Antipsychotics are the mainstay treatment for schizophrenia and are used both to control acute relapses of symptoms and in maintenance therapy to reduce the risk of relapse [1,2]. They are classified into two main groups according to their chemical characteristics, effects on psychotic symptoms and adverse effect profiles: first-generation antipsychotics, or typical antipsychotics (TAP), and second-generation antipsychotics, or atypical antipsychotics (AAP) [3].

TAP are effective in alleviating positive symptoms but often cause unpleasant extrapyramidal effects that lead to poor treatment adherence. In addition to controlling positive symptoms, AAP might be better than TAP because they may have a relevant effect on negative and mood symptoms [4–6]. AAP are not a homogeneous class of drugs, and differences among them may influence clinicians when deciding to use one of them. A meta-analysis by Leucht et al. [7], which included 212 trials with 43,049 participants, concluded that AAP differ substantially in side effects (including metabolic and extrapyramidal), and also found small differences in efficacy among them. Some AAP (clozapine, amisulpride, olanzapine, and risperidone) were found to have higher efficacy than the TAP they were compared against in the meta-analysis (haloperidol and chlorpromazine). Other AAP, such as, aripiprazole, paliperidone, or ziprasidone had similar efficacy to TAP [7]. Clozapine is the most effective atypical antipsychotic and is useful in the treatment of resistant schizophrenia, but its use is limited due to the risk of agranulocytosis [4,6,7].

Despite the superiority of some AAP and the recommendation of clinical practice guidelines for treating schizophrenia with monotherapy [8–11], polypharmacy is a widespread practice around the world [12]. The rates of antipsychotic polypharmacy have been described as ranging from 4.1% to 57.7% [13–15]. Prescription patterns may vary from one country to another because they are determined by health care models, as well as because of cost and availability [12]. For example, a report of antipsychotic use patterns from Belgium showed that most patients were treated with AAP monotherapy [16], whereas a study from Germany found that only 10.5% of patients were treated with a single antipsychotic [17].

In Spain, the use of antipsychotics has increased remarkably in recent decades, going from 3 Defined Daily Doses [DDD]/1000 inhabitants/day in 1992 to over 8 DDD/1000 inhabitants/day in 2006, coinciding with the commercialization of diverse AAP [18]. Bernardo et al. [19] examined some patterns of antipsychotic prescriptions using the official medical prescription registry for the region of Barcelona (Catalonia, Spain). They found a 66.7% rate of antipsychotic monotherapy, with risperidone and olanzapine as the most frequently prescribed drugs, and a low frequency of clozapine use (2.3%). Unfortunately, their study did not record diagnostic categories, and so there is no way to know whether the antipsychotics were prescribed for schizophrenia, bipolar disorder or other psychiatric and neuropsychiatric conditions.

There are no published data on the prescription patterns for antipsychotics in all schizophrenia patients located in a specific catchment area from Spain. This is partially due to the lack of electronically recorded prescription data until relatively recently. In order to contribute to the global mapping of the use of antipsychotics in real-life settings, we describe the prescription patterns of antipsychotics in outpatients in the public mental health care network of services in the province of Tarragona (Catalonia, Spain). The frequency of the prescription of each medication, dosage, long-term antipsychotic polypharmacy, and the use of other psychiatric treatments are described.

Five hundred and forty-eight (31%) of the 1,765 schizophrenia patients were female, and 1,217 (69%) were male. The mean age was 43.60±13.60 years.

The most frequent schizophrenia subtype was paranoid (73.3%), and the mean duration of the disorder was 13.90±7.10 years. More than half of the patients (64.8%) were classified as SMD cases. In addition, 40% of the patients had registered a psychiatric co-morbidity, and 27.7%, a substance abuse-related disorder (18.6% for tobacco and 9.1% for alcohol, THC, and cocaine combined); 1.1% had registered an affective disorder, and 1%, an anxiety disorder.

We describe patterns of prescribing antipsychotics in the schizophrenia patient population from a catchment area in a southern European province, considering the principal antipsychotic used and its dosage, long-term antipsychotic polymedication, and concomitant use of other psychiatric medications. An AAP was the principal treatment of choice in almost 8 of every 10 patients. Risperidone, olanzapine, and paliperidone were commonly prescribed, followed by the first TAP on the list (zuclopenthixol). Almost half of the patients were on a LAI. Antipsychotics were generally prescribed in the recommended therapeutic dose, though for clozapine, ziprasidone, paliperidone (LAI), and risperidone (LAI) it was at the upper end of their recommended ranges. Otherwise, 7 of every 10 patients were on antipsychotic polypharmacy, and the prescription of other psychiatric drugs was high, with almost half of the patients taking anxiolytics.

Our results were similar to those reported in outpatients with schizophrenia in New Zealand, for whom risperidone and olanzapine were the most frequently prescribed drugs [22]. In addition to being the most common oral antipsychotic, risperidone was the most common LAI in our study. Such findings are similar to those reported in other developed countries such as the United Kingdom [23] and the United States [24]. The preferential use of these two drugs may be a consequence of their entering the market earlier compared to other drugs such as quetiapine, as well as their diverse formulation possibilities (especially for risperidone which is available as an LAI and in various oral presentations). Administrative restrictions by the Health Care System on the use of the newer antipsychotics (aripiprazole and paliperidone) in our catchment area during the study period may also have influenced our specific pattern.

