This article has Open Peer Review reports available.
Antipsychotic polypharmacy in a regional health service: a population-based study
© Bernardo et al.; licensee BioMed Central Ltd. 2012
Received: 9 November 2010
Accepted: 17 February 2012
Published: 15 May 2012
To analyse the extent and profile of outpatient regular dispensation of antipsychotics, both in combination and monotherapy, in the Barcelona Health Region (Spain), focusing on the use of clozapine and long-acting injections (LAI).
Antipsychotic drugs dispensed for people older than 18 and processed by the Catalan Health Service during 2007 were retrospectively reviewed. First and second generation antipsychotic drugs (FGA and SGA) from the Anatomical Therapeutic Chemical classification (ATC) code N05A (except lithium) were included. A patient selection algorithm was designed to identify prescriptions regularly dispensed. Variables included were age, gender, antipsychotic type, route of administration and number of packages dispensed.
A total of 117,811 patients were given any antipsychotic, of whom 71,004 regularly received such drugs. Among the latter, 9,855 (13.9%) corresponded to an antipsychotic combination, 47,386 (66.7%) to monotherapy and 13,763 (19.4%) to unspecified combinations. Of the patients given antipsychotics in association, 58% were men. Olanzapine (37.1%) and oral risperidone (36.4%) were the most common dispensations. Analysis of the patients dispensed two antipsychotics (57.8%) revealed 198 different combinations, the most frequent being the association of FGA and SGA (62.0%). Clozapine was dispensed to 2.3% of patients. Of those who were receiving antipsychotics in combination, 6.6% were given clozapine, being clozapine plus amisulpride the most frequent association (22.8%). A total of 3.800 patients (5.4%) were given LAI antipsychotics, and 2.662 of these (70.1%) were in combination. Risperidone was the most widely used LAI.
The scant evidence available regarding the efficacy of combining different antipsychotics contrasts with the high number and variety of combinations prescribed to outpatients, as well as with the limited use of clozapine.
Antipsychotic drugs are often combined in the clinical treatment of schizophrenia, despite the lack of a solid evidence base for this strategy. Indeed, the combination of antipsychotics has yet to be studied in sufficient detail, although numerous pharmaco-epidemiological studies describing the phenomenon of antipsychotic polypharmacy have been conducted internationally. However, these studies are highly heterogeneous and differ in terms of methodology, sample size, chronology, diagnostic criteria, the treatments included and the salvage therapy options [1–8].
The prevalence of antipsychotic polypharmacy in the USA ranges from 7% to around 50% [9–18], including a study in child and adolescent population , with most studies reporting rates between 10 and 30%. Similarly, European data on patients diagnosed with schizophrenia and being treated in acute psychiatric units reveal that antipsychotic polypharmacy is a common (if not the most common) strategy and that it is not reserved for the most treatment-resistant cases [20, 21].
Some authors have also reported a trend towards an increased use of antipsychotic polypharmacy in the same patient over time [11, 22], although evidence-based guidelines only recommend concomitant antipsychotic treatment after several failed attempts at monotherapy, including with clozapine [23, 24]. Indeed, the various clinical guidelines with stronger consensus [25–27] place clear limitations on the use of antipsychotic polypharmacy.
It has been suggested that some antipsychotics, both first (FGA) and second (SGA) generation, are especially used in polytherapy, whereas others, such as clozapine, tend to be used as monotherapy . This contrasts with the large number of published studies on the use of clozapine in combination as opposed to many of the combinations that are currently used [29, 30]. There is no specific antipsychotic combination recommended in the current guidelines [25–27]. In this regard, it would also seem advisable to analyse the use of long-acting injections (LAI) of antipsychotics and determine their profile of use in monotherapy or combination.
In the case of schizophrenia, resistance to treatment and the unsatisfactory functional outcomes remain a significant problem in both the clinical context and in terms of public health [9, 31–33]. To date, clozapine is the only treatment to have shown significantly better outcomes than other antipsychotics in partial or non-responder patients to antipsychotic monotherapy [34–36]. Furthermore, although numerous maximization strategies have been tried in randomised controlled studies, none of them has proved the effectiveness in non-responders to monotherapy [1–4]. On the other hand, in some cases antipsychotics could be associated to treat some symptoms like insomnia, especially clotiapine.
