The pharmacological treatment of schizophrenia: how far have we come?

“42 There is abundant data indicating that individuals who will fail to respond to nonclozapine antipsychotics may be more likely to respond to clozapine, 43 suggesting possibly a distinct neurobiology 44 and certainly the need to stratify treatment accordingly.”

“25 Thus, it is conceivable that the two share genetic liability that manifests in maladaptive reward processing, 26 and/or one predisposes to the other (e.g., substance use to compensate for deficits resulting from aberrant signaling in the mesolimbic dopamine pathway).”

“Given the much shorter life expectancy for people with schizophrenia, 32 and the known overall association between greater use of antipsychotic medication and longer life expectancy in schizophrenia, it is hypothesized, with some data supporting, 33 that by guaranteeing continuous drug delivery and…”

“…with metabolic disturbance, mortality, and antipsychotic drugs is complex, since although antipsychotics are known to cause metabolic disturbance, 34 this is very likely offset in terms of risk of premature mortality by better symptom control and higher levels of functioning, which would…”

“16 Additional outcomes of interest for the care of those living with schizophrenia, beyond psychopathology and functional outcomes, are those related to substance use and medical comorbidities.”

“The criteria to define so ‐ called “ treatment resistance, ” and thus of clozapine eligibility, has been recently agreed on, 45 and in essence it applies to subjects for whom the trials were at least 6 weeks in duration, with an equivalent daily dose of at least 600 mg of chlorpromazine, for which…”

“31 In fact, physical health and premature mortality have gained attention in recent years, given the worrisome statistic that individuals with schizophrenia live an average of about 15 years less than those without schizophrenia.”

“53 Also, similar studies relate the clinical efficacy of antipsychotic drugs to the postsynaptic dopamine 2/3 receptor modulation within a critical window.”

“88 Also, some uncontrolled and/or unrandomized data have shown better recovery outcomes in individuals who discontinue antipsychotics over the long term compared to those who continue treatment.”

“81 However, there is growing recognition of the importance of making LAIs the preferred formulation for the treatment of schizophrenia in earlier phase treatment, before several relapses have occurred.”

“8 EIS constitutes at minimum regularly monitored psycho-pharmacological treatment, family psychoeducation, and counseling.”

“74 This finding has been consistently replicated in mirror ‐ image study and epidemiological sample meta ‐ analyses.”

“66 Circumstances that increase the risk for nonadherence in schizophrenia are being at an earlier phase of treatment, 67,68 comorbid substance use, 69 social exclusion (i.e., homelessness), and high side effect burden.”

“63,64 The factors influencing medication nonadherence are complex and include insight, lifestyle, psychological well ‐ being, health literacy, support systems, and side effects of medications.”

“89,90 Altogether, these data questioned whether the benefit of maintenance treatment would dissipate over time or, as has been proposed by some, whether it could have long ‐ term detrimental effects.”

“66 Circumstances that increase the risk for nonadherence in schizophrenia are being at an earlier phase of treatment, 67,68 comorbid substance use, 69 social exclusion (i.e., homelessness), and high side effect burden.”

“21 Depending on how it is measured, nonadherence is present in between 10% and 60% of individuals receiving pharmacological treatment for schizophrenia at any given time.”

“17 Importantly, this comorbidity is linked to poorer clinical outcomes in the domains of psychopathology, 18 functional outcomes, 19 and physical health.”

“23 The reason for the strong association between these two types of disorders is complex.”

“65 In schizophrenia, issues like lack of insight, insufficient social support, cognitive symptoms, or side effects of medication play a negative role in the ability to be adherent with antipsychotic maintenance over the long term.”

“76 In addition, the clinical trial itself changes the ecology of care and might promote better adherence in the control condition than usual care.”

“75 It is very likely that inconsistency in RCTs is related to individuals agreeing to participate in clinical trials being less at risk of treatment nonadherence than those who are represented in epidemiological datasets.”

“5 Thus, the role of the prescriber, in what is known as shared decision ‐ making, 37 is to identify the patient preferences and values in regard to control of psychopathology, goals of psychosocial and vocational functioning, and physical health in order to support the patient's choice among…”

“17 Importantly, this comorbidity is linked to poorer clinical outcomes in the domains of psychopathology, 18 functional outcomes, 19 and physical health.”

“101 Of note, the most relevant side effects were peripheral anticholinergic, but they were modest and other adverse events were minimal.”