Though paliperidone was introduced in Spain as an LAI in late 2011 and there is a restriction on its use in Tarragona, it was the third most commonly prescribed drug among all antipsychotics and the second most common among LAIs, perhaps due to its more convenient monthly administration and its favorable metabolic profile compared with LAI risperidone [25]. The third most prescribed LAI in our area was a TAP (zuclopenthixol), which has been in use for many years.

Contrary to recommendations in the literature [8–11], the prescription frequency for antipsychotic monotherapy was low (less than 3 of every 10 patients), with the majority of patients being on antipsychotic polypharmacy and/or other psychiatric co-medication. According to the European College of Neuropsychopharmacology consensus on the advantages and disadvantages of combination treatment with antipsychotics, antipsychotic polypharmacy and the high use of other psychiatric medications, as found in this report, may be partially explained by the following four reasons [26]:

Despite all of these arguments supporting the use of polymedication, our results call attention to the long-lasting concerns about the discrepancy between guidelines and the real-world treatment of schizophrenia (the so called “dirty little secret” of psychiatry) [32,33]. Current guidelines basically recommend antipsychotic monotherapy for schizophrenia treatment with the combination of two or more antipsychotics only as a last resort and clozapine as the treatment of choice for cases that are resistant to individual therapies [8–11]. In contrast, like others [34–36], we found an extensive use of antipsychotic polypharmacy together with the relatively limited use of clozapine. Moreover, we are not the only ones to find use of the irrational quetiapine+olanzapine combination, where both drugs have a similar receptor profile, there is no evidence of additional efficacy, and there is a higher prevalence of adverse events [37,38]. We also found the use of three antipsychotics in almost 2 of every 10 patients.

The multivariate analysis of the relationship between diverse clinical characteristics and antipsychotic polypharmacy showed that a low-potency antipsychotic such as quetiapine, and LAI prescriptions had a high likelihood of being related to the prescription of multiple antipsychotics. A high-potency antipsychotic, such as risperidone, and younger age were protective against polypharmacy. It is noteworthy that this analysis based on clinical and pharmacological variables left approximately 60% of the variance unexplained. These unexplained reasons could be related to psychiatrists’ preferences or worries. For example, it is possible that psychiatrists are prone to continue long-term polypharmacy after trying to switch to avoid destabilizing a patient [39]. Psychiatrists may also prefer polypharmacy because of skepticism about the usefulness of algorithms (like those in guidelines) [33], or they may feel that polypharmacy is justified after non-response to or non-tolerance of clozapine, even though there is little evidence for the efficacy of this approach [40].

According to Correll et al. [40], those who use antipsychotic polypharmacy tend to be attending psychiatrists rather than residents, have been practicing for a longer time, see more patients per week, and have a preferred combination of antipsychotics. On the other hand, as suggested by Goren et al [35]., the reasons for clozapine underutilization could include a high prescribing burden (including registration requirements), significant side effects, and the requirement of frequent laboratory testing.

Future analyses of polypharmacy patterns might usefully include both clinical/pharmacological variables and the characterization of clinicians (including the evaluation of reasons for prescribing more than two long-term antipsychotics and the non-prescription of clozapine). Continuing medical education and training on prescribing antipsychotics, including LAI and clozapine, and the simplification of administrative requirements for prescribing this latter drug, could reverse the pattern of polypharmacy and low clozapine use. The impact of these interventions on clinical practice could be assessed by means of clinical trials.

In summary, contrary to the recommendation for monotherapy in the treatment of schizophrenia, antipsychotic polypharmacy is widespread and clozapine use is relatively scarce. The use of low-potency antipsychotics such as quetiapine is associated with polypharmacy, and patients who are on LAI also have a higher probability of being on polypharmacy. Antipsychotic dosage was concordant with Spanish safety data, though clozapine, ziprasidone, paliperidone (LAI), and risperidone (LAI) were prescribed at the upper end of their recommended ranges.

The strengths of this naturalistic study include its description of real-life practice and the coverage of a population of more than 1,700 adult patients with schizophrenia from a defined catchment area, without the use of exclusion criteria, making it a representative population of patients. However, even though we are the only providers of public mental health in our province, it is probable that we will have missed an unknown number of patients cared for by private practitioners or insurance companies. It is also probable that there are some patients who have not contacted a mental health professional. Other limitations of our study include the fact that the information was obtained from a secondary source and not from prospective structured evaluation of the patients and/or interview with their psychiatrists. The study design may have led to a less accurate registration of certain variables, such as secondary diagnosis, or to the loss of other information with clinical relevance, such as adherence to prescribed treatment. Finally, this study focused on long-term antipsychotic polypharmacy, whereas short-term polypharmacy or the switching patterns of prescriptions were not examined. Our team is working on a specific study about such prescription patterns for both oral and LAI treatments and their associated factors.