psychotic disorders is estimated to be 2.7 per 100,000 person-years, with a conversion rate to schizophrenia-spectrum disorders ranging between one-third and one-half.Cannabisuser patients developing schizophrenia disorders report higher levels of positive and negative symptoms compared to those not using cannabis.Moreover, people developing schizophrenia following the use of cannabis have a worse long-term outcome in terms of days of hospitalization, adherence and compliance to pharmacological treatment, number of relapses, and levels of functioning.The management plan of patients with cannabisinduced psychosis and schizophrenia has not been clarified yet by guidelines, and there is no specific treatment with a clear superiority to another.Therefore, the case report by Ricci et al. [39] reporting the efficacy of lurasidone treatment in reducing the severity of both positive and depressive symptoms in patients with cannabis-induced psychosis is very relevant and encouraging.However, such data must be complemented by evidence coming from more structured and rigorous controlled-randomized trials.
Only two studies specifically evaluated safety, tolerability, and patients' satisfaction with the medication, confirming that lurasidone has a good tolerability and safety profile.In particular, the principal advantages of lurasidone over some other antipsychotics are its highly favorable metabolic profile and once-daily dosing regimen.In the selected studies, patients did not report any significant side effects, which should have improved adherence to treatment and long-term outcomes in patients with schizophrenia.However, further welldesigned studies are needed to confirm the good tolerability profile of lurasidone in treating the depressive symptoms of patients with schizophrenia.Moreover, the final aim of the management plan for patients with schizophrenia is represented not only by the remission of clinical symptoms but also by improving their quality of life and long-term recovery.Therefore, selecting pharmacological treatments with a good safety and tolerability profile is essential for the appropriate management of patients with schizophrenia [60].
The present review has some limitations that need to be acknowledged.First, it was not possible to perform a meta-analytic analysis because of the extreme variation in the assessment tools used to evaluate the presence and severity of depressive symptoms in patients with schizophrenia.The tools included the PANSS or the MADRS, while one study used a non-validated assessment tool.Therefore, the high heterogeneity of such assessment tools, with none specifically designed to assess depressive symptoms in patients with schizophrenia, highlights the need to promote future validation studies of assessment tools tailored to the specific psychopathological features of depressive symptoms reported by patients with schizophrenia.It should be useful to use a multilevel approach, starting with a focus group involving users, caregivers, and experts in the field of psychometric development and schizophrenia research, to identify the most important specific features of depressive symptoms reported by patients with schizophrenia.A subsequent step should include the development of a preliminary new questionnaire to be validated in a large and representative sample of patients with schizophrenia.
Although a systematic search has been performed, it is possible that some trials have been omitted due to restrictive selection criteria or the language of publication, which could have introduced a selection bias.
The limitations of the selected studies should be acknowledged, including the short follow-up period [33,34,40,41,44], the lack of an active comparator [35,36,[40][41][42], and the strict patient inclusion criteria.In addition, only one study [42] included patients in an acute phase/exacerbation of schizophrenia, so further real-world studies are needed to expand the generalizability of the findings.
Furthermore, studies are limited regarding the long-term effects of lurasidone on patients with schizophrenia; therefore, there is a need to promote further real-world studies with a longitudinal design and robust methodology in order to fill this gap.

Conclusions
Depressive symptoms in patients with schizophrenia have traditionally been overlooked and not considered of primary clinical relevance, especially when compared to positive and negative dimensions.A modern clinical approach to schizophrenia requires a personalized treatment plan that takes into account all clinical domains, including the positive, cognitive, negative, and depressive dimensions of psychosis.In addition, the clinical characterization of each individual case requires a detailed assessment of other variables, including the presence of adverse childhood experiences, personality traits, recovery styles, and coping strategies [61].The selection of the most appropriate pharmacological and non-pharmacological treatments, targeting the different clinical domains, should be based on a careful characterization of the individual case.Among pharmacological treatments, lurasidone seems to be particularly effective for the depressive symptomatology of schizophrenia.
The neglected treatment of depressive symptoms, the persistence of residual symptoms, and the adoption of unhealthy lifestyle behaviors represent some of the most relevant clinical unmet needs in the management of patients with schizophrenia [62,63].The dichotomy between psychotic and depressive dimensions could be overcome by adopting a transnosographic approach to mental disorders [21].For example, Demyttenaere et al. [64] found an association between depressive symptoms and other clinical dimensions in schizophrenia and highlighted the need for more tailored intervention efforts across mood and psychotic disorders.There is a need to dedicate more attention to the needs of patients with schizophrenia, who report high levels of depressive symptoms.In particular, it should be useful to develop innovative assessment tools in order to capture the complexity of such clinical presentations [43,[65][66][67][68][69][70].
In conclusion, we believe that lurasidone is a promising treatment option for patients with schizophrenia, including those with depressive symptoms.Lurasidone is effective for positive, negative, and depressive symptoms in patients with schizophrenia, has a positive impact on long-term outcomes, and may be beneficial in the early stages of the illness [71][72][73][74][75].

Supplementary Materials:
The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/brainsci14030225/s1,Clinical cases on the use of lurasidone for the treatment of depressive symptoms in patients with schizophrenia.Table S1

Table 1 .
Experimental studies included in the narrative review (N = 11).
PANSS negative subscale (−1.9 vs. −1.7),andglobalscores(−5.1 vs. −3.8)compared to modal 40 mg/d.Treatment with lurasidone compared to placebo has resulted in a broad range of benefits, including improvements in depressive and cognitive symptoms.Patients reported a significant reduction in clinical sympotmatology, scoring −29.4 (17.6) at the PANSS total score in the double blind and −8.8(13.3)in the open-label study.The CDSS score was stable.An improvement in quality of life evaluated at EQ-5D-3L was found at week 12. Patients reported an overall mean (SD) increase of 0.097 (0.190) (double-blind study) and 0.028 (0.141) (open-label study).

Table 2 .
Case series/case studies included in the narrative review (N = 4).