*Review* **Second-Generation Antipsychotics' Effectiveness and Tolerability: A Review of Real-World Studies in Patients with Schizophrenia and Related Disorders**

**Michele Fabrazzo \*, Salvatore Cipolla, Alessio Camerlengo, Francesco Perris and Francesco Catapano**

Department of Psychiatry, University of Campania "Luigi Vanvitelli", Largo Madonna Delle Grazie 1, 80138 Naples, Italy; salvatore2211@gmail.com (S.C.); alessiocamerlengo90@gmail.com (A.C.); francesco.perris@unicampania.it (F.P.); francesco.catapano@unicampania.it (F.C.) **\*** Correspondence: michele.fabrazzo@unicampania.it; Tel.: +39-(0)-81-566-65-29; Fax: +39-(0)-81-566-65-23

**Abstract:** Despite methodological limitations, real-world studies might support clinicians by broadening the knowledge of antipsychotics' (APs) effectiveness and tolerability in different clinical scenarios and complement clinical trials. We conducted an extensive literature search in the PubMed database to evaluate the effectiveness and tolerability profiles of second-generation antipsychotics (SGAs) from real-world studies to aid clinicians and researchers in selecting the proper treatment for patients with schizophrenia and related disorders. The present review evidenced that SGAs demonstrated superior effectiveness over first-generation antipsychotics (FGAs) in relapse-free survival and psychiatric hospitalization rate and for treating negative symptoms. Persistence and adherence to therapy were higher in SGAs than FGAs. Most studies concluded that switching to long-acting injectables (LAIs) was significantly associated with a lower treatment failure rate than monotherapy with oral SGAs. Considerable improvements in general functionality, subjective well-being, and total score on global satisfaction tests, besides improved personal and social performance, were reported in some studies on patients treated with LAI SGAs. Clozapine was also associated with the lowest rates of treatment failure and greater effectiveness over the other SGAs, although with more severe side effects. Effectiveness on primary negative symptoms and cognitive deficits was rarely measured in these studies. Based on the data analyzed in the present review, new treatments are needed with better tolerability and improved effectiveness for negative, affective, and cognitive symptoms.

**Keywords:** schizophrenia; negative symptoms; real-world studies; real-world effectiveness; tolerability; treatment adherence; second-generation antipsychotics; long-acting injectable antipsychotics

#### **1. Introduction**

Schizophrenia is among the most disabling mental health conditions [1] and affects approximately 24 million people worldwide [2,3]. In addition, subjects affected by schizophrenia and related disorders have a 10–25-year reduction in life expectancy than the general population due to the increased rates of comorbid physical illnesses, smoking, and substance abuse, rates of suicide as common causes of death, and reduced health-seeking behavior [4–6].

Patients with schizophrenia and related disorders may experience positive, negative, affective, and cognitive symptoms influencing many aspects of their daily functioning [7–13].

The psychopharmacological treatment of schizophrenia and other psychotic disorders relies mainly on antipsychotics (APs), which are traditionally divided into two classes: firstgeneration antipsychotics (FGAs) and second-generation antipsychotics (SGAs) [14–16]. Both classes of drugs are effective in relieving the positive symptoms of schizophrenia. Instead, evidence of the efficacy on negative, affective, and cognitive symptoms is inconclusive, and these dimensions remain the unmet needs of schizophrenia treatment [17–19].

**Citation:** Fabrazzo, M.; Cipolla, S.; Camerlengo, A.; Perris, F.; Catapano, F. Second-Generation Antipsychotics' Effectiveness and Tolerability: A Review of Real-World Studies in Patients with Schizophrenia and Related Disorders. *J. Clin. Med.* **2022**, *11*, 4530. https://doi.org/10.3390/ jcm11154530

Academic Editor: Armida Mucci

Received: 13 June 2022 Accepted: 1 August 2022 Published: 3 August 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

APs may also induce different side-effect profiles [20], occasionally perceived by patients as distressing and disabling [21]. In general, side effects include extrapyramidal side effects (EPS), increased prolactin plasma levels, metabolic complications such as weight gain, metabolic syndrome, hyperlipidemia, and type 2 diabetes, which may reduce life expectancy [22–24]. Specifically, FGAs might induce hyperprolactinemia and frequent adverse motor effects, such as EPS, as well as increasing disability and stigma related to the disease [24].

