Psychopharmacological treatment of 2195 in-patients with borderline personality disorder: A comparison with other psychiatric disorders.

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Psychopharmacological treatment of 2195 in-patients with borderline personality disorder: A comparison with other psychiatric disorders René Bridlera, Anne Häberleb, Sabrina T. Müllera, Katja Cattapana,e, Renate Grohmannb, Sermin Totoc, Siegfried Kasperd, Waldemar Greila,b,n a

Sanatorium Kilchberg/Zurich, Private Psychiatric Hospital, Alte Landstr. 70, CH-8802 Kilchberg ZH, Switzerland b Department of Psychiatry and Psychotherapy, Ludwig Maximilian University of Munich, Nussbaumstr. 7, D-80336 Munich, Germany c Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany d Department of Psychiatry and Psychotherapy, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria e University Hospital of Psychiatry, Bolligenstr. 111, CH-3060 Bern, Switzerland Received 19 August 2014; received in revised form 16 February 2015; accepted 31 March 2015

KEYWORDS

Abstract

Borderline personality disorder; Psychotropic drugs; Prescription drugs; Drug safety; Quetiapine; Antidepressants

Patients with borderline personality disorder (BPD) are usually prescribed a variety of psychotropic drugs; however, none is recommended in the guidelines nor has any been approved for this indication. As data on drug prescriptions for BPD are sparse, cross-sectional data from the European Drug Safety Project AMSP were used to analyse drug prescriptions of 2195 in-patients with BPD between 2001 and 2011, and the mean values, confidence intervals and regression analyses were calculated. 70% of all BPD patients were medicated with antipsychotics and/or antidepressants, 33% with anticonvulsants, 30% with benzodiazepines, and 4% with lithium; 90% received at least one, 80% Z2, and 54% Z3 psychotropic drugs concomitantly (mean: 2.8). Prescription rates for quetiapine, the single drug most often used in BPD (22%), increased significantly over time. In view of the high percentage of young females with BPD, 18–40 year-old female patients with BPD were compared with patients of the same age but with depression (unipolar and bipolar) and schizophrenia. Typical sedative antipsychotics and anticonvulsants were prescribed more often in BPD than in the other diagnostic groups,

n Corresponding author at: Department of Psychiatry, Munich University (LMU), Nussbaumstr. 7, D-80336 Munich, Germany. Tel.: + 49 89 4400 55511; fax: + 49 89 4400 54749. E-mail address: [email protected] (W. Greil).

http://dx.doi.org/10.1016/j.euroneuro.2015.03.017 0924-977X/& 2015 Published by Elsevier B.V.

Please cite this article as: Bridler, R., et al., Psychopharmacological treatment of 2195 in-patients with borderline personality disorder: A comparison with other psychiatric disorders. European Neuropsychopharmacology (2015), http://dx.doi.org/10.1016/j.euroneuro.2015.03.017

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R. Bridler et al. with the exception of bipolar depression; this was true for the single substances quetiapine, levomepromazine, chlorprothixene, carbamazepine, and valproate. A limitation of the study was the use of clinical data without verifying the diagnoses by structured interviews. Contrary to the guidelines, about 90% of in-patients with BPD received psychotropic drugs. Polypharmacy was common, and antipsychotics with sedative profiles such as quetiapine and mood-stabilizing anticonvulsants such as valproate appear to be preferred. & 2015 Published by Elsevier B.V.

Introduction Patients with borderline personality disorder (BPD) seem to be routinely prescribed a variety of psychotropic drugs. However, to date no drug has officially been approved for this indication. Intensive research on the effective use of drugs for this indication has yet to be conducted, and the data on prescription patterns for BPD in psychiatric hospitals are sparse. A study by Pascual et al. (2010) reported on drug treatment in 226 BPD out-patients in Spain, showing that more than 90% of patients received psychotropic drugs and that multiple drug use appeared to be common practice. Haw and Stubbs (2011) reported in their study of 79 in-patients in the UK with BPD that 80% received psychotropic drugs and about half were administered two or more different psychotropic substances simultaneously. In a Cochrane analysis, Lieb et al. (2010) and Stoffers et al. (2010) came to the conclusion that there are no promising results available on the efficacy of drugs used to counteract the core BPD symptoms: feelings of emptiness and abandonment as well as identity disturbances. The present study investigated prescription trends of psychotropic drugs for BPD. It aimed to describe the actual treatment practices compared with general recommendations made in reviews, text books, and guidelines: APA (APA, 2001), APA update (APA, 2005), WFSBP (Herpertz et al., 2007), NICE (NICE, 2009) and NHMRC (NHMRC, 2012). It was hypothesised that (1) there are a few specific trends in prescription patterns in BPD due to special requirements, e. g. the avoidance of potentially toxic drugs such as lithium and tricyclic antidepressants (TCAs) and the preference of drugs against agitation; and (2) prescriptions reflect general pharmacotherapeutic trends as the efficacy of drugs in BPD is still controversial. Since actual prescription practice is largely unknown, the prescription rates of psychotropic drugs in 2195 hospitalised patients with BPD were investigated. To identify specific pharmacotherapeutic trends, the prescription rates in BPD were compared with those in-patients with other psychiatric disorders. The analysed data were provided by the European drug surveillance programme AMSP (Arzneimittelsicherheit in der Psychiatrie).