As regards the safety of antipsychotic polypharmacy, there are data which suggest that its use does not increase side effects or the risk of death by natural causes , although some studies do report a moderate and additive risk of adverse effects .
The present study sought to evaluate the profile of antipsychotic drugs dispensation in a broad sample over a one-year period (2007). The aim was to determine the extent to which these dispensations were in line with current guidelines and to indicate to policy makers, managers, clinicians and trainee physicians those areas which require further research.
The study was conducted in the Barcelona Health Region (BHR), which provides healthcare to 5,105,555 people, making it the largest in Catalonia. Catalonia is an autonomous region in the northeast of Spain that covers an area of 32,114 km², its official population in December 2007 being 7,503,118 inhabitants. Medical consultations and hospital admissions are fully covered by the local Catalan Health Service (CatSalut). Prescriptions are free to retired people, while their cost is partially covered for those in employment. In the BHR, 81.0% of people entitled to public healthcare are older than 18, and of these, 51.6% are women (data from the local central register for December 2007).
Using the database of official medical prescriptions (DATAMART®) processed by the Catalan Health Service we selected all out-patient prescriptions for one or more antipsychotic drugs prescribed by a physician of CatSalut (independently of the speciality) to a person over the age of 18 in the BHR, and dispensed during 2007 in a pharmacy in Catalonia. Antipsychotic drugs prescribed to inpatients at hospital units were not considered for the purposes of the present study.
The antipsychotic drugs analysed were all those included (with the exception of lithium) under the code N05A of the Anatomical Therapeutic Chemical (ATC) classification system and marketed in Spain. FGAs (chlorpromazine, clotiapine, fluphenazine, haloperidol, levomepromazine, perphenazine, periciazine, pimozide, pipothiazine, sulpiride, tiapride, trifluoperazine and zuclopenthixol) were distinguished from SGAs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindol and ziprasidone), as well as oral formulations from long-acting injections (LAI) (fluphenazine LAI, pipothiazine LAI, risperidone oral and LAI, and zuclopenthixol oral and LAI).
The aim of the study was to apply a retrospective epidemiological analysis to determine the use of antipsychotic treatments in combination and as monotherapy, with particular attention to the use of clozapine and injectable forms.
Criterion 1: Regularly-dispensed antipsychotic treatment: at least three packages of any antipsychotic dispensed during 2007.
Criterion 2: Monotherapy: for those patients who were given at least three packages of an antipsychotic a distinction was made between those prescribed just one antipsychotic (monotherapy) and those who received two or more different antipsychotics (antipsychotic polytherapy).
Criterion 3: Antipsychotic combination treatment: for those patients receiving antipsychotic polytherapy, further three filters were applied, based on a review of the literature [34–36], to define the criterion of antipsychotic combination:
1- At least two packages of two or more antipsychotic drugs dispensed in the three months prior to the last prescription supplied.
2- The filter 1 was not fulfilled, but more than one package was dispensed in the fourth month prior to the last prescription supplied.
3- Filters 1 and 2 were not fulfilled, but at least six packages of each antipsychotic were dispensed during the year in question.
We assumed that, in general, at least 1 box of medication covers 1 month of treatment. Further on, we developed different filters to precise the identification of patients with antipsychotic combinations. Criterion 1 was used to identify the population with regular dispensation of antipsychotics. Criterion 2 was used to distinguish patients who received one antipsychotic from those who received more than one. In any case, receiving more than one during a year does not mean that they were used simultaneously; consequently we applied the 3rd criterion to identify the simultaneous use of antipsychotics and distinguish it from the sequential use.
In the 3rd criterion, Filter 2 is used to detect patients to whom the 1st filter does not apply because multiple packages have been dispensed simultaneously during the 4th month prior to the last dispensation and consequently the patient has enough medication to cover a longer period.
The variables recorded referred to demographics (age and sex) and prescription characteristics (antipsychotic, route of administration and packages dispensed). No personal or clinical data of patients have been collected. This study has been realized with general data obtained from the pharmacy prescription database, not with individual data of subjects. Therefore, no ethical approval had to be obtained for this study.