SGAs are associated, although not consistently [25–27], with a reduced incidence of EPS, compared to FGAs, with a few distinctions between both medications [28,29]. However, the difference between the two classes of APs is clinically relevant, as EPSs are associated with reduced treatment adherence, depression, suicide, secondary negative symptoms, worse cognitive performance, deficits in motor skills and verbal learning, attention, and working memory [30–33]. Furthermore, EPSs often require additional treatment with anticholinergic drugs, burdening patients with adverse effects such as memory impairment, delirium, and autonomic nervous system dysfunctions.

APs may prove to be ineffective for many patients [34]. In addition, a few of them experience at least one relapse over the five years after the beginning of therapy [35]. Between a quarter and a third of affected patients manifest treatment resistance, and only 17.5% might respond to clozapine [34,36]. Therefore, a key component of the long-term management of schizophrenia and related disorders is to select an appropriate antipsychotic treatment for the needs of each individual [37,38]. The efficacy and tolerability of antipsychotic treatment might profoundly affect adherence to therapy and clinical response, with the risk of relapses [39,40].

Adverse effects are also a frequent cause for discontinued treatment, besides lack of insight, disease severity, and treatment characteristics. In addition, adverse effects may impact environmental factors such as patient's erroneous belief in the effectiveness of medication, and substance abuse [39]. For this reason, there is a need for new treatments with improved tolerability and efficacy for negative, affective, and cognitive symptoms.

In the last 15 years, some studies have investigated the effectiveness of SGAs compared to FGAs for schizophrenia and related disorders, leading to reconceiving trials' design using APs, as in the US Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) [26] and the UK Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS) [17]. The two trials measured short- and mid-term outcomes, not always considering the real-world clinical practice and outcome measures besides positive symptoms (e.g., exclusion of comorbidity with substance abuse, predominance of chronic patients, and lack of quality of life/well-being measures) [40]. Furthermore, the European First Episode Schizophrenia Trial (EUFEST) compared the effectiveness of some SGAs with that of a low dose of haloperidol in first-episode schizophrenia at 1-year follow-up. SGAs were associated with a higher retention rate than haloperidol (primary outcome). However, the psychopathological scores' mean reduction did not vary [41]. A secondary analysis showed that most SGAs had higher response and remission rates than haloperidol [42]. All treatment groups were associated with worsened hypertriglyceridemia or hyperglycemia. Only ziprasidone was less associated with weight gain [43]. These results disagreed with those reported in a chart review demonstrating that SGAs in first-episode patients had a three times higher incidence of metabolic syndrome with respect to FGAs [44]. However, the study had a longer follow-up period (3 years) than the EUFEST trial. Overall, the available evidence does not coherently indicate superior effectiveness and tolerability for SGAs.

One of the most considerable challenges in treating patients with schizophrenia and related disorders is the life-long functional disability associated with negative symptoms, cognitive impairment, and increased treatment resistance after each acute episode. Consequently, the primary goal of antipsychotic treatment should be not only to achieve a partial (or optimal) remission of symptoms in the acute phase but also to improve long-term

outcomes and reduce the risk of secondary negative symptoms and worsening of cognitive impairment [45,46].

Harmonizing the results of randomized clinical trials (RCTs) with those of observational studies remains a challenge for clinical medicine. Although RCTs are considered the "gold standard" for evaluating the efficacy and safety of an intervention, observational studies conducted in a real-world scenario help provide evidence of the intervention in clinical practice effectiveness. Ref. [47], indeed, reported that "real-world effectiveness" is one of the last five years' significant research trends [47].

For a clinician, assessing both efficacy and effectiveness remains a crucial factor. Indeed, observational studies are beneficial in clinical situations rarely tested in RCTs and provide reliable real-world evidence. Specifically, RCTs evaluate interventions under ideal conditions in highly selected populations, whereas observational studies examine effects in naturalistic settings. Furthermore, RCTs results might not apply to the entire population of patients due to complex clinical presentations and poor responses to standard treatments in "real-world" settings.

On the other hand, dissimilar findings may arise due to such issues as selection bias, confounding, statistical power, and differential adherence and follow-up. Furthermore, real-world studies encompass a wide range of research methods and data sources and can be broadly categorized as non-interventional studies, patient registries, claims database studies, patient surveys, and electronic health record studies. Real-world studies can also be categorized into prospective studies, which generally require primary data collection, and retrospective studies, which use secondary data gathered over a long period (i.e., data initially collected for other purposes). Nevertheless, a recent Cochrane review showed little evidence that the results of observational studies and RCTs are systematically discordant [48]. Thus, studies on clinical effectiveness and naturalistic outcomes cannot replace RCTs, which remain complementary and fundamental to gathering helpful information.

