Antipsychotic medications constitute a critical intervention for acute and long-term management of severe mental illness such as psychosis, bipolar disorder and treatment-resistant cases of major depressive disorder.¹ However, these medications are associated with serious adverse effects; therefore, clinical practice guidelines recommend principles of rational prescribing and monitoring to enhance patient safety.^2,3 Antipsychotic medications are broadly divided into two categories: first-generation antipsychotics (FGAs), which include haloperidol, chlorpromazine and sulpride, and second-generation antipsychotics (SGAs), which include olanzapine, quetiapine and risperidone.¹ First-generation antipsychotics act through dopamine receptor (D2) antagonism in the brain, whereas SGAs block serotonin (5-HT2A) and dopamine (D2) neurotransmission.¹

Evidence-based guidelines recommend antipsychotic monotherapy prescribed at the lowest effective dose.^2,3 The use of high-dose antipsychotic therapy, whether originating from single or multiple medications, is not currently endorsed by guidelines.^2,3 According to the American Psychiatric Association and the British Association for Psychopharmacology, high-dose antipsychotic therapy is reserved as the last resort for the management of treatment-resistant cases, which fail to achieve optimal response to an adequate trial of two antipsychotics from two different classes, and clozapine is tried and is either ineffective or not tolerated.^2,3

Despite guidelines recommendations, observational studies show that prescription of antipsychotic polypharmacy and high-dose antipsychotics appear to be common in clinical practice.⁴ The prevalence of antipsychotic polypharmacy among inpatients varies globally between 20% and 66%.⁴ According to a study in Australia, the rate of high-dose antipsychotics is 27.0% among patients receiving compulsory treatment in the community.⁵ Similarly, a recent study in Italy reported a high rate of 50.8% among 730 forensic psychiatric inpatients.⁶ Furthermore, a study in Cyprus found that among 482 patients in psychiatric compulsory care settings, the rate of high-dose prescription was 27.2%.⁷ High-dose prescribing has been linked to various factors such as younger age, male gender, schizophrenia diagnosis, inpatient status, greater number of admissions, longer duration of hospital stay, prescription of antipsychotic polypharmacy, long-acting antipsychotics, anticholinergics, or FGAs.^8,9

In acute adult psychiatric settings, antipsychotic polypharmacy, a key contributor to high-dose prescribing, is often used to stabilise patients with behavioural disturbances, promote rapid control of symptoms, and return the patient to baseline level of functioning.¹⁰ However, according to neuroimaging studies, increasing the dose does not necessarily increase the clinical response rates.¹¹ Side effects of antipsychotics are dose-related.¹² Therefore, increasing the dose increases the frequency and severity of side effects such as sedation, hypotension, extrapyramidal side effects, hyperprolactinaemia, neuroleptic malignant syndrome, seizure, arrhythmia, and sudden cardiac death.¹² Thus, because of the potential harm associated with high-dose antipsychotic prescribing, physical and metabolic health monitoring has become a key performance indicator for patients receiving high-dose in the United Kingdom, North America, and Australia.¹³

Patients with severe mental illness exhibit a reduced life expectancy compared to the general population, which is attributed, in part, to the prescription of combined and high-dose antipsychotics.⁹ High-dose antipsychotics increase the risk of adverse drug events such that the incidence of sudden cardiac death is approximately doubled in patients receiving high doses compared to those receiving low doses.^8,14 Furthermore, recent evidence indicates that antipsychotic dose reduction in patients with schizophrenia led to improvement in cognitive function without an increase in the risk of relapse.¹⁵ Evaluation of high-dose antipsychotic prescription trends can assess adherence to prescription guidelines and inform policymakers on implementing strategies to optimise treatment outcomes. Most of the evidence related to high-dose antipsychotic prescribing is derived from studies conducted in developed countries; studies evaluating the magnitude of high-dose antipsychotic prescribing in Iraq are currently lacking. We aim to address this gap in the literature by determining the prevalence and predictors of high-dose antipsychotic therapy among adult psychiatric inpatients in Baghdad, Iraq.