“51 Unfortunately, one limitation of using clinical markers to inform subsequent treatment decisions is that they rely on trial and error, which means longer time experiencing symptoms until the optimal treatment is identified.”

“93 In our opinion, 94 in agreement with other experts, 95 there is insufficient data to suggest that the benefits of antipsychotic drugs would disappear over time or that they would indeed become harmful.”

“…evidence and clear criteria to stratify treatment according to previous treatment history, especially after two failed trials, the use of clozapine is often delayed for years 48 and overall usage is much lower than would be expected based on the incidence of treatment ‐ resistant schizophrenia.”

“98 Until recently, the most relevant progress was the development of second ‐ generation anti-psychotic drugs in the 1980s, which in addition to having dopaminergic modulation also had serotoninergic effects, which are not considered as mechanistic towards antipsychotic efficacy but may result in a…”

“63,64 The factors influencing medication nonadherence are complex and include insight, lifestyle, psychological well ‐ being, health literacy, support systems, and side effects of medications.”

“Neurochemical imaging with positron emission tomography (PET) consistently shows an association between elevated dopamine synthesis capacity in the striatum, preferentially in the associative portion, 52 and symptom severity of psychosis.”

“In particular, xanomeline, 101 a muscarinic agonist, and SEP ‐ 363856, 102 a trace amine ‐ associated receptor 1 (TAAR 1) agonist, have gone through phase 2 studies with promising results.”

“27 One of the comorbidities with most implications, because of its impact and prevalence, is nicotine smoking.”

“…the main treatment in schizophrenia, often are associated with side effects such as weight gain, metabolic disturbance, or tardive dyskinesia, 35,40 which makes it necessary to be able to inform treatment decisions so that efficacy and effectiveness are maximized while the price paid in terms…”

“25 Thus, it is conceivable that the two share genetic liability that manifests in maladaptive reward processing, 26 and/or one predisposes to the other (e.g., substance use to compensate for deficits resulting from aberrant signaling in the mesolimbic dopamine pathway).”

“41 In the treatment of schizophrenia, such stratification of treatment is conducted primarily based on clinical markers, although there is promising research indicating that biomarkers may inform those treatment decisions in the future.”

“…between greater use of antipsychotic medication and longer life expectancy in schizophrenia, it is hypothesized, with some data supporting, 33 that by guaranteeing continuous drug delivery and being used for longer periods of time compared to their oral counterparts, the use of LAIs is…”

“17 Importantly, this comorbidity is linked to poorer clinical outcomes in the domains of psychopathology, 18 functional outcomes, 19 and physical health.”

“55,56 Similarly, studies of fMRI signal in the striatum in response to reward anticipation also suggest such a pattern of blunted response at baseline that is corrected along with treatment response.”

“96 In our interpretation, given the serious validity concerns about the data supporting long ‐ term discontinuation of antipsychotic maintenance treatment after the initial 2 – 3 years, and the robustness of the data supporting antipsychotic maintenance prior to that time point, we would argue…”

“91 These theories have been hypothesized because of antipsychotic withdrawal, which would result in rebound psychosis, 92 but this theory has not been validated by either clinical research of abrupt versus progressive treatment discontinuation, 88 nor neurobiological research on dopamine receptor…”

“Most recently, interest in the contribution of neural circuits modulated by muscarinic receptors to the pathophysiology of schizophrenia has surged, 104,105 and with it the experimentation of muscarinic agonists as antipsychotic drugs.”

“Most recently, interest in the contribution of neural circuits modulated by muscarinic receptors to the pathophysiology of schizophrenia has surged, 104,105 and with it the experimentation of muscarinic agonists as antipsychotic drugs.”

“57,58 These advances in understanding the pathophysiology of the illness have supported the development of prognostic neuroimaging biomarkers.”

“55,56 Similarly, studies of fMRI signal in the striatum in response to reward anticipation also suggest such a pattern of blunted response at baseline that is corrected along with treatment response.”

“82 Unfortunately, despite the advantages of LAIs guaranteeing treatment delivery in the relapse ‐ prevention phase of illness, some individuals will relapse despite ongoing treatment.”

“42 There is abundant data indicating that individuals who will fail to respond to nonclozapine antipsychotics may be more likely to respond to clozapine, 43 suggesting possibly a distinct neurobiology 44 and certainly the need to stratify treatment accordingly.”