This review aims to provide an update of the primary therapeutic and side-effect profiles of SGAs, focusing on real-world studies to enable clinicians and researchers to select the most appropriate treatment for adult patients ≥ 18 years diagnosed with schizophrenia or related disorders.

#### **2. Methods**

We conducted an extensive literature search in the PubMed database from inception until May 2022, with English as a language filter. This review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement, as applicable [49]. The search was conducted with the following terms (MeSH headings): (("Adult"[Mesh]) AND ("Humans"[Mesh]) AND ("Real-World") AND (("Schizophrenia"[Mesh]) OR ("Schizophrenia Spectrum and Other Psychotic Disorders"[Mesh])) AND (("Antipsychotic Agents/adverse effects"[Mesh]) OR ("Antipsychotic Agents/therapeutic use"[Mesh])) NOT ("Electroconvulsive Therapy"[Mesh]) NOT ("Transcranial Magnetic Stimulation"[Mesh])). In addition, we hand-searched the reference lists of included articles of any study on our topic of interest.

We focused on real-world studies, including prevalently longitudinal comparative studies (i.e., cohort or case–control studies). We identified schizophrenia and/or schizophrenia spectrum and other psychotic disorders as the mental disorders of interest for the scoping review, including only studies on psychopathological symptoms assessment through standardized rating scales. Furthermore, we included studies on patients treated with SGAs, or co-treated with FGAs and SGAs in the oral or long-acting injectable (LAI) formulations. Specifically, we selected studies containing data on individual drugs or grouped SGAs that reported the effectiveness and tolerability outcomes for adult participants ≥18 years. Moreover, we included studies evaluating both effectiveness and/or tolerability in patients switching from oral SGAs or FGAs to LAI SGAs.

The primary outcomes of interest were the effectiveness of oral and/or LAI formulations of SGAs on positive, negative, affective, and cognitive symptoms and their tolerability

profile. In particular, we considered of interest studies reporting one or more of the following elements: (1) ≤20% reduction on the psychopathology assessment scale (i.e., BPRS); (2) improvements in quality of life rated by specific scales (i.e., Subjective Well-Being under Neuroleptics Scale [SWN-S] and the Treatment Satisfaction Questionnaire for Medication [TSQM]); (3) magnitude of treatment effects on severity measures (i.e., the Positive and Negative Syndrome Scale [PANSS], the Brief Psychiatric Rating Scale [BPRS], the Clinical Global Impression—Severity scale [CGI-S], and Quality of Life [QoL] scores); (4) improvement in negative symptoms; (5) effects on cognitive performance (evaluated by standard neuropsychological instruments); (6) improvement in global and social functioning, selfcare, and disturbing/aggressive behavior (i.e., evaluated by the Global Assessment of Functioning [GAF] or the Personal and Social Performance [PSP] scale scores or defined as an increase in at least one activity in which the patient participated, compared to the baseline activity); (7) assessment of rate and time to treatment discontinuation, defined as stopping the AP medication started in baseline conditions and/or adding a new AP; (8) persistence/compliance/adherence on medications (measured as pill counts, pharmacy records, and proportion of adherent/non-adherent patients); (9) occurrence of any mental health events (suicide, hospitalization, or emergency department visits); (10) risk of rehospitalization and treatment failure (suicide attempt, discontinuation or switch to other medications, or death).

In addition, we considered of interest studies reporting any new onset or worsening side effects, i.e., EPS, hyperprolactinemia, diabetes, ketoacidosis, hyperglycemic state, weight gain/overweight/obesity, hyperlipidemia or hypercholesterolemia, hypertriglyceridemia, hypertension, and metabolic syndrome. We considered suitable and recorded any definition of these clinical entities, including diagnoses based on any coding system (e.g., ICD-10) and exposure to specific treatments (e.g., antihypertensives).

We excluded studies on pregnant women and considered only studies containing results on at least one outcome of interest (effectiveness or tolerability, or both).

S.C. and A.C. extracted the relevant data, and synthesized them in a tabular format; F.M., F.P. and F.C. triple-checked the extracted data for accuracy; M.F., S.C. and A.C extracted the data on study characteristics (type of study, number of participants/sample size, and psychopathological diagnostic tools), outcome measures (proportion of patients with schizophrenia and related disorders, psychopathological assessment tools used to evaluate the severity of disease), and therapeutic intervention types (oral vs. LAI SGAs).