In this study, all patients received SGAs, while 23.1% also received FGAs. Olanzapine was the most commonly prescribed antipsychotic medication at a rate of 73.3% followed by quetiapine at 56.1%. Polypharmacy was common, with 47.6% of patients receiving more than one antipsychotic medication: 35.6% received two antipsychotics and 12.0% received three. High-dose antipsychotics, which were prescribed to 35.6% of patients, result primarily from polypharmacy. Notably, 45.0% of high-dose prescriptions exceeded 150% of the recommended dose limit. Multivariate regression analysis indicated no association between high-dose antipsychotic prescription and demographic or clinical factors such as age, sex, psychiatric diagnosis, length of hospital stay, number of admissions, and discharge status. Predictors of receiving high-dose include antipsychotic polypharmacy, FGAs, quetiapine, antidepressants, and anticholinergic prescribing. Our findings are in line with an Australian study, which found that treatment-related factors were the primary predictors of high-dose antipsychotic prescribing.⁵

In this study, 35.6% received high-dose antipsychotic therapy. This rate is comparable to the 27.0% rate reported in Australia and Cyprus, but is lower than the 50.8% rate reported in Italy.^5,6,7 There is no reliable evidence that increasing the dose beyond the standard dose is associated with better response; this practice is associated with increased frequency and severity of side effects, particularly sudden cardiac death.¹⁷ For antipsychotics to be effective, they should achieve 65% – 80% D2 receptor occupancy in the brain.¹¹ Although there are reports of altered numbers or function of D2 receptors in a subgroup of patients, there is little evidence to support this, because therapeutic response is achieved in low to moderate doses.¹¹ Schizophrenia and related psychoses are heterogeneous illnesses with multiple aetiologies, and in some patients, symptoms may not be dopamine-mediated. Therefore, increasing the dose of antipsychotics is clearly pointless.¹¹ Furthermore, in a recent randomised study of 54 inpatients who were receiving high-dose antipsychotics before admission, lowering the administered antipsychotic dose to half, led to faster symptom improvement compared to those who stayed on high doses (1–3 weeks versus 4–9 weeks).¹⁸

Polypharmacy was a predictor of receiving high-dose, which is in line with other studies.⁸ In this study, only 6.2% received high-dose through monotherapy. A similar study in Italy indicates that patients on antipsychotic polypharmacy are 2.75 times more likely to receive high-dose antipsychotics.⁶ In the largest UK audit, the Prescribing Observatory for Mental Health, which analysed prescription patterns of antipsychotics among 3492 inpatients, found that 25.0% of inpatients were receiving high-dose antipsychotics, which occurred as a result of antipsychotic polypharmacy in 86.0% of cases.¹⁹ Similar findings were reported in a Saudi Arabian study.²⁰

In this study, 47.6% of patients received polypharmacy which is similar to a study in Qatar that included inpatients and outpatients where 55.9% of patients were on monotherapy, 29.6% on dual and 14.5% on more than two agents.²¹ The antipsychotic polypharmacy rate was also similar to that reported in the United Kingdom (50.5%), Australia (43%), Canada (45.0%) and Italy (55.0%), but lower than 24.0% and 35.0% as reported in Japan and Denmark, respectively.^{4,6,10,22,23,24} As the number of prescribed antipsychotic increases, the life span shortens.⁹ Thus, prescribing antipsychotic polypharmacy is not only against guidelines recommendations but can also risk patient safety; even in treatment-resistant schizophrenia, clozapine monotherapy is recommended before antipsychotic polypharmacy.^2,3 Evidence for antipsychotic polypharmacy is only available for clozapine in treatment-resistant schizophrenia. Clozapine has a weak D2 receptor affinity. The addition of potent D2 receptor blockers such as sulpride, amisulpride or aripiprazole, would provide a greater coverage of receptors for optimised antipsychotic efficacy.²⁵ In addition, aripiprazole decreases the metabolic side effects of clozapine and thus, improves tolerability.²⁵

Receiving FGAs was a predictor of receiving high-dose antipsychotics, which is in line with other studies.²⁶ In this study, SGAs were the most commonly used, which is in line with a recent scoping review that indicates higher utilisation of olanzapine and quetiapine (SGAs) and lower prescription of haloperidol (FGAs).¹² Second-generation antipsychotics are preferred by clinicians as first-line therapy; thus, the addition of FGAs to suppress residual positive symptoms may indicate treatment resistance.¹⁰ Thus, this may suggest that these patients may meet the criteria of treatment resistance and thus are more likely to receive high-dose. Likewise, SGAs were a predictor of receiving high-dose, which is in line with other studies.²⁶ Quetiapine may also be employed as a hypnotic, and it also has antianxiety and antidepressant properties.²⁷