Experimental procedures Data source The current study used prescription data provided by the European Drug Safety in Psychiatry (AMSP) programme. AMSP is an ongoing

international multicenter drug safety programme that has collected data on pharmacotherapy and adverse drug reactions from psychiatric hospitals in a naturalistic setting since 1994. Its methods have been described in detail elsewhere (Engel et al., 2004; Grohmann et al., 2004). Briefly, AMSP has collected data at psychiatric hospitals or psychiatric departments in Germany, Switzerland and Austria, and for a short period of time at a hospital in Belgium and in Hungary. The number of participating hospitals increased from 9 in 1994 to 58 in 2011. In a cross-sectional approach all participating hospitals surveyed psychiatric in-patients on two reference days per year. All drugs administered on these days were recorded along with the patients' age, gender and leading psychiatric diagnosis. Furthermore, severe adverse drug reactions that occurred at these hospitals in association with psychopharmacological treatment were reported and have been collected continuously. This study was based on only a cross-sectional AMSP data set of prescriptions for 88,793 patients surveyed between the years 2001 and 2011.

Study population Within the AMSP data set all patients with a current primary diagnosis of borderline type (F 60.31, BPD) were selected. Secondary diagnoses were not assessed in AMSP during the period 2001– 2011. Drug prescriptions for BPD were also compared with those for other diagnoses. For this part of the study, female patients between 18 and 40 years of age were selected to ensure better comparability. A total of 87.2% (n=1913) of all BPD patients were namely females, and 70.7% (n=1522) of all BPD patients were females between ages 18 and 40. The following groups were selected for comparison: all female patients of the same age group with a diagnosis of depressive episode and recurrent (unipolar) depression, i.e. diagnostic codes ICD 10: F 32–F 33.9, bipolar depression, F 31.3– F 31.5 or schizophrenia, F 20–F 20.99, and all females between 18 and 40 years of age, regardless of their psychiatric diagnoses.

Statistical methods Analyses of group means: The mean frequencies of prescriptions of drug groups and single drugs between 2001 and 2011 for various diagnostic groups and the 95% confidence intervals (CI) were calculated using the Clopper Pearson method, with α=0.05 (Clopper and Pearson, 1934). A statistically significant difference between the prescription rates in the diagnostic groups was defined as non-overlapping confidence intervals of these relative frequencies. A marginal overlap was defined as a statistical trend. If appropriate, mean values of the years 2001–2003 and means of 2009–2011 are given for the assessment of time-related trends. Regression analyses: To analyse the relationship between the relative frequencies of prescriptions of drug classes and of single substances over time, the prescription rates were calculated for each year. Data were plotted over time and the logistic regression was calculated. Linear regression was used for the analysis of the


Psychopharmacological treatment of 2195 in-patients relationship between the numbers of concomitantly used drugs over the specified periods of time. Minor differences in the prescription rates given in Table 1 and in some parts of Results are due to the differences that occurred during the calculation of the mean values for prescriptions for the entire period of time and the mean of the mean values of prescription rates per year, respectively. Permission to use the special data set of BPD and that of the comparison patient groups was given by the publication commission, which was composed of the presidents of the AMSP associations in Germany, Austria and Switzerland. The Ethics Committee at the Ludwig Maximilian University of Munich, where the main AMSP data center is located, approved the analysis of the AMSP data with a waiver of authorisation.