Two authors of the present review (S.C. and A.C.) independently assessed the quality and risk of bias in the non-randomized studies of interventions (NRSIs) included in the present review through the ROBINS-I tool (Risk of Bias in Non-randomized Studies of Interventions). Such a tool [50] comprises three main domains for bias evaluation: preintervention, during the intervention, and post-intervention. The risk of bias was judged for each domain and sub-domain and classified as low, moderate, high, or no information (Supplementary Table S1).

The two authors resolved disagreements through discussion or involving a third author (F.P.). In line with the ROBINS-I tool, the authors considered an NRSI at low risk if judged at low risk of bias for all domains; at moderate risk if judged at moderate risk for at least one domain; at high risk if judged at high risk of bias for at least one domain but not at critical risk of bias in any domain; and at critical risk if judged at critical risk in at least one domain. In addition, we indicated "no information" for an NRSI in case no clear judgment of high or critical risk of bias was possible and in case information about one or more key domains was missing.

#### **3. Results**

As shown in Supplementary Figure S1, we retrieved 188 articles and excluded 115 by initial screening of titles and abstracts as not addressing the topics of interest. We included the remaining 73 articles in the final analysis as relevant for the full-text screening. We excluded 39 of them after careful reading: 10/73 were narrative reviews or reviews that did not analyze studies on patients in real-world conditions or therapeutic and/or tolerability outcomes, 26/73 were studies including patient populations different from the target ones, and 3 were studies with only abstracts written in the English language. The remaining 34 articles were eligible to be included in our review.

We further subdivided the 34 studies according to the outcome analyzed regarding effectiveness and tolerability, which were examined based on the type of AP formulation (oral vs. LAI) used to treat enrolled patients, as reported in Supplementary Figure S1. Thus, the studies reporting the effectiveness of SGAs were sub-grouped into oral SGAs (15/34) and LAI SGAs (19/34) subgroups. Finally, only 11 studies reported data on the tolerability profile of SGAs, namely 3 studies involving oral SGAs and 8 LAI SGAs (Supplementary Figure S1).

The overall risk of bias was moderate for most non-randomized clinical studies (20/34). Instead, the risk of bias appeared low for one study, with those remaining (13/34) presenting a high risk (Supplementary Table S1).

#### *3.1. Studies Investigating the Effectiveness of SGAs*

All the 34 retrieved studies reported the effectiveness of SGAs in patients with a diagnosis of schizophrenia or related disorders. A total of 15 studies evaluated the effectiveness of SGAs in patients treated with oral formulations and the other 19 in patients treated with LAI SGAs.

SGAs included amisulpride, clozapine, olanzapine, quetiapine, risperidone, paliperidone, ziprasidone, aripiprazole, brexpiprazole, and lurasidone, as a monotherapy or in combination. All the studies emphasized that clozapine was not to be used in combination with other SGAs.

FGAs were prevalently used as an all-drug comparison group and included haloperidol, zuclopenthixol, flupentixol, and sulpiride. In some studies, FGAs were also used in combination therapy with SGAs.

#### 3.1.1. Studies Investigating the Effectiveness of Oral SGAs Treatments

In Table 1, we summarized the results of our literature search on effectiveness outcomes. We described the effectiveness of each treatment and subdivided the 15 studies we analyzed as follows: six studies were on SGAs vs. FGAs, four on olanzapine vs. risperidone, two on ziprasidone not compared with other SGAs or FGAs, one on clozapine vs. other SGAs or FGAs, and one on lurasidone and brexpiprazole, each drug vs. other SGAs.

**Table 1.** Real-world population-based studies investigating the effectiveness of oral SGAs in patients with schizophrenia and related disorders.