A classification algorithm, implemented in Visual Basic for Applications (VBA), was designed to classify those patients who met the criteria for receiving antipsychotic drugs in combination. The results of the tables are obtained from descriptive statistics. The comparisons between proportions were made using a Z-test with a level of significance of 0.05. This statistical analysis was performed using SPSS v. 16.0.
The initial analysis identified 117,811 patients who had been dispensed at least one antipsychotic during 2007. Application of the above mentioned selection criteria revealed that of these, 71,004 had been regularly dispensed an antipsychotic drug, of whom 47,386 (66.7%) were given the antipsychotic as monotherapy and 9,855 (13.9%) received more than one antipsychotic combined. The remaining 13,763 (19.4%) were classified as cases of unspecified antipsychotic polytherapy as they did not fulfil criterion number 3 (Figure 1).
Distribution of the study sample according to age and sex
Initial Sample (N = 71,004)
Antipsychotic monotherapy (n = 47,386)
Antipsychotics combined (n = 9,855)
Distribution of the population according to the antipsychotic used (the table only shows those drugs that were used in more than 1% of the total sample)
Initial sample (N = 71,004)
People given monotherapy (N = 47,386)
People given antipsychotics in combination (N = 9,855)
Antipsychotics in combination
Application of the three filter criterion to patients prescribed two or more antipsychotic drugs during the year in question revealed that 9,855 people were given a combination of antipsychotics. The age and sex distribution of these patients are shown in Table 1. Men accounted for 58.0% of those patients, more frequently in the age range 19–40. Conversely, in women antipsychotic polypharmacy was more frequent in the age range 41–60. Overall, however, antipsychotic combination was most likely prescribed to both men and women aged 19–60 (84.3% and 65.5%, respectively).
The frequency of drug combinations is displayed in Table 2. The antipsychotics that showed the highest rates of use in polytherapy were olanzapine (37.1%), oral risperidone (36.4%), quetiapine (29.3%), haloperidol (27.9%), levomepromazine (26.5%) and clotiapine (21.9%).
Combinations of two antipsychotics (the table only shows those combinations used in more than 2% of patients)
Risperidone (oral) + Quetiapine
Risperidone (oral) + Haloperidol
Haloperidol + Levomepromazine
Risperidone (oral) + Olanzapine
Risperidone (oral) + Levomepromazine
Olanzapine + Haloperidol
Olanzapine + Quetiapine
Haloperidol + Quetiapine
Olanzapine + Levomepromazine
Olanzapine + Clothiapine
Risperidone (oral) + Risperidone LAI
Olanzapine + Amisulpride
Olanzapine + Risperidone LAI
Levomepromazine + Quetiapine
Risperidone (oral) + Clothiapine
As regards the total number of combinations according to the type of antipsychotic, 6,106 (62.0%) of patients were dispensed both FGAs and SGAs, while 2,699 (27.4%) received different combinations of SGAs and 1,050 (10.6%) used different combinations of FGAs.
Patients with antipsychotic combinations according to type and route of administration
FGA and SGA
FGA and SGA
Antipsychotics in monotherapy
Women accounted for 58.6% of people in antipsychotic monotherapy. Table 1 shows that men aged 19–40 were dispensed more antipsychotic drugs than their female counterparts (30.1% versus 12.6%), whereas women accounted for a higher proportion of dispensations in those aged over 80 (30.2% vs. 13.3%).
A total of 81.3% of people were given monotherapy with one of the following five drugs: oral risperidone (24.5%), olanzapine (20.3%), sulpiride (14.6%), quetiapine (12.5%) or haloperidol (9.4%) (Table 2).
Use of clozapine
Clozapine was dispensed to 1,615 patients (2.3%) in the study sample (N = 71,004), of whom 65.4% were men. Of those patients on antipsychotic monotherapy, 667 (1.4%) were given clozapine. In combination therapy, 652 (6.6%) patients were dispensed clozapine, 345 of them in combinations of three or more antipsychotics.