“For instance, in a recent meta ‐ analysis of 43 studies, Samara et al. 50 examined the prognostic capability of early nonresponse (ENR) to predict failure to a trial of antipsychotic drugs.”

“93 In our opinion, 94 in agreement with other experts, 95 there is insufficient data to suggest that the benefits of antipsychotic drugs would disappear over time or that they would indeed become harmful.”

“46 However, this remains controversial given the limitations of the data used to make such a recommendation, including lack of a control condition or the possibility of treatment nonadherence with only one trial, which is particularly high in the earlier phases of treatment.”

“36 What is the role of the prescriber in the framework of recovery ‐ oriented care, given the intervention targets of symptoms, functioning, substance use comorbidities, and physical health?”

“10 In a cluster randomized clinical trial, the RAISE ‐ early treatment program (ETP) study compared CSC to treatment as usual (TAU) in 34 nonacademic clinics across the United States with real ‐ world funding contingencies.”

“57,58 These advances in understanding the pathophysiology of the illness have supported the development of prognostic neuroimaging biomarkers.”

“54 Functional MRI (fMRI) data suggest aberrant striatal functional connectivity in relation to symptom severity and normalization of such baseline aberrant functional connectivity with antipsychotic treatment response.”

“Although several options, including a medication event monitoring system (MEMS), tablets that can register when they are ingested, 72 or digital applications that can document when a pill is ingested, 73 the most reliable and scalable option to address nonadherence is use of an LAI antipsychotic.”

“66 Circumstances that increase the risk for nonadherence in schizophrenia are being at an earlier phase of treatment, 67,68 comorbid substance use, 69 social exclusion (i.e., homelessness), and high side effect burden.”

“…effects, which are not considered as mechanistic towards antipsychotic efficacy but may result in a more favorable tolerability profile, 99 as well as the so ‐ called “ third generation, ” such as aripiprazole, brexpiprazole or cariprazine, which are partial agonists, rather than…”

“…to oral antipsychotics, a meta ‐ analysis did not find many meaningful differences in terms of side effects between LAIs and oral antipsychotics, 78 and recent data on neuroleptic malignant syndrome, probably one of the most serious side effects of antipsychotic treatment, showed longer time to…”

“7 In addition, it has been suggested that better control over the illness in the first 2 years is an important prognostic indicator.”

“5 Thus, the role of the prescriber, in what is known as shared decision ‐ making, 37 is to identify the patient preferences and values in regard to control of psychopathology, goals of psychosocial and vocational functioning, and physical health in order to support the patient's choice among…”

“For instance, in a recent meta ‐ analysis of 43 studies, Samara et al. 50 examined the prognostic capability of early nonresponse (ENR) to predict failure to a trial of antipsychotic drugs.”

“87 Thus, it can be concluded from this body of research that unless there has been sustained remission of symptoms, it is generally recommended to continue with the same dose of antipsychotics that was used for symptom stabilization.”

“84 In this study, presence of tardive dyskinesia was the strongest predictor of relapse despite ongoing treatment, pointing out a possibly shared mechanisms between the pathophysiology of tardive dyskinesia and relapse in psychosis.”

“In the RAISE ‐ ETP study, ~40% of individuals had a psychopharmacology regimen that deviated from these basic recommendations, 14 and a cohort of 6246 individuals from a Medicaid claims data set found that a similar proportion of patients with early phase schizophrenia were receiving treatment that…”

“66 Circumstances that increase the risk for nonadherence in schizophrenia are being at an earlier phase of treatment, 67,68 comorbid substance use, 69 social exclusion (i.e., homelessness), and high side effect burden.”

“In the RAISE study, despite the relatively young age of study participants, the prevalence of smoking was about 50%, 29 compared to about 14% in the general population.”

“91 These theories have been hypothesized because of antipsychotic withdrawal, which would result in rebound psychosis, 92 but this theory has not been validated by either clinical research of abrupt versus progressive treatment discontinuation, 88 nor neurobiological research on dopamine receptor…”

“This scenario may call for motivational interviewing, 38 in which the role of the prescriber is not to only provide information about treatment options, but also to help the client solve the ambivalence between goals and choices by formulating questions whose answers may point towards those…”

“13 Such recommendations are based on a compelling amount of literature, some of which we will expand on later in this review.”

“Although several options, including a medication event monitoring system (MEMS), tablets that can register when they are ingested, 72 or digital applications that can document when a pill is ingested, 73 the most reliable and scalable option to address nonadherence is use of an LAI antipsychotic.”