*J. Clin. Med.* **2022**, *11*, 4530


**Table 1.** *Cont.*


Syndrome Scale; CGI-S = Clinical Global Impression—Severity scale; GAF = Global Assessment of Functioning Scale; AP = Antipsychotic; FGAs = First-Generation Antipsychotics; Chlorpro = Chlorpromazine; Fluph= Fluphenazine; Flup = Flupentixol; Halo = Haloperidol; Perph = Perphenazine; Peros = Perospirone; Zuclo = Zuclopenthixol; Sulp = Sulpiride; SGAs = Second-Generation Antipsychotics; Blo = Blonanserin; Zipra = Ziprasidone; Ami = Amisulpride; Clo = Clozapine; Ola = Olanzapine; Que = Quetiapine; Ris = Risperidone; Pali = Paliperidone; Ari = Aripiprazole; Brex = Brexpiprazole; Lura = Lurasidone; Zote = Zotepine; COMETA = COMpliance, costs and quality of life-clinical experience in antipsychotic therapy; HRQoL = Health-Related Quality of Life; SF-36 PCS and MCS = Physical (PCS) and Mental (MCS) Component Summary scores of SF-36; SOHO = Schizophrenia Outpatient Health Outcomes; SALT-C = Schizophrenia by Atypical Antipsychotic Treatment in China; CGI-SCH = Clinical Global Impressions Severity Scale—Schizophrenia version; PSP = Personal and Social Performance.

Most studies evaluated the effectiveness of SGAs vs. FGAs [55–57,59,62,65]. Olanzapine, in particular, emerged as an effective treatment option among the atypical agents [51].

Only a few studies directly evaluated the therapeutic effects of SGAs on positive, negative, and affective symptoms [41,42,46,55,56], and none reported antipsychotic effectiveness in disabling cognitive symptoms.

Persistence, adherence, or failure to treatment, as well as the rate of SGAs discontinuation or risk of hospitalization, were analyzed in most studies [52–55,57–62,64,65]. Overall, olanzapine demonstrated superior real-world effectiveness vs. risperidone in relapse-free survival and psychiatric hospitalization [61]. Moreover, switching to clozapine, to risperidone or to olanzapine oral monotherapy was also associated with significantly better persistence in treatment [62]. In addition, Hatta et al. (2022) [65] suggested that switching to LAIs or APs polytherapy might be more likely associated with a low treatment failure rate [65]. Clozapine, as well, was associated with the lowest rates of treatment failure and more marked effects vs. other SGAs in reducing the period of hospitalization [58].

Refs. [52,53] reported on ziprasidone effectiveness, concluding that the improvement in PANSS factors and GAF scores was significant but associated with a discontinued treatment for any cause in more than 50% of patients [52,53]. Discontinuation due to lack of clinical effectiveness was linked more to patients' perceptions (25.7%) than to physicians' conclusions (8.6%). However, both studies did not include a control group for comparison. Differently, the study by [60] reported that patients treated with lurasidone demonstrated greater adherence when compared to patients treated with other SGAs [60]. Finally, when brexpiprazole treatment was examined compared to other SGAs, it was found to be associated with fewer psychiatric hospitalizations per year than paliperidone and quetiapine. No significant differences in other efficacy measures emerged between patients treated with brexpiprazole and those with other SGAs [63].

The overall risk of bias for most non-randomized clinical studies reporting the effectiveness of oral SGAs was moderate (11/15).

#### 3.1.2. Studies Investigating the Effectiveness of LAI SGAs Treatments

Most studies reporting on LAI APs treatments included patients that had been previously treated with oral FGAs or SGAs or switched from one LAI FGA/SGA to another LAI SGA treatment (Table 2). Some studies described patients previously treated with the corresponding oral formulation and then shifting to LAI therapy. Furthermore, most

studies included patients treated with once-monthly paliperidone palmitate (PP1M) and aripiprazole LAI (Table 2). On the other hand, only a few studies compared the effectiveness of LAI SGAs vs. LAI FGAs, or oral FGAs/SGAs vs. LAI FGAs/SGAs, or oral SGAs vs. LAI SGAs [66].

**Table 2.** Real-world population-based studies investigating the effectiveness of SGAs LAI formulations in patients with schizophrenia and related disorders.







**Table 2.** *Cont.*

AP = Antipsychotic; FGAs = First-Generation Antipsychotics; SGAs = Second-Generation Antipsychotics; PANSS = Positive and Negative Syndrome Scale; QOLS = Quality of Life scale; PSP = Personal and Social Performance Scale; SWN-S = Subjective Well-being under Neuroleptics Scale; TSQM = Treatment Satisfaction Questionnaire for Medication; PALMFlexS = Paliperidone Palmitate Flexible Dosing in Schizophrenia; CGI-C = Clinical Global Impression—Change; CGI-S = Clinical Global Impression Severity Scale; BPRS = Brief Psychiatric Rating Scale; GAF = Global Assessment of Function; Mini-ICF-APP = Mini-ICF (International Classification of Functionality, Disability and Health) rating for Activity and Participation Disorders in Psychological Illnesses; PP1M = once-monthly paliperidone palmitate; PRIDE = Paliperidone Palmitate Research in Demonstrating Effectiveness; PP3M = once-every-3-months paliperidone palmitate; LDPS = Lifetime Dimensions of Psychosis Scale; SCI-PSY = Structured Clinical Interview for the Psychotic Spectrum; SCWT = Stroop Color and Word Test; ROCF = Rey–Osterrieth Complex Figure Test.