Patients with two antipsychotics combined including clozapine
Use of long-acting injections of antipsychotics
Type of antipsychotic combinations in patients with LAI antipsychotics
Monotherapy (N = 47,386)
Combination with one oral antipsychotics (N = 5,692)
Combination with ≥2 antipsychotics(N = 4,163)
This study reveals that antipsychotic polypharmacy was dispensed to 13.8% of people who were regularly dispensed an antipsychotic drug during 2007. The observed rate of use of antipsychotic polytherapy is similar to that reported in previous studies. For example, Kogut et al. (2005)  found, in a population drawn from US Medicaid users, that 10.1% were given antipsychotic polypharmacy. The criteria used by Kogut et al. to classify a patient as an antipsychotic user and to define antipsychotic polypharmacy were similar to those applied here. Also, other studies reported a prevalence of polypharmacy of 15.6% . However, some studies have used an antipsychotic polypharmacy criterion that, in our view, is too broad (two or more antipsychotics used simultaneously) [16, 40], thus yielding notably higher prescription rates (41% and 50%). Given that the central aim of the present study was to analyse the regular use of antipsychotic combinations, three restrictive criteria were applied to avoid including combinations when the patient was switching between antipsychotic treatments. Yang et al. (2008) , applying shorter time criteria (at least six weeks of simultaneous use and twelve weeks if one of the drugs used was clozapine), reported an increased rate of use from 1.9% in 1997 to 5.5% in 2000. Another study of community-treated patients with schizophrenia found that 42.5% were given more than one antipsychotic , although this variation may be due to differences in the methods used.
Overall, men were more likely to be given an antipsychotic when they were aged under 60. The profile of use of drug combinations in women extends beyond 80 years of age. The present findings are consistent with previous reports showing that antipsychotic polypharmacy is more widely used in men [39, 42], possibly due to the increased severity of treatment-resistant schizophrenia among males .
The 57.8% of all combinations involved two antipsychotic drugs, most commonly oral risperidone plus quetiapine. Of those treated with combinations, 25.6% were given three antipsychotics. The 16.6% of patients were dispensed four or more antipsychotics.
One notable pattern of use identified in this study involved the combination of a FGA and a SGA (62.0%), which contrasts with previous reports in the literature (79.3% used two non-conventional antipsychotics or SGA) .
Clozapine was given to 1,615 (2.3%) patients, 41.3% of these in monotherapy and as part of antipsychotic polytherapy in 58.7%. The most common combination was clozapine plus amisulpride. The rate of clozapine use found in the present study is lower than that previously reported. For example, Pickar et al. (2008)  stated that 18% of their patients were given clozapine, although this higher rate may be related to the fact that they only included patients with severe schizophrenia treated in the community.
LAI formulations are frequently used to ensure treatment adherence that was not achieved with the oral formulation. Consequently, oral and LAI risperidone overlap could be accepted during a switching period from oral to LAI formulation, but not when used as a combination. As the criteria used to identify antipsychotic combinations tried to avoid the switching periods, the 162 patients identified in our study would correspond to combinations that are difficult to explain.
Clinicians continue to face numerous challenges in the treatment of schizophrenia, since ‘antipsychotic’ drugs do not function as ‘anti-schizophrenic’ drugs and do not act on comorbid conditions such as anxiety, or associated problems such as aggressiveness or suicidal risk. This leads to the use of multiple drug therapies, especially for reducing the mean length of hospital admissions. In our view, clinicians often base their arguments on the pharmacodynamic, pharmacokinetic or tolerance characteristics of different drugs, although psychiatrists generally consider antipsychotic polypharmacy as a largely ineffective strategy for patients who present resistant positive symptoms of psychosis .
Initiatives developed in this regard include the software package Psychiatric Clinical Knowledge Enhancement System (PSYCKES) , which enables clinicians to easily track the medication taken by their patients, as well as that prescribed by their peers, increasing the robustness of the decision-making process. A similar strategy was described in the Developing Evidence-Based Implementation Trial (DEBIT) , based on a multi-faceted intervention involving an educational/cognitive-behaviour therapy workbook, an educational visit to consultants and a reminder system on medication charts. Both strategies led to reductions in the costs resulting from polypharmacy, crucial when prescribing antipsychotic combinations.
