Cognitive impairment is one of the core features of people with schizophrenia (Reichenberg et al., 2009; McCleery and Nuechterlein, 2019), including neurocognitive domains (e.g., attention, processing speed, verbal and visual memory, working memory, and executive functioning (Fervaha et al., 2014; Käkelä et al., 2014; Quee et al., 2014)), as well as social cognitive domains (e.g., emotional control and social perception (Minzenberg et al., 2004; Hill et al., 2010)), and is associated with functional deficiencies (Green, 2016). This directly or indirectly reduces the quality of life of patients (Buchanan et al., 1994; Gallhofer et al., 1996; Fagerlund et al., 2004) and is one of the main limiting factors in the rehabilitation of mental disorders (Green et al., 1997; Green et al., 2002; Goldberg et al., 2007). Some studies have found that cognitive impairment may be present early in the disease, even before the onset of psychiatric symptoms (Bora et al., 2017; Glenthøj et al., 2020). As time progresses, most cognitive functions may improve longitudinally or remain unchanged over the disease trajectory, while a minority of cognitive functions progressively deteriorate (Bozikas and Andreou, 2011; Chan et al., 2023). A recent meta-analysis found that patients with TRS had significant deficits in all domains of cognitive functioning compared with patients treated effectively with antipsychotics (Millgate et al., 2022). However, results of current studies on the effects of antipsychotics on cognitive function in patients with schizophrenia are inconsistent. A recent network meta-analysis by Baldez et al. analysed randomised controlled trials using different antipsychotic medications to compare their effects on cognitive function in patients with mental disorders. They found that different antipsychotics improved cognitive function; however, the cognitive domains were improved by different drugs. For example, olanzapine improved several cognitive functions, while clozapine performed poorly in executive functioning and verbal learning (Baldez et al., 2021). Another meta-analysis comparing the cognitive effects of second-generation antipsychotics in patients with schizophrenia found that clozapine negatively affected verbal working memory and executive function but improved verbal fluency (Nielsen et al., 2015). However, these studies did not limit the population to patients with TRS and did not consider the level of cognitive function in patients before and after medication. As the only effective antipsychotic drug for TRS, is important to clarify the effect of clozapine on cognitive function in patients with TRS in future studies, both in terms of medication selection and the prognosis of TRS.

In addition to pharmacological interventions, studies on psychosocial interventions for cognitive deficits in patients with schizophrenia have attracted the attention of most researchers, with cognitive remediation therapy (CRT) showing the most evidence of effectiveness; however, few studies have been conducted on the application of CRT to TRS. CRT is a behavioural training-based intervention designed to improve cognitive processes (Bowie et al., 2020). Martini et al. evaluated the efficacy of CRT in TRS for the first time and compared the cognitive performance of patients with TRS and patients without TRS before and after CRT. Their study found that patients with TRS showed more pronounced improvements in verbal memory and executive functioning than patients with schizophrenia without drug resistance.

In addition, some non-pharmacological treatments based on the promotion of neuroplasticity, such as physical exercise (especially aerobic exercise), have been shown to be beneficial in improving social and cognitive functioning in patients with schizophrenia (Rosenbaum et al., 2014; Dauwan et al., 2016; Firth et al., 2017). A randomised controlled study by Shimada et al. in Japan confirmed that a treatment regimen of aerobic exercise superimposed on conventional treatment (medication and other rehabilitation programs) is more effective and safe than conventional treatment in improving cognition, internal motivation, and interpersonal relationships in patients with schizophrenia (Shimada et al., 2019). However, there is no evidence of aerobic exercise in patients with TRS.

Cognitive impairment has a significant impact on symptom recovery and social functioning rehabilitation in patients with TRS; thus, improvement of cognitive impairment in patients with TRS remains a pressing issue. Despite this, existing evidence for methods of cognitive improvement in TRS is limited, further highlighting the urgent need for new and effective interventions and further exploration of the mechanisms of cognitive deficits in patients with TRS, as well as the optimisation of current conventional treatment protocols. Therefore, the improvement of cognitive deficits in patients with TRS will be an important research topic for future studies.

Medication is one of the preferred treatments for schizophrenia, but approximately one-third of people with schizophrenia respond poorly to antipsychotic medications (first- or second-generation antipsychotics) (Kane et al., 2019; Wagner et al., 2019), with a <20% reduction in positive and negative syndrome scale scores before and after retreatment. The poor efficacy of antipsychotic medications in patients with TRS is usually associated with poorer prognosis, higher risk of suicide, and poorer social functioning and quality of life, placing a significant economic burden on the patient’s family and society (Kane et al., 2019).