Finally, only the study by [69] presented results on the effectiveness of LAI risperidone in a retrospective cohort study vs. all-oral SGAs and FGAs and vs. oral risperidone [69]. All the studies, including patients treated with PP1M, reported significant improvements in subjective well-being and global satisfaction, and improved personal and social performance [59,65,67,68,70–72,74–76,78,79,82]. Furthermore, functionality improvement was more remarkable in patients with a disease duration of 5 years or less [75]. Finally, in a longitudinal prospective study, Ref. [79] reported that PP1M and once-monthly aripiprazole

LAI improved social and cognitive functioning in patients who had already experienced relief compared with the corresponding oral formulations of SGAs [79]. In addition, a few studies reported that high doses of PP1M (175 mg equivalent/28 days) in patients with severe schizophrenia improved the drug's effectiveness [71]. Furthermore, when patients receiving doses of PP1M ≥175 mg Eq were compared to patients treated with high doses of risperidone-LAI (dose ≥ 75 mg) or aripiprazole-LAI (dose ≥ 600 mg/month), PP1M showed better clinical effectiveness, besides reducing the risk of hospital admissions and suicide attempts [78].

Additionally, patients enrolled in other studies showed a low dropout rate, reduced acute healthcare use, and significantly improved neurocognitive function after 12 months of treatment with LAI SGAs, besides better effects on positive, negative, and affective symptoms, psychosocial functioning, and quality of life [79,82]. Furthermore, the transition from PP1M to PP3M evidenced a substantial decrease in combined medications and healthcare resource use, and increased adherence [74].

Treatment with once-monthly aripiprazole LAI improved BPRS and CGI-S scores, especially in younger patients (age ≤ 35 years) [71] and was less likely to be associated with discontinuation of treatment when compared with the corresponding oral group or other SGAs [65,72,73,77,79–81]. Thus, adherence and the hospitalization rate appeared to be improved. Such a pharmacological pattern indicates the potential for greater clinical stability in patients who initiated aripiprazole LAI than that achieved with their previous treatments [60].

The risk of bias for non-randomized clinical studies reporting the effectiveness of LAI SGAs was almost equally distributed between moderate (9/19) and high (10/19) risk.

#### *3.2. Studies Investigating Tolerability of Oral or LAI SGAs*

Table 3 illustrates real-world studies investigating the tolerability of oral or LAI SGAs in patients with schizophrenia and related disorders.


**Table 3.** Real-world population-based studies investigating the tolerability of oral and/or LAI formulations of SGAs in patients with schizophrenia and related disorders.





EPS = Extrapyramidal Symptoms; ESRS = Extrapyramidal Symptom Rating Scale; DSAS = Distress Scale for Adverse Symptoms; ADR = Adverse Drug Reaction; DAI-30= Drug Attitude Inventory; EHR = Electronic Health Records; PP1M = Paliperidone palmitate once-monthly; MetS = Metabolic Syndrome; PRIDE study = Paliperidone Palmitate Research in Demonstrating Effectiveness study.

Ref. [51] sustained that the number of patients presenting side effects when treated with SGAs (amisulpride, clozapine, olanzapine, quetiapine, and risperidone) was in the range of 25–63.3%. However, the authors did not specify the secondary or adverse effects reported by patients [51]. On the other hand, among all patients who completed treatment with oral ziprasidone monotherapy, the most common adverse events from baseline to endpoint were mild/moderate [53].

Ref. [83] reported that most frequent adverse effects in patients treated with clozapine (N = 2835) were observed in the three months following treatment start [83]. However, higher percentages of all adverse effects appeared in the first month of clozapine therapy. Furthermore, the data analysis showed a significant negative association between most adverse drug reactions and smoking status, hospital admission conditions, gender, ethnicity, and age of the included patients [83].