The first limitation concerns the lack of diagnoses associated with the database used. Although antipsychotics are the drugs of choice for schizophrenia they may also be indicated in bipolar disorder, behavioural disorders associated with cognitive deterioration, and in other psychiatric or neurological disorders. It is important to clarify that the objective of the study is to describe the use of antipsychotic combination, independent of the diagnoses. Further research could be conducted linking our database with others containing diagnoses (since ours had no diagnoses). This could help to analyse the differences and preferences on the use of antipsychotic combinations depending on the diagnoses. Moreover, the lower rate of clozapine use found in the present study, compared with that reported in other studies, doesn’t necessarily mean a lower rate of use for schizophrenia, as this study includes patients with different possible diagnoses. The fact of not knowing the diagnosis makes it impossible to analyse the use of antipsychotic combinations depending on the severity of the illness. Also it’s impossible to know if there is a great potential for off label use in our sample.
The second limitation is that the analysis did not consider antipsychotic drugs prescribed neither in private practice nor to inpatients. The data correspond to drugs dispensed by pharmacies when presented with a prescription by a doctor from the Catalan National Health Service, which includes mental health centres, out-patient and emergency departments, community rehabilitation centres and other out-patient facilities. These account for the majority of prescriptions issued, since in our healthcare context the cost of these drugs makes it unlikely that they would be widely prescribed on a private basis. All the population from Catalonia is insured by the Catalan Health Service and pharmacy products are covered for the 98% of the patients insured. However, it is not possible to know precisely if we have considered all the antipsychotics used, due to the fact that part of the population may also have a private insurance and thus pay themselves for the treatment. Interventions that aim to promote the rational use of antipsychotics should also include prescription rates upon hospital discharge or in emergency units, since these can influence the maintenance treatment subsequently received by a patient.
The third limitation relays on the nature of our data. We used an administrative database of prescriptions processed by the National Health Service, and the measure taken into account was the number of packages dispensed to a patient upon presenting a prescription in a pharmacy. Therefore, the analysis concerned drugs dispensed rather than the prescription itself. It was also not possible to study the prescribed dose. Evaluating the treatment and its results, although interesting, was not an aim of our study. The prescribed dose could also affect the number of packages dispensed in a period of time, which would interfere with our study because the criteria we used to establish the study population were based on the number of packages dispensed. Similar studies using databases of medical records could complement the results of the present study.
Moreover, the criteria established to define the study sample tried to identify the simultaneous use of antipsychotic and distinguish it from the sequential use. The only way to accurately identify antipsychotic combination would have been through the prescription date but that was not available in our administrative database. Consequently, the filters used to identify antipsychotic combination were restrictive and a large proportion of patients were excluded from this definition and labelled as unspecified polytherapy.
The fourth limitation concerns the safety of using combinations of antipsychotics. As the data analysed do not include morbidity rates they are unable to shed any light on this aspect. In our view, there is a need for further research that takes an approach like the STAR*D  study with antidepressants, analysing different strategies of sequenced treatment with antipsychotics.
Although antipsychotic polypharmacy is widely used in our healthcare setting, it appears not to follow the available clinical practice guidelines indicating the use of using antipsychotic monotherapy, not in combination. Although there is no evidence of any effective antipsychotic combination, it could be very interesting to analyse in depth which are the most appropriate antipsychotic combinations used in the population of Catalonia. This would guide psychiatrists and general practitioners in their everyday clinical practice. Developing strategies for enhancing the use of recommendations in clinical practice will render the work clinicians more efficient and understandable in the eyes of policy makers, and vice-versa.
The authors thank the Government of Catalonia, Comissionat per Universitats I Recerca del Departament d’Innovació, Universitats I Empresa (DIUE) 2009SGR1295 and Mike Maudsley at the Language Advisory Service, University of Barcelona, Spain, for manuscript translation. Also, the authors thank to Cristina Oliveira, MD, PhD, Alicia Valiente, MD, and Clemente García, MD, PhD, the support in this project.