Results Out of a total of 88,793 patients, 2195 (2.5%) had been diagnosed to have BPD. Whereas 54% of the entire patient group were females, the percentage of females was significantly higher within the BPD group (87%). Table 1 shows that 1972 out of 2195 patients (90%) in the BPD group were medicated with psychotropic drugs from 2001 to 2011. About 70% of patients were medicated with antipsychotics and with antidepressants. Overall, 33% received anticonvulsants, 30% tranquilisers, and 16% hypnotics; 30% received the group of benzodiazepines (used as tranquilisers or as hypnotics) as medication. Only 4% of the BPD patients were treated with lithium.

Polypharmacy Polypharmacy, i.e. the concomitant use of two or more psychotropic drugs, was observed in 80% of the patients with BPD; 54% three or more psychotropic drugs. The number of concomitantly prescribed drugs for BPD remained stable between 2001 and 2011 (according to linear regression analyses). On average, patients received about

Table 1

3 three psychotropic drugs simultaneously (mean: 2.8). If nonpsychotropic drugs were included, the number of concomitant drugs rose to about 4 per patient (mean: 4.0). This finding is consistent with the number of drugs administered per patient in the AMSP project in general: a total of 353,796 prescriptions for all 84,860 patients on drug treatment (mean: 4.2 drugs per patient, see Table 1). The “somatic” drugs given to BPD patients were – in the order of their frequency – predominantly gastrointestinal drugs, cardiovascular agents and thyroid hormones.

Prescription rates of psychotropic drugs The prescription rates of drug classes for BPD patients show that between 2001 and 2011 both antidepressants and antipsychotics were prescribed on average at a steady rate of 70.3% and 68.7%, as were anticonvulsants and lithium, at a rate of 31.5% and 4.7%, respectively. In contrast, the use of hypnotics significantly decreased from 21.4% (mean 2001– 2003) to 14.6% (mean 2009–2011). Tranquilisers also showed a decreasing statistical trend from 34.1% (mean 2001–2003) to 25.8% (mean 2009–2011) (significant changes calculated using logistic regression analyses) (see Complementary Figure i). The prescription rate of atypical antipsychotics (second generation antipsychotics) increased from 36.3% to 47.6% (means: 2001–2003 and 2009–2011); this is statistically significant according to logistic regression analysis. The prescription rate of typical high potency and typical sedative low potency antipsychotics (first generation antipsychotics) decreased from 19.0% to 10.8% and from 37.5% to 29.8%, respectively. Figure 1 shows the prescription rates of single antipsychotic substances for BPD patients. Prescription rates of quetiapine (22%; mean 2001–2011) increased significantly from 7.5% (mean 2001–2003) to 32.9% (mean 2009–2011) as did that of aripiprazole (mean 2009–2011: 5.8%; 2011: 7.2%). Prescription rates of olanzapine decreased significantly from 13.3% (mean

Patients with the diagnosis BPD and drug prescriptions. Number of patients

Psychiatric diagnoses All patientsc Borderline type (BPD) F 60.31 Psychotropic drugs (F 60.31) Antidepressants Antipsychotics Anticonvulsants Tranquilizerse Hypnoticse Lithium

Medicateda 84,860 (83,084) 2035 (1972) Medicated 1424 1406 662 602 332 87

Prescriptions All 88,793 2195 %d 70.0 69.1 32.5 29.6 16.3 4.3

Number of prescriptionsb 353,796 8088 Number of prescriptionsb 1709 2070 722 650 344 87

Number of patients in the time period 2001–2011 with the diagnosis of Borderline Personality Disorder (BPD, Borderline Type, F 60.31) and prescription rates. a Number of patients medicated, in brackets: medicated with psychotropic drugs. b Number of prescriptions exceeds the number of patients per group due to polypharmacy. c All patients including all diagnoses in the AMSP project (2001–2011). e Benzodiazepines (tranquilisers or hypnotics): 606 patients (29.9%), 682 prescriptions. d Rates of prescriptions (%) defined as the number of patients receiving a particular drug over the number of all patients.


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Figure 1 Prescription rates of atypical antipsychotics for patients with BPD diagnosis F 60.31. Percentages of patients receiving the drugs are shown. Logistic regression models show that prescriptions of quetiapine increase significantly with y =0.2x 350.5; χ2 (1,10)= 83.9; po0.01 as well as the prescriptions of aripiprazole: y =0.2x 428.5; χ2 (1,10) =24.6; po0.01. Prescriptions of olanzapine decrease significantly with: y = 0.16x+308.4; χ2 (1,10) =20.9; po0.01 as well as the prescriptions of amisulpride with y = 0.2x +340.3; χ2 (1,10) =11.7; po0.01.