Among studies on the tolerability profile of LAI SGAs, six out of eight studies included patients under PP1M treatment. Most studies evidenced treatment-related adverse effects occurring in ≥5% of patients and mainly represented by pain in the injection site (2.3%), insomnia (8.6%), anxiety (6.7%), psychotic disorder (6.1%), headache (5.6%), weight increase (11.9%), and akathisia (11.1%) [67,68,70,71,73,75,78]. Instead, at each assessment point, no significant differences arose in blood pressure, glycemia, triglycerides, total cholesterol, and HDL cholesterol mean scores [71,84]. In the total patient population, 5.7% had a potentially prolactin-related adverse effect (prolactin elevation, amenorrhea/menstrual irregularity in female patients, galactorrhea, gynecomastia, erectile dysfunction, and decreased general sexual function in males) which greatly affected compliance to treatment [67,68,70,75,78,84]. Furthermore, when used at higher doses than standard ones (≥175 mg Eq), PP1M showed a good tolerability profile [71].

The overall risk of bias for non-randomized clinical studies reporting the tolerability results of oral or LAI SGAs was moderate (6/11) and high (5/11).

#### **4. Discussion**

Overall, the real-world studies analyzed in the present review evidenced that SGAs effectiveness proved superior vs. FGAs, in terms of relapse-free survival, discontinuation rate, and psychiatric hospitalization rate. Furthermore, SGAs were likely superior to FGAs for treating negative symptoms.

On the contrary, RCT results showed that SGAs did not appear to have a better efficacy on negative symptoms than FGAs, although some other studies showed a good efficacy associated with a favorable side-effect profile [85–87]. The CATIE study evidenced that all APs had limitations. Therefore, 74% of patients discontinued their randomized treatment over 18 months due to inefficacy or intolerable side effects. Additionally, SGAs differed neither from each other nor from perphenazine (an FGA) concerning effectiveness or EPS. Several studies included in the present review compared SGAs prevalently to haloperidol, which has an increased propensity to cause drug-induced EPS. Accordingly, there was no evidence that SGAs were better for negative symptoms and cognitive deficits. Individual drugs differed in specific side effects. Olanzapine, for example, proved to be the most effective concerning discontinuation rate (64%), although causing the highest side-effect burden [26].

Furthermore, from studies examined in the present review, LAI APs appeared as the pharmacologic treatments with the highest prevention rates of relapse in patients with schizophrenia and related disorders. The risk of psychiatric rehospitalization was the lowest during monotherapy with once-monthly paliperidone LAI, zuclopenthixol, perphenazine, and olanzapine compared with no use of APs [44]. In addition, all LAI APs appeared to be associated with a lower risk of rehospitalization also when compared with the equivalent oral formulations (i.e., oral olanzapine) [44]. Switching from oral SGAs or FGAs to LAIs or APs polytherapy in early non-responders appeared beneficial for preventing treatment failure in hospitalized patients with acute schizophrenia [46,65]. Better relapse prevention and clinical stability were achieved by switching from one LAI to another when deemed

necessary [65]. Finally, a more favorable tolerability profile was described in patients switching from oral aripiprazole to aripiprazole LAI [73]. Side effects, such as weight gain, EPS, those related to hyperprolactinemia, and sexual dysfunction, rarely emerged [71,78]. Overall, EPS were present only in patients > 35 years diagnosed with schizophrenia more than 5 years before.

Different long-term SGAs efficacy and tolerability patterns emerged prevalently from meta-analyses of RCTs, which indicated that: (1) regarding all-cause discontinuation, clozapine, olanzapine, and risperidone were significantly superior to several other SGAs, while quetiapine was inferior to several other SGAs [88,89]; (2) as to psychopathology, clozapine and olanzapine were superior to several other SGAs, while quetiapine and ziprasidone were inferior to several other SGAs [90,91]; (3) regarding intolerability-related discontinuation, risperidone was superior and clozapine inferior to several other SGAs [20,92,93]. Concerning weight gain, olanzapine was worse than all the other compared non-clozapine SGAs, and risperidone was significantly worse than several other SGAs. Regarding prolactin increase, risperidone and amisulpride were significantly worse than several other SGAs. Regarding parkinsonism, olanzapine was superior to risperidone, without significant differences about akathisia. Concerning sedation and somnolence, clozapine and quetiapine were significantly worse than a few other SGAs.

However, the apparent improvement in key clinical domains (e.g., negative symptoms) reported by meta-analyses may be largely attributable to improvements in a related clinical domain, such as positive symptoms or fewer AP-related side effects (e.g., EPS), a problem often referred to as pseudospecificity [94].