- Megna JL, Kunwar AR, Mahlotra K, Sauro MD, Devitt PJ, Rashid A: A study of polypharmacy with second generation antipsychotics in patients with severe and persistent mental illness. J Psychiatr Pract. 2007, 13 (2): 129-137. 10.1097/01.pra.0000265773.03756.3e.View ArticlePubMedGoogle Scholar
- Hazra M, Mamo DC, Remington G: Adjunctive versus monotherapeutic treatment for schizophrenia: addressing antipsychotic side effects. Am J Psychiatry. 2008, 165 (3): 396-397. 10.1176/appi.ajp.2007.07111738. author reply 397–398View ArticlePubMedGoogle Scholar
- Gilmer TP, Dolder CR, Folsom DP, Mastin W, Jeste DV: Antipsychotic polypharmacy trends among Medicaid beneficiaries with schizophrenia in San Diego County, 1999–2004. Psychiatr Serv. 2007, 58 (7): 1007-1010. 10.1176/appi.ps.58.7.1007.View ArticlePubMedGoogle Scholar
- Kreyenbuhl J, Marcus SC, West JC, Wilk J, Olfson M: Adding or switching antipsychotic medications in treatment-refractory schizophrenia. Psychiatr Serv. 2007, 58 (7): 983-990. 10.1176/appi.ps.58.7.983.View ArticlePubMedPubMed CentralGoogle Scholar
- Xiang YT, Weng YZ, Leung CM, Tang WK, Ungvari GS: Clinical and social determinants of antipsychotic polypharmacy for Chinese patients with schizophrenia. Pharmacopsychiatry. 2007, 40 (2): 47-52. 10.1055/s-2007-970062.View ArticlePubMedGoogle Scholar
- Kreyenbuhl JA, Valenstein M, McCarthy JF, Ganoczy D, Blow FC: Long-term antipsychotic polypharmacy in the VA health system: patient characteristics and treatment patterns. Psychiatr Serv. 2007, 58 (4): 489-495. 10.1176/appi.ps.58.4.489.View ArticlePubMedPubMed CentralGoogle Scholar
- Morrato EH, Dodd S, Oderda G, Haxby DG, Allen R, Valuck RJ: Prevalence, utilization patterns, and predictors of antipsychotic polypharmacy: experience in a multistate Medicaid population, 1998–2003. Clin Ther. 2007, 29 (1): 183-195. 10.1016/j.clinthera.2007.01.002.View ArticlePubMedGoogle Scholar
- Broekema WJ, de Groot IW, van Harten PN: Simultaneous prescribing of atypical antipsychotics, conventional antipsychotics and anticholinergics-a European study. Pharm World Sci. 2007, 29 (3): 126-130. 10.1007/s11096-006-9063-1.View ArticlePubMedPubMed CentralGoogle Scholar
- Lieberman JA, Stroup TS, McEvoy JP, et al: Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005, 353 (12): 1209-1223. 10.1056/NEJMoa051688.View ArticlePubMedGoogle Scholar
- Correll CU, Frederickson AM, Kane JM, Manu P: Does antipsychotic polypharmacy increase the risk for metabolic syndrome?. Schizophr Res. 2007, 89 (1–3): 91-100.View ArticlePubMedGoogle Scholar
- Ganguly R, Kotzan JA, Miller LS, Kennedy K, Martin BC: Prevalence, trends, and factors associated with antipsychotic polypharmacy among Medicaid-eligible schizophrenia patients, 1998–2000. J Clin Psychiatry. 2004, 65 (10): 1377-1388. 10.4088/JCP.v65n1013.View ArticlePubMedGoogle Scholar
- Faries D, Ascher-Svanum H, Zhu B, Correll C, Kane J: Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics. BMC Psychiatry. 2005, 5: 26-10.1186/1471-244X-5-26.View ArticlePubMedPubMed CentralGoogle Scholar
- Kreyenbuhl J, Valenstein M, McCarthy JF, Ganoczy D, Blow FC: Long-term combination antipsychotic treatment in VA patients with schizophrenia. Schizophr Res. 2006, 84 (1): 90-99. 10.1016/j.schres.2006.02.023.View ArticlePubMedGoogle Scholar
- Tapp A, Wood AE, Secrest L, Erdmann J, Cubberley L, Kilzieh N: Combination antipsychotic therapy in clinical practice. Psychiatr Serv. 2003, 54 (1): 55-59. 10.1176/appi.ps.54.1.55.View ArticlePubMedGoogle Scholar