Patients receiving high doses are less likely to receive procyclidine. Other studies reported the opposite, with high-dose antipsychotics increasing the likelihood of receiving anticholinergics.^8,28 This may be because of our exclusion of prescribed as-required medications, which are haloperidol and chlorpromazine (FGAs). By including only regular medication, which are mostly SGAs, the need for anticholinergics is greatly reduced in line with other studies.²³ Other studies also reported FGA use as a predictor of anticholinergic prescription.²⁸ The APA advocates short-term prophylactic use of anticholinergics only in high-risk patients susceptible to dystonia, such as young males receiving parenteral highly potent FGA.²

Less antidepressant use was a predictor of high-dose, which is in line with other studies.²⁹ Patients receiving high-dose have more severe psychopathology and are likely treatment-resistant; thus, antipsychotics rather than antidepressants constitute the primary treatment option for this group of patients.¹¹ In addition, clinicians may be concerned about increasing the side effect burden and drug interactions emerging from the addition of antidepressants to high-dose antipsychotics.

In this study, no patients received clozapine, which aligns with the findings from a study in Qatar, where only 2.4% received clozapine.³⁰ Clozapine is indicated in treatment-resistant schizophrenia, which affects 30.0% of patients with schizophrenia.¹⁰ However, this medication has a special protocol for initiation and titration and is associated with a list of side effects that require regular monitoring, such as agranulocytosis.³¹ Thus, acutely unwell patients may not consent to blood sampling, and this hinders its widespread use.³² In those with treatment resistance, only 4.0% trialled clozapine before using antipsychotic polypharmacy.⁹ This implies that polypharmacy is considered early and that clinicians may delay prescribing clozapine, which contributes to increased morbidity and mortality.⁹

This is the first national study to describe the magnitude and factors associated with high-dose antipsychotic therapy, providing a baseline for future monitoring of prescribing trends. The study is considered representative because the study site is one of two hospitals in Iraq that provide inpatient psychiatric care. Although the study design is retrospective, the data were collected by one experienced clinical pharmacist researcher, thus minimising variation and enhancing the data quality. However, because of the cross-sectional nature, causality cannot be established. In addition, we excluded as-required antipsychotic medications; thus, the rate of antipsychotic polypharmacy and high-dose antipsychotics may be underestimated.

We observed a high rate of antipsychotic polypharmacy and high-dose antipsychotics, which are unaligned with standard practice guidelines, increase side effects and drug interactions, and thus risk patient safety.^2,3 Although antipsychotic polypharmacy may be required initially during acute hospitalisation, reverting to monotherapy is recommended long-term to sustain response.¹² Recent evidence suggests that antipsychotic polypharmacy prescribing at discharge increases the risk of psychiatric readmission.³³ Thus, the goal is to review treatment at discharge to ensure optimal evidence-based prescribing.

It is possible that clinicians were unaware that they were pursuing high-dose therapy because, in most cases, high-dose antipsychotics result from polypharmacy. Education programmes for clinicians are vital to enhance adherence to guidelines and ensure optimal delivery of psychopharmacological therapy. Clozapine and long-acting injectable antipsychotics are effective in reducing the risk of relapse, and thus, improving the utilisation of these agents as maintenance therapy, when appropriate, especially in those with multiple admissions, should be considered.^2,11 Information regarding the adverse effects of antipsychotics or previous clozapine trial for those receiving antipsychotic polypharmacy is lacking in the medical records. Reasons for prescribing antipsychotic polypharmacy should be clearly documented in the medical records. Furthermore, the inclusion of pharmacists specialised in mental health as a part of a multidisciplinary team is important to enhance guideline adherence and promote optimal use of antipsychotics. Finally, a qualitative survey to assess the psychiatrists’ knowledge, attitudes, and practices towards the prescription of combined and high-dose antipsychotics is warranted.

The study’s findings indicate that one in three patients received high-dose antipsychotics. Patients receiving combined antipsychotics or FGAs are particularly at risk. This practice, which is not endorsed by guidelines, should be reviewed to ensure patient safety. Targeted educational interventions are recommended to enhance adherence to prescription guidelines and optimise treatment outcomes.