2001–2003) to 3.6% (mean 2009–2011). Risperidone stayed at a constant rate of 5.4% during the entire time period. Amisulpride use decreased from 5.4% (mean 2001–2003) to 1.1% (mean 2009–2011) and a similar but not statistically significant result was found for clozapine (mean 2.3%) (all statistical analyses according to logistic regression). Interestingly, single sedative low potency typical antipsychotics were quite commonly prescribed (not shown in Figure 1): levomepromazine was administered on average in 6.3% of the patients, chlorprothixene in 12.1% and promethazine in 7.1% during the entire time period; pipamperone and melperone remained at a stable rate of 4.1% and 3.0%, respectively. The high potency typical antipsychotics, haloperidol (3.3%), zuclopenthixol (2.1%) and flupentixol (1.4%) were administered at relatively low but steady rates. The prescription rates of perazine (mean: 5.2%, not shown) decreased significantly from 7.1% (mean 2001–2003) to 4.0% (mean 2009–2011). The prescription rate of antidepressants for BPD (see also Table 1) remained rather steady at 70.3%. The most frequently prescribed antidepressants were SSRIs (selective serotonin reuptake inhibitors), which were given to 39.2% of the patients at a stable rate between 2001 and 2011. In contrast, the prescriptions of tricyclic antidepressants decreased significantly from 17.2% to 10.1% (means of 2001–2003 and 2009–2011), whereas prescriptions of SNRIs (serotonin and norepinephrine reuptake inhibitors) increased significantly from 6.6% to 18.2% (means of 2001– 2003 and 2009–2011), as did the prescription rates of the drug class “other antidepressants” – i.e. trazodone (mean 2.8%), bupropion (mean 0.7%), reboxetine (mean 1.5%), nefazodone, agomelatine and mianserine – from 3.0% up to 10.5% (statistical results based on logistic regression). Prescription rates of single substances within the group of antidepressant drugs, e.g. trimipramine (mean 5.3%), paroxetine (mean 5.8%) and fluoxetine (mean 7.0%), decreased

within the period 2001–2011. Prescriptions of escitalopram (mean 11.2%), citalopram (mean 10.2%) and trazodone (mean 4.2%) increased (means of 2009–2011 are given). Other substances such as doxepin (mean 2.7%), amitriptyline (mean 3.3%), sertraline (mean 7.2%), mirtazapine (mean 10.6%) and venlafaxine (mean 13.1%) were administered at stable rates.

Prescription rates in diagnostic groups To compare prescriptions for BPD with those for other diagnoses, female patients aged 18 to 40 were selected, because a majority of BPD patients (71%) were females in this age range (see Methods). Table 2 presents the prescription patterns for the various diagnoses: BPD (F 60.31, n= 1552), depression (unipolar, n = 3999), depression (bipolar, n= 241), schizophrenia (n =3679) and an overall (all diagnoses) comparison group ( n = 16,115) between 2001 and 2011. Table 2 shows that patients with BPD were younger than patients with other diagnoses: 31% of all female BPD patients were between 21 and 25 years of age (Table 2). There were statistically significant differences (marked with arrows) in the prescription rates for BPD compared with those made for other diagnoses or with those for all female patients between 18–40 years of age (see Table 2). The frequency of antipsychotic prescriptions was higher in the BPD patients than in patients with unipolar depression (64% vs 43%) but equivalent in bipolar depression and the overall group (62% and 64%, respectively). Antipsychotics were prescribed to patients with schizophrenia at a much higher rate (97%). Within the group of antipsychotics, especially atypical antipsychotics (second generation antipsychotics) were administered to BPD patients (42%), followed by typical sedatives (31%,


Psychopharmacological treatment of 2195 in-patients

Table 2

5

Prescription rates in female patients aged 18 to 40 with different psychiatric diagnoses.