Clozapine is the first second-generation antipsychotic, the first to treat TRS effectively, and the only FDA-approved drug for TRS treatment (Pandey and Kalita, 2022). Unlike traditional first-generation antipsychotics, clozapine has a short duration of action on the D2 receptors, rapid dissociation, and a mechanism of action involving multiple receptors (5-HT2a, alpha-adrenergic, and NMDA receptors). In a real-world study by Tiihonen et al., 29,823 patients with schizophrenia were followed up for rehospitalisation and treatment outcomes, and the results showed that clozapine and long-acting injectable antipsychotics were the most advantageous medications for preventing relapses in schizophrenia (Tiihonen et al., 2017). The results of a recent study showed that patients with TRS who started clozapine later (≥20 years from diagnosis of schizophrenia to initiation of clozapine) had a significantly higher risk of rehospitalisation than those who started treatment earlier (Hatano et al., 2023). In other words, the delayed use of clozapine may increase the risk of long-term hospitalisation in patients with schizophrenia. However, this was a retrospective cohort study based on medical records, which had incomplete data, selection bias, and a small sample size. Therefore, the findings cannot be generalised to the entire population of patients with TRS. Although most studies now consider clozapine as an effective therapeutic agent for TRS, some have reached different conclusions. A network meta-analysis by Mishra et al. that summarised 47 randomised controlled studies showed that combining escitalopram, glycine, or mianserin with antipsychotics was superior to clozapine treatment in patients with TRS. This seems inconsistent with the general consensus in clinical practice (Mishra et al., 2024). It has been shown that about 40%–70% of patients with TRS are poorly treated with single-agent clozapine (Muscatello et al., 2014; Siskind et al., 2017; Roerig, 2019), and the concept of clozapine-resistant schizophrenia (CRS) has been proposed by some researchers. The current key elements regarding CRS include maintenance of a therapeutic dose of 200–500 mg/d, blood levels ≥350 ng/mL, duration of treatment of at least 2–3 months, and good adherence to treatment (ability to take more than 80% of the prescribed dose), but moderately-severe disease and functional impairment persisting despite adequate treatment with clozapine (Mouaffak et al., 2006; Tranulis et al., 2006; Lee et al., 2015). Current research on CRS has provided less high-quality evidence to support the idea that other psychotropic medications and non-pharmacologic treatments can increase the efficacy of clozapine. The addition of another antipsychotic medication to clozapine is currently one of the most common clinical treatments for CRS (Buckley et al., 2001; Pai et al., 2012; Muscatello et al., 2014; Lally and Gaughran, 2019). However, several studies have shown that clozapine in combination with another antipsychotic does not significantly improve overall symptom severity or positive symptom severity (Miyamoto et al., 2015; Faden and Citrome, 2019; Lally and Gaughran, 2019; Roerig, 2019). A few studies on the effects of clozapine in combination with other antipsychotics on negative and depressive symptoms have been published, and no consistent conclusions have been reached. There is less reliable evidence that antidepressants and mood stabilisers increase the efficacy of clozapine. In addition to studies on psychiatric medications that increase the efficacy of clozapine, studies on non-pharmacological treatments, such as ECT, to assist in the treatment of TRS, have begun to receive attention from researchers. Results show that ECT is an effective augmentation strategy (especially when medications do not improve positive symptoms) (Lally and Gaughran, 2019; Roerig, 2019; Wagner et al., 2019), and the modality is fast-acting and relatively safe in combination with antipsychotics. However, ECT has been poorly studied in patients with CRS, and further confirmation of its efficacy in large-sample, rigorously-designed trials is warranted. Moreover, repetitive transcranial magnetic stimulation therapy does not seem to be effective in the treatment of CRS (Wagner et al., 2019; Wagner et al., 2021). A randomised controlled study by Morrison et al. evaluated the efficacy of cognitive therapy (CBT) in patients with CRS and followed them for 21 months. The results showed that CBT provided a statistically significant improvement in overall symptoms in patients with CRS at the end of treatment compared with conventional treatment, but the follow-up results showed that CBT did not produce a lasting improvement in overall symptoms in patients with CRS (Morrison et al., 2018). The results of a recent meta-analysis suggest that CBT is effective in treating positive symptoms in clozapine-resistant patients; however, its efficacy in treating negative symptoms is uncertain (Polese et al., 2019).

