Prescription practices in the treatment of agitation in newly hospitalized Chinese schizophrenia patients: data from a non-interventional naturalistic study

Agitation among psychiatric inpatients, particularly those with schizophrenia or bipolar disorder, is a major public health concern. It can rapidly escalate to aggression and violence and poses a considerable risk to the patients themselves and to others [1, 2]. Recent studies indicate that agitation significantly contributes to rising medical costs and caregiver burden [3, 4]. In the United States alone, agitated patients with schizophrenia accounted for 900,000 annual visits to psychiatric emergency services, representing 21% of all psychiatric emergency visits [5]. According to the State of Acute Agitation at Psychiatric Emergencies in Europe (STAGE) study, schizophrenia was the underlying in 47.27% (78 of 165) of psychiatric agitation episodes [6]. In China, we previously screened 1400 newly hospitalized patients with schizophrenia, finding that 60.92% (853 of 1400) were agitated [7]. Current psychiatric recommendations on agitation promote the early use of verbal de-escalation techniques [2, 8]. However, a considerable percentage of schizophrenia patients with agitation still require psychopharmacological approaches, including typical or first-generation antipsychotic drugs, atypical or second-generation antipsychotic drugs, and benzodiazepines [9, 10]. Depending on the patient’s level of cooperation or the perceived onset of the drug effect, there are four routes available in clinical practice: inhalation, oral administration, intramuscular injection, and intravenous injection. Therefore, an array of pharmacological options administered via different routes exists, providing physicians with numerous treatment alternatives.

Typical antipsychotics have proven effectiveness in the treatment of agitation, particularly haloperidol [10]. However, considering the high risk of extrapyramidal side effects and their superior efficacy and lower adverse effect burden, atypical antipsychotics are highly preferred in clinical practice [8, 9]. Although monotherapy is recommended in clinical practice guidelines for the use of antipsychotics in the management of schizophrenia [11, 12], polypharmacy is common, ranging from 20.4 to 69.6% across different countries [13‐16]. In a 2002 study investigating the factors influencing the prescription of antipsychotics to patients with schizophrenia in China, about 25.9% of 3523 patients received polypharmacy [17]. In Hong Kong, a survey investigated the current prescribing patterns of agitation in emergency departments for patients without a specific diagnosis on record [18]. There are no published data on prescription practices for schizophrenia with agitation in China. Thus, the aim of our study was to reveal the prescription practices in the treatment of agitation in Chinese patients with schizophrenia.

To our knowledge, this is the first report of prescription patterns among schizophrenia patients with agitation in China. The current expert guidelines and research data [9, 10, 19, 20] indicate that, in the management of agitation due to a psychiatric illness, second-generation antipsychotics (risperidone, olanzapine, ziprasidone) are to be selected as first-line agent. In our study, most patients (94.81%) received atypical antipsychotics. The widespread use of second-generation antipsychotics may be due to their well-known superiority in terms of adverse effects. Specifically, the most used antipsychotic was haloperidol, identified in 302 patients (35.66%), followed by olanzapine in 276 (32.59%) and risperidone in 258 (30.46%). Given its easy accessibility and its long track record of efficacy in the management of agitation, haloperidol is an important treatment choice in cases of limited resources. Previous studies reported economic status as a major factor in antipsychotic prescription in Chinese outpatients with schizophrenia [17]. Consequently, the lower price of haloperidol may also have contributed to its popularity.

The American Association for Emergency Psychiatry (AAEP) and World Federation of Societies of Biological Psychiatry (WFSBP) consensus guidelines recommend oral antipsychotics over intramuscular injections if possible [9, 12]. Our study found that 385 of 847 patients (45.5%) received intramuscular injections. An unstable course of illness, irritability, and uncooperativeness promote the use of intramuscular injections in agitation management. Additionally, intramuscular administration is preferred by clinicians for rapid and effective treatment. Note that a systematic review of studies from 2001 to 2010 showed that oral and intramuscular medications are equally effective in rapidly reducing psychotic agitation in the emergency department [21]. Nonetheless, further studies are needed.

Approximately 51.36% of patients were prescribed antipsychotic polypharmacy. Our rate of polypharmacy is much higher than the rate from a 2011 report on schizophrenia in China in both inpatients and outpatients [17] and the rate from a 2015 report in a Hong Kong emergency department [18]. There are two possible reasons for this difference: (1) newly hospitalized patients with agitation usually have more severe symptoms, increasing the difficulty of treatment; and (2) the desire to enhance or accelerate treatment efficacy [22] or to reduce the dose of antipsychotics with certain adverse effects [23, 24].

The key factors associated with polypharmacy in the present study were a high BARS score (OR 2.091, 95%CI 1.1400–3.124) and severe agitation (OR 1.846, 95%CI 1.266–2.693). The seven-point BARS assesses behavioral activities in agitated patients with high reliability and convenience, with results ranging from sedation, to normal activity, to agitation [25]. Agitation is an established short-term factor associated with physical aggression [26]. The assessment of behavioral activities in agitated patients at an early stage may help to identify the risk of aggression and suggest specific treatment interventions. According to a recent survey of 583 community-dwelling patients with schizophrenia or bipolar disorder, the most common experience of agitation was in the form of internal feelings, including uneasiness, restlessness, and nervousness [27]. A qualitative study with healthcare professionals defined three states of agitation, with aggression or violence only included in severe agitation [28]. Better assessment and effective management of severe agitation could potentially avoid aggressive episodes. In agreement with this, several studies and published consensus guidelines have focused on acute episodes of severe agitation [29‐31]. We also found that unemployment or retirement (OR 1.614, 95%CI 1.189–2.190) and aggressiveness at baseline (OR 1.469, 95%CI 1.032–2.091) were associated with polypharmacy. Unemployment may be a sign of disease severity.

In contrast with previous research [32, 33], we observed a negative association between polypharmacy and male sex (OR 0.592, 95%CI 0.436–0.803). In a study of 43 severely agitated patients with schizophrenia spectrum disorders, there was a sex effect in the poor treatment response in women [30]. Furthermore, some studies reported that women committed more physical assaults than men during the 4-week inpatient treatment [34, 35]. These two findings could imply a tendency toward polypharmacy in women. Our findings are consistent with existing research that older people with schizophrenia (age ≥ 55 years) are less likely to receive antipsychotic polypharmacy [32, 33]. In contrast to younger schizophrenia patients, older patients are more prone to adverse effects, including extrapyramidal side effects and metabolic syndrome [36]. It is advisable to start with a single, low initial dose and titrate slowly. A study comprising 8792 elderly schizophrenia patients suggested that the combined use of first- and second-generation antipsychotics was positively associated with relapse (OR 1.70, 95%CI 1.25–2.31) [37]. Besides the consideration of safety, older patients are less prone to aggressive episodes [38].

With a large sample size and a large number of participating sites involved in a standardized assessment, our findings have some important clinical implications. The present study demonstrates that monotherapy and polypharmacy are equally common in antipsychotic application in managing agitation associated with schizophrenia in China. The extent and behavioral activities of agitation and several other factors were associated with polypharmacy. Additional factors should be evaluated in future studies.