The implications of the early treatment decisions in schizophrenia: getting it right from the start

Citing a 2019 network meta-analysis, Professor Correll stated that antipsychotics are the mainstay of schizophrenia treatment and available treatments are broadly similar in terms of efficacy, though some gradual differences exist.⁴ However, there are statistically and clinically relevant difference in terms of side effect profiles.⁴

A study published in 2020 demonstrated that between half and two-thirds of patients with schizophrenia experienced a negative impact on function due to side effects of their medication.⁵

Furthermore, adverse events from antipsychotics have also been known to lead to treatment non-adherence.⁶

Could you see this agitated patient for me? Solving challenges in the inpatient ward

Professor Pai described agitation as excessive motor activity associated with a feeling of inner tension​.⁷ Other features include non-productive and repetitious activity consisting of behaviours such as pacing, fidgeting, wringing of the hands, pulling of clothes, and inability to sit still.⁷ Progression of severity of agitation can lead to aggressive and violent behaviours.⁸ 

Professor Pai proposed that rather than wait until a patient develops violent behaviour, it should be possible to observe tell-tale symptoms as agitation progresses and provide treatment to prevent further escalation.³

Adapted from Martínez-Raga et al. 2018⁸

Professor Pai recommended that when an agitated patient presents to the hospital, it is necessary to conduct a risk evaluation that includes actuarial assessments and structured clinical judgement assessment.² Following this risk assessment, a detailed description of symptoms should be obtained in order to rule out other medical conditions.⁹ The next step is recommendation of non-pharmacological interventions to de-escalate symptoms before considering appropriate antipsychotic treatment.⁹ De-escalation involves respecting the personal space of the patients, creating a calm environment, being mindful of non-verbal communication, avoiding behaviours that could be seen as confronting, and listening carefully to identify what the patient wants.⁹

Determining choice of medication​

The choice of antipsychotic medication should be based on a patient’s preference (after risks and potential benefits have been explained), the patient’s prior response to treatment (if any), and medication side effects.¹ Choosing a drug with low risk of extrapyramidal symptoms, such as an atypical antipsychotic, can help facilitate treatment adherence.^1,6

An overview of REXULTI^® (brexpiprazole) as a therapeutic option 

Professor Correll discussed where REXULTI^® (brexpiprazole) falls in the treatment paradigm for patients with schizophrenia and its mechanism of action. REXULTI is indicated in adult patients for the treatment of schizophrenia.¹⁰ REXULTI has high affinity (K_i<5 nM) for multiple monoaminergic receptors. It acts as a partial agonist at 5-HT_1A, D₂, and D₃ receptors and as an antagonist at 5-HT_2A, 5-HT_2B, 5-HT₇, α_1A, α_1B, α_1D, and α_2C receptors.¹⁰

The efficacy of REXULTI in the treatment of adults with schizophrenia was demonstrated in two 6-week, randomised, double-blind, placebo-controlled, fixed-dose clinical trials (Beacon¹¹ and Vector¹²) and one randomised, double-blind, 52-week trial (Equator¹³) in subjects who met DSM-IV-TR criteria for schizophrenia. In pooled data from Beacon and Vector, treatment with REXULTI 2 mg/day and 4 mg/day led to a statistically significant mean improvement in PANSS total score at Week 1 (p<0.05 vs placebo, 2mg; p<0.01 vs placebo, 4 mg), while at Week 6 the improvement was statistically significant (p<0.001 vs placebo, 2 mg and 4 mg) and the absolute reduction from baseline was clinically relevant.¹⁴ In the Beacon study, the primary endpoint was not met in the 2 mg group.¹¹

As maintenance treatment for the prevention of relapse, REXULTI resulted in a 71% reduced risk of impending relapse compared with placebo (p<0.0001, HR=0.292).¹³ REXULTI was also associated with statistically significant improvements in functioning as measured by PSP and GAF scores (LOCF, p<0.01 vs placebo).¹³

In the aforementioned pivotal trials, REXULTI was well tolerated. There were no common adverse reactions that met the criteria “incidence ≥5% and at least twice the rate of placebo.”¹⁰ The adverse reactions associated with REXULTI (incidence of 2% or greater and REXULTI incidence greater than placebo incidence) are shown in the table below.¹⁰

Use of REXULTI in patients with agitation

Professor Pai spoke about REXULTI treatment as it relates to agitation in schizophrenia. The efficacy of REXULTI on reducing agitation in patients with schizophrenia was explored in a post-hoc analysis¹⁵ of data from the short-term studies Beacon and Vector and data from Zenith¹⁶, a 52-week, open-label, extension study. In the Beacon study, the primary endpoint was not met in the 2 mg group.¹¹

In the sample of patients hospitalised with an acute exacerbation of schizophrenia, REXULTI 4 mg/day consistently improved symptoms of agitation over 6 weeks (p<0.001 vs placebo, as measured by change from baseline in PANSS-EC score).¹⁵ REXULTI 2 mg/day also showed a statistically significant benefit over placebo (p<0.05) with a smaller effect on PANSS-EC score over 6 weeks.¹⁵

During long-term treatment with open-label REXULTI, further improvement in agitation was observed and maintained over a total of 58 weeks (p value not reported).¹⁵

TEAEs reported in ≥2% of REXULTI-treated patients and that occurred at greater incidence than placebo-treated patients in short-term and long-term studies¹⁰

NR, not reported. 
a Musculoskeletal and connective tissue disorders categorised differently in short and long-term trials. 

Please refer to the approved Product Information for full safety and tolerability information.¹⁰

DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, fourth edition, Text Revision; GAF: Global Assessment of Functioning; HR: hazard ratio; LOCF: last observation carried forward; PANSS: Positive and Negative Syndrome Scale; PANSS-EC: PANSS Excited Component; PSP: The Personal and Social Performance; TEAE: Treatment emergent adverse event.

Key Points

• Antipsychotics are the mainstay of schizophrenia treatment⁴
• Adverse effects from antipsychotics can affect outcomes via possible worsening of functioning and adherence^5,6
• Identifying early symptoms of agitation may make it possible to prevent escalation to aggressive and violence behaviour³
• REXULTI^® (brexpiprazole) has the potential to be an efficacious and well-tolerated treatment for agitation in schizophrenia¹⁵