Our analysis evidenced that SGAs therapy persistence and adherence to treatment were higher than with FGAs. Furthermore, some studies concluded that switching to LAIs or APs polytherapy was associated with a lower treatment failure. In addition, general functionality, subjective well-being, global satisfaction, and improved personal and social performance were reported in patients treated with LAI formulations of SGAs (namely, PP1M and once-monthly aripiprazole LAI) when compared with the corresponding oral formulations.

Clozapine, as well, was associated with the lowest rates of treatment failure and greater efficacy vs. the other SGAs, despite being administered exclusively for intolerant and/or non-responder patients and presenting neurocognitive compromise (mainly reduced performance on attention and memory), plus an unfavorable metabolic and hematological adverse-event profile [83,95]. In the 99% of patients entering CATIE phase 2, clozapine also emerged as significantly more effective than the other SGAs, with a median time to discontinuation of 10 months, twice the length of the following best AP, namely olanzapine [96]. Thus, in both CATIE and CUtLASS studies, SGAs were not found to be more effective (except for olanzapine in CATIE) and did not produce measurably fewer EPS overall. Furthermore, clozapine was the most effective for treatment-resistant patients [26,27].

Among the real-world studies we analyzed, only a few reported on new SGAs, such as lurasidone and brexpiprazole. However, patients treated with lurasidone displayed greater adherence when compared to patients treated with other SGAs [60]. Furthermore, one study analyzed the efficacy of brexpiprazole, and no significant differences emerged when treated patients were compared with those treated with other SGAs [63].

No real-world studies on the effectiveness and tolerability outcomes of patients treated with cariprazine were retrieved by our literature search, although the FDA had approved the drug in 2015.

Most studies selected in this literature review present a few methodological limitations relating to the standard use of medical data from insurance companies, patient registries, administrative and healthcare claims database. Such limitations include no verification of the psychiatric diagnosis and treatments received, high polypharmacy rates, limited knowledge of earlier treatment conditions, and emerging side effects. Furthermore, these studies typically do not present measures of laboratory biological parameters, relying on surrogate markers for the presence of a disease (i.e., for diabetes, the prescription of

a hypoglycemic agent, or an ICD code for diabetes). Furthermore, the heterogeneity of the studies conducted in different populations over several decades will likely introduce relevant biases. One of the significant limitations of some studies was the limited or absent control over the data collection quality, which reduced the internal validity of the results. Other potential biases may result from unmeasured confounders and insufficient statistical adjustment of confounders. In this respect, retrospective study data do not meet the criteria of reliability and accuracy required by the methodological rigor of RCTs.

#### **5. Conclusions**

The present review evidenced that SGAs demonstrated superior effectiveness over FGAs in relapse-free survival and psychiatric hospitalization rate and for treating negative symptoms, while no clear evidence emerged regarding the effectiveness on cognitive deficits. In addition, persistence and adherence to therapy were higher with SGAs than FGAs. Most studies concluded that switching to LAIs was significantly associated with a low treatment failure rate than monotherapy with oral SGAs. Significant improvements in general functionality, subjective well-being, and global satisfaction, besides improved personal and social performance, were reported in some studies on patients treated with LAI SGAs. Furthermore, considering safety and tolerability, our literature review suggests that in adult patients with schizophrenia and related disorders, there may be a lower association of weight gain and adverse metabolic effects with ziprasidone, aripiprazole, and some FGAs compared with olanzapine, clozapine, quetiapine, and risperidone.

Finally, it is crucial for the clinicians to be familiar with the various therapeutic options, not neglecting the old medications, which are still in use with acceptable effectiveness.

**Supplementary Materials:** The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/jcm11154530/s1, Table S1: Risk of bias assessments in non-randomized clinical studies. Figure S1: Flow diagram showing study selection process of included articles.

**Author Contributions:** Conceptualization, M.F. and F.C.; methodology, M.F., S.C., A.C. and F.P.; software, S.C. and A.C.; validation, S.C. and A.C.; formal analysis, S.C.; investigation, M.F. and F.C.; resources, M.F., F.C. and F.P.; data curation, M.F., F.C. and F.P.; writing—original draft preparation, M.F.; writing—review and editing, M.F. and F.C.; visualization, A.C. and S.C.; supervision, F.C.; project administration, M.F.; funding acquisition, M.F. and F.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** All data relevant to this paper are included in the article.

**Acknowledgments:** We would like to thank Marinella Simioli for her professional language and editing assistance.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