- Procyshyn RM, Honer WG, Wu TK, Ko RW, McIsaac SA, Young AH, Johnson JL, Barr AM: Persistent antipsychotic polypharmacy and excessive dosing in the community psychiatric treatment setting: a review of medication profiles in 435 Canadian outpatients. J Clin Psychiatry. 2010, 71 (5): 566-573. 10.4088/JCP.08m04912gre.View ArticlePubMedGoogle Scholar
- Karagianis J, Williams R, Davis L, et al: Antipsychotic switching: results from a one-year prospective, observational study of patients with schizophrenia. Curr Med Res Opin. 2009, 25 (9): 2121-2132. 10.1185/03007990903102966.View ArticlePubMedGoogle Scholar
- Smith G, Malla A, Williams R, Kopala L, Love L, Balshaw R: The Canadian national outcomes measurement study in Schizophrenia: overview of the patient sample and methodology. Acta Psychiatr Scand Suppl. 2006, 430: 4-11.View ArticlePubMedGoogle Scholar
- Ranceva N, Ashraf W, Odelola D: Antipsychotic polypharmacy in outpatients at Birch Hill Hospital: incidence and adherence to guidelines. J Clin Pharmacol. 2010, 50 (6): 699-704. 10.1177/0091270009350625.View ArticlePubMedGoogle Scholar
- Mojtabai R, Olfson M: National trends in psychotropic medication polypharmacy in office-based psychiatry. Arch Gen Psychiatry. 2010, 67 (1): 26-36. 10.1001/archgenpsychiatry.2009.175.View ArticlePubMedGoogle Scholar
- Lerma-Carrillo I, de Pablo Bruhlmann S, del Pozo ML, Pascual-Pinazo F, Molina JD, Baca-Garcia E: Antipsychotic polypharmacy in patients with schizophrenia in a brief hospitalization unit. Clin Neuropharmacol. 2008, 31 (6): 319-332. 10.1097/WNF.0b013e31815cba78.View ArticlePubMedGoogle Scholar
- Divac N, Jasovic-Gasic M, Samardzic R, Lackovic M, Prostran M: Antipsychotic polypharmacy at the University Psychiatric Hospital in Serbia. Pharmacoepidemiol Drug Saf. 2007, 16 (11): 1250-1251. 10.1002/pds.1421.View ArticlePubMedGoogle Scholar
- Clark RE, Bartels SJ, Mellman TA, Peacock WJ: Recent trends in antipsychotic combination therapy of schizophrenia and schizoaffective disorder: implications for state mental health policy. Schizophr Bull. 2002, 28 (1): 75-84. 10.1093/oxfordjournals.schbul.a006928.View ArticlePubMedGoogle Scholar
- Miller AL, Hall CS, Buchanan RW, et al: The Texas Medication Algorithm Project antipsychotic algorithm for schizophrenia: 2003 update. J Clin Psychiatry. 2004, 65 (4): 500-508. 10.4088/JCP.v65n0408.View ArticlePubMedGoogle Scholar
- Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, Kreyenbuhl J: Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004, 161 (2 Suppl): 1-56.PubMedGoogle Scholar
- Ministerio dSyC: Guía de práctica clínica para la atención al paciente con esquizofrenia. Available at: http://www.gencat.cat/salut/depsan/units/aatrm/pdf/gpc_esquizofrenia-aatrm09.pdf
- American PA: Guideline for the treatment of patients with schizophrenia [monografía en Internet]. Available at: http://www.pbhcare.org/pubdocs/upload/documents/APA%20Schzophrenia%20Guidelines%202004.pdf
- Texas MAPT: Algorithm for the Treatment of Schizophrenia.Google Scholar
- Correll CU, Rummel-Kluge C, Corves C, Kane JM, Leucht S: Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. 2009, 35 (2): 443-457. 10.1093/schbul/sbn018.View ArticlePubMedGoogle Scholar
- Barbui C, Signoretti A, Mule S, Boso M, Cipriani A: Does the addition of a second antipsychotic drug improve clozapine treatment?. Schizophr Bull. 2009, 35 (2): 458-468. 10.1093/schbul/sbn030.View ArticlePubMedGoogle Scholar
- Cipriani A, Boso M, Barbui C: Clozapine combined with different antipsychotic drugs for treatment resistant schizophrenia. Cochrane Database Syst Rev. 2009, CD006324-3Google Scholar