“…increases by more than twofold the risk of schizophrenia relapse, 21 and is associated with greater rates of persistent depression and poorer quality of life over time, 22 as well as greater rates of poorer treatment compliance, violence, incarceration, housing instability, and homelessness.”

“89,90 Altogether, these data questioned whether the benefit of maintenance treatment would dissipate over time or, as has been proposed by some, whether it could have long ‐ term detrimental effects.”

“86 Similarly, a frequentist dose – response meta ‐ analysis of 72 dose arms, corresponding to 4776 individuals, of randomized controlled trials of antipsychotics for relapse preventions in schizophrenia found hyperbolic efficacy ‐ related dose – response curves, meaning that the risk of relapse…”

“Clients and prescribers should be careful about monitoring the impact of antipsychotic side effects by screening for metabolic effects regularly, 35 managing or referring to primary care if disorders of metabolism are identified, and choosing antipsychotic agents carefully.”

“71 The main intervention of this cluster ‐ randomized trial was training clinicians on how to talk to patients about LAIs in the experimental clinics as compared to those in the clinics delivering usual care.”

“97 The question is whether the risk of relapse following antipsychotic discontinuation can be determined at the level of the individual, so that informed decisions can be made about for whom it would be recommendable to discontinue treatment.”

“9 This healthcare policy decision was supported by the results of the Recovery After an Initial Schizophrenia Episode (RAISE) study, funded by the National Institute of Mental Health.”

“The mesolimbic dopamine pathway has been involved in the reward mechanism for drugs 24 as well as in the aberrant salience associated with positive symptoms in schizophrenia.”

“49 Another clinical marker that can be used to inform clinical decisions is early nonresponse (ENR).”

“85”

“100 At the same time, we are still uncertain as to the mechanistic reasons for clozapine's established superiority in treatment ‐ resistant schizophrenia (TRS) patients, despite many years of availability.”

“79,80 These data suggest that LAIs should probably be used from the early phase of treatment since this is one of the periods with greater risk of treatment nonadherence, 67,68 and because preventing relapses early in the course of illness may mitigate their impact on social and occupational…”

“77 This benefit may be particularly important for individuals in the earlier phases of treatment, who are much more likely to interrupt treatment and experience a subsequent relapse.”

“70 These data highlight how even when identifying treatment adherence status is most critical, such as in an emergency caused by acute psychosis, clinician assessment is very unreliable, very often by overestimating treatment adherence.”

“…muscarinic effects have been targeted as potential antipsychotic agents, with experimentation that dates back to the 1950s with anti ‐ and pro ‐ muscarinic drugs, 103 although given the problems with tolerability, particularly peripheral effects, this line of research was abandoned for decades.”

“93 In our opinion, 94 in agreement with other experts, 95 there is insufficient data to suggest that the benefits of antipsychotic drugs would disappear over time or that they would indeed become harmful.”

“79,80 These data suggest that LAIs should probably be used from the early phase of treatment since this is one of the periods with greater risk of treatment nonadherence, 67,68 and because preventing relapses early in the course of illness may mitigate their impact on social and occupational…”

“83 This phenomenon has been challenging to study, given the confounder of nonadherence in relapse in schizophrenia.”

“61”

“60 The ultimate goal of this research is developing biomarkers of relapse risk that facilitate decision ‐ making about long ‐ term treatment, for example to inform whether antipsychotics should be maintained long ‐ term after remission for a given individual.”

“59 Most recently, the development of prognostic biomarkers for treatment response in the context of psychotic relapse has shown promise.”

“47 Despite the compelling evidence and clear criteria to stratify treatment according to previous treatment history, especially after two failed trials, the use of clozapine is often delayed for years 48 and overall usage is much lower than would be expected based on the incidence of treatment ‐…”

“15 This finding is not completely surprising given the known statistic that evidence ‐ based recommendations may take close to two decades to transition from publication to adoption in routine care.”

“…of chlorpromazine and haloperidol seven decades ago, the number of drugs for psychosis has steadily increased with new drug entities and formulations resulting in dozens of treatment options for schizophrenia and other major psychiatric disorders (Rubio and Kane, 2022; Taylor et al., 2021).”

“4) [260, 261].”

“Contemporary first-line treatments for schizophrenia are second-generation (atypical) antipsychotics, developed in the 1980s and preceded by first-generation (typical) antipsychotics in the 1950s (Rubio and Kane, 2022).”