CRS may be the most challenging type of schizophrenia to treat, but there is insufficient evidence to provide uniform and effective recommendations for treatment regimens for clozapine-resistant patients. Therefore, optimising clozapine treatment and exploring augmentation therapies for clozapine will be a hot topic for future research. In addition, negative and cognitive symptoms in patients with TRS appear to be less responsive to medication and have a more protracted course than those with positive symptoms. Therefore, exploring treatments for negative and cognitive symptoms of TRS will also be a future research direction in the field of TRS.

TRS is a serious mental disorder and one of the main causes of dysfunction and disability in patients; however, the treatment method for TRS is a tricky issue in current clinical practice. Clozapine is the only effective evidence-based drug available for the treatment of TRS. Guidance from the National Institute for health and Care Excellence (NICE) recommend that people with schizophrenia be offered clozapine if their psychotic symptoms do not significantly improve despite the use of ≥2 different antipsychotics in adequate doses (NICE, 2014). However, it is currently impossible for clinicians to accurately predict which patients will not respond to first-line antipsychotic treatment prior to medication administration, making early identification of TRS particularly important given that this has the potential to improve clinical outcomes as early as possible and to reduce social and functional disability due to TRS (Wheeler et al., 2009; Stroup et al., 2016). Lally et al. (2016) followed 246 patients with first-episode schizophrenia for 5 years to assess the clinical and demographic risk factors associated with the emergence of TRS. The results showed that 34% of the patients eventually developed refractory disease, with 70% of patients failing to respond to antipsychotic medication from onset. Furthermore, they found that patients with an earlier age of onset (<20 years) were more likely to develop refractory disease later in life than those with nonrefractory onset. Other studies support the idea that early-onset schizophrenia (EOS) has a worse prognosis than adult-onset schizophrenia (Röpcke and Eggers, 2005; Vyas et al., 2007).

EOS is defined as schizophrenia with an age of onset of 13–17 years (Clemmensen et al., 2012), and a lower prevalence rate than in the general population (Jerrell and McIntyre, 2016; Driver et al., 2020). However, negative symptoms are more common (Rammou et al., 2019), symptoms are more severe (Coulon et al., 2020), and prognosis is poorer in patients with EOS compared to patients with schizophrenia presenting in adulthood (Díaz-Caneja et al., 2015; Stentebjerg-Olesen et al., 2016; Immonen et al., 2017). More importantly, the risk of developing drug resistance is higher (Smart et al., 2021; Iasevoli et al., 2022; Siskind et al., 2022). Nevertheless, this particular group of adolescents is in a period of growth and development, and early manifestations of schizophrenia, neurodevelopmental comorbidities, and other psychiatric disorders may be difficult to differentiate, leading to misdiagnosis and underdiagnosis being more common. Therefore, timely and accurate diagnosis of schizophrenia in adolescents is of great significance for the detection of TRS.

Antipsychotics are currently the first-line clinical treatment for EOS in adolescents (Abidi et al., 2017). An umbrella review from Correll et al. reviewed the safety and tolerability of a variety of medications in children/adolescents with psychiatric disorders and found that antipsychotics (first- or second-generation antipsychotics) were effective for EOS (Correll et al., 2021). Although medication is safer for patients with EOS (Solmi et al., 2020), adolescents are more sensitive to medication side effects compared with adults (Liu et al., 2019). Currently available medications approved for use in adolescents with schizophrenia are limited (Lopez-Morinigo et al., 2022; Smogur et al., 2022), and extra-approved medications will be used in clinical practice after informing the guardian and obtaining his or her consent. Second-generation antipsychotics, such as olanzapine and risperidone, are currently preferred in the clinic; however, their effects on metabolic and endocrine functions should be carefully considered before use. Recent studies suggest that clozapine is more effective than other antipsychotics in the treatment of EOS (Arango et al., 2020; Correll et al., 2021; Adnan et al., 2022), even for refractory EOS (Schneider et al., 2014), with clozapine exhibiting the best results. Age-related differences in drug metabolism and adverse effects must also be considered. In addition, for patients who do not respond to early treatment with antipsychotics, a change in medication or an appropriate dose increase should be considered. However, the identification of TRS and early use of clozapine in patients with EOS remains a concern. All current randomised controlled trials of antipsychotics have been conducted in adult patients, and there is a lack of evidence in patients with EOS.

Based on our findings, the hotspots for future research will include methods for accurately diagnosing EOS at an early stage, identification of patients who may develop refractory TRS at a later stage, selection of reasonable and appropriate antipsychotics, and how to target specific age groups and assign individualised treatment regimens.