- Hegarty JD, Baldessarini RJ, Tohen M, Waternaux C, Oepen G: One hundred years of schizophrenia: a meta-analysis of the outcome literature. Am J Psychiatry . 1994, 151 (10): 1409-1416.View ArticlePubMedGoogle Scholar
- Jones PB, Barnes TR, Davies L, et al: Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1). Arch Gen Psychiatry. 2006, 63 (10): 1079-1087. 10.1001/archpsyc.63.10.1079.View ArticlePubMedGoogle Scholar
- Robinson DG, Woerner MG, McMeniman M, Mendelowitz A, Bilder RM: Symptomatic and functional recovery from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry. 2004, 161 (3): 473-479. 10.1176/appi.ajp.161.3.473.View ArticlePubMedGoogle Scholar
- Kane JM, Honigfeld G, Singer J, Meltzer H: Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull. 1988, 24 (1): 62-67.PubMedGoogle Scholar
- McEvoy JP, Lieberman JA, Stroup TS, et al: Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006, 163 (4): 600-610. 10.1176/appi.ajp.163.4.600.View ArticlePubMedGoogle Scholar
- Lewis SW, Barnes TR, Davies L, et al: Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006, 32 (4): 715-723.View ArticlePubMedPubMed CentralGoogle Scholar
- Baandrup L, Gasse C, Jensen VD, et al: Antipsychotic polypharmacy and risk of death from natural causes in patients with schizophrenia: a population-based nested case–control study. J Clin Psychiatry. 2009, 71 (2): 103-108.View ArticlePubMedGoogle Scholar
- Tranulis C, Skalli L, Lalonde P, Nicole L, Stip E: Benefits and risks of antipsychotic polypharmacy: an evidence-based review of the literature. Drug Saf. 2008, 31 (1): 7-20. 10.2165/00002018-200831010-00002.View ArticlePubMedGoogle Scholar
- Kogut SJ, Yam F, Dufresne R: Prescribing of antipsychotic medication in a medicaid population: use of polytherapy and off-label dosages. J Manag Care Pharm. 2005, 11 (1): 17-24.PubMedGoogle Scholar
- Schumacher JE, Makela EH, Griffin HR: Multiple antipsychotic medication prescribing patterns. Ann Pharmacother. 2003, 37 (7–8): 951-955.View ArticlePubMedGoogle Scholar
- Yang M, Barner JC, Lawson KA, Rascati KL, Wilson JP, Crismon ML, Worchel J, Mascarenas CA: Antipsychotic medication utilization trends among Texas veterans: 1997–2002. Ann Pharmacother. 2008, 42 (9): 1229-1238. 10.1345/aph.1L155.View ArticlePubMedGoogle Scholar
- Pickar D, Vinik J, Bartko JJ: Pharmacotherapy of schizophrenic patients: preponderance of off-label drug use. PLoS One. 2008, 3 (9): e3150-10.1371/journal.pone.0003150.View ArticlePubMedPubMed CentralGoogle Scholar
- Usall J, Suarez D, Haro JM: Gender differences in response to antipsychotic treatment in outpatients with schizophrenia. Psychiatry Res. 2007, 153 (3): 225-231. 10.1016/j.psychres.2006.09.016.View ArticlePubMedGoogle Scholar
- Pandurangi AK, Dalkilic A: Polypharmacy with second-generation antipsychotics: a review of evidence. J Psychiatr Pract. 2008, 14 (6): 345-367. 10.1097/01.pra.0000341890.05383.45.View ArticlePubMedGoogle Scholar
- Uttaro T, Finnerty M, White T, Gaylor R, Shindelman L: Reduction of concurrent antipsychotic prescribing practices through the use of PSYCKES. Adm Policy Ment Health. 2007, 34 (1): 57-61. 10.1007/s10488-006-0075-x.View ArticlePubMedGoogle Scholar
- Thompson A, Sullivan SA, Barley M, Strange SO, Moore L, Rogers P, Sipos A, Harrison G: The DEBIT trial: an intervention to reduce antipsychotic polypharmacy prescribing in adult psychiatry wards - a cluster randomized controlled trial. Psychol Med. 2008, 38 (5): 705-715.View ArticlePubMedGoogle Scholar
- Insel TR: Beyond efficacy: the STAR*D trial. Am J Psychiatry. 2006, 163 (1): 5-7. 10.1176/appi.ajp.163.1.5.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/12/42/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.