N 18–20 21–25 26–30 31–35 36–40 Antipsychotics

Atypicals

Quetiapine

Olanzapine

Risperidone

Sedatives, typical

Levomepromazine

Chlorprothixene

Antidepressants

SSRI

SNRI

Anticonvulsants

Carbamazepine

Lamotrigine

BPD

Depression (unipolar)

Depression (bipolar)

Schizophrenia

Overall

1552 257 17% 474 31% 339 22% 254 16% 228 14% 986 63%

3999 282 6% 669 18% 807 20% 970 24% 1271 32% 1704 43%

241 7 3% 37 15% 38 16% 65 27% 94 39% 150 62%

16,115 1391 9% 3177 20% 3370 21% 3608 22% 4569 28% 10,348 64%

61–66%

41–44%

56–68%

3679 176 5% 654 18% 838 23% 909 25% 1102 30% 3560 97% 96–97%

656 42%

1148 29%

120 50%

3087

7981

40–45% 366 24% 22–26%

27–30% 537 13% 12–15%

43–56% 66 27% 22–33%

84% 83–85% 712 19% 18–20.67%

50% 49–51% 2811 17% 17–18%

79 5%

274 7%

26

731

1874

4–6% 94 6%

6–8% 164 4%

11% 7–15% 13 5%

20% 19–21% 769 21%

12% 11–12% 1627 10%

5–7% 486 31% 29–34% 104 7% 6–8% 150 10% 8–11% 1007 65%

4–5% 687 17% 16–18% 48 1% 1–2% 160 4% 3–5% 3461 87%

3–9% 10 4% 2–7% 4 2% 0–4% 7 3% 1–6% 196 81%

20–22% 676 18% 17–20% 103 3% 2–3% 187 5% 4–6% 667 18%

10–11% 3191 20% 19–20% 453 2.8% 2.6–3.1% 879 6% 5–6% 8600 53%

63–67% 587 38% 35–40% 207 13%

86–88% 1607 40% 39–42% 972 24.3%

76–86% 90 37% 31–44% 64 27%

17–19% 403 11% 10–12% 90 2.5%

53–54% 4468 28% 27–28% 1898 11.8%

12–15% 446 29%

23–26% 567 14%

21–32% 127 53%

2–3% 552 15%

11–12% 3415 21%

27–31% 88 6% 5–7% 70 5%

13–15% 93 2.3% 1.9–2.9% 152 3.8%

46–59% 15 6% 4–10% 48

14–16% 86 2.3% 1.8–2.9% 49 1%

21–22% 643 4% 3,7–4.3% 551 3.4%

4–7%

3.2–4.4%

1–2%

3.1–3.7%

20% 15–26%

64–65%


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R. Bridler et al. Table 2 (continued )

Valproic acid

BPD

Depression (unipolar)

Depression (bipolar)

Schizophrenia

Overall

208 13%

180 5%

64 27%

360 10%

1631 10%

12–15%

4–6%

21–33%

9–11%

10–11%

Patients with BPD, unipolar depression, bipolar depression, schizophrenia and an overall (all diagnoses) comparison group in the time period from 2001 to 2011. The number of patients is listed, as well as mean prescription rates and their 95% Confidence Intervals (CIs). Significant differences between diagnoses groups are marked with arrows.

Table 2). The difference in prescription rates of these two subclasses of antipsychotics is statistically significant (see the CIs in Table 2). Table 2 illustrates that second generation antipsychotics were prescribed less frequently to patients with BPD (42%) than to patients with schizophrenia (84%) and the entire patient group (50%), but more frequently than to patients with depression (29%). The data for bipolar depression (50%) are comparable to the data for BPD. The single substance quetiapine was used more frequently in patients with BPD (24%) than in unipolar depression (13%), schizophrenia (19%) and the overall patient group (17%), but its use in bipolar depression was comparable (27%). Quetiapine was the most preferred single drug prescribed for patients with BPD (see also Figure 1). In contrast, olanzapine was prescribed less frequently for BPD (5%) than for bipolar depression (11%), schizophrenia (20%) and the overall comparison group (12%). Within the subgroup of typical sedatives, the prescription rates of levomepromazine and chlorprothixene were significant in BPD patients (7% and 10%, respectively). These substances as well as sedative antipsychotics in general were prescribed more frequently in patients with BPD (31%) than in unipolar depression (17%), bipolar depression (4%), schizophrenia (18%) and the overall group (20%). The prescription rates for these substances were similar for BPD in the countries and hospitals participating in the programme. The results suggest that levomepromazine and chlorprothixene as well as typical sedative antipsychotics in general may be considered as preferred drugs for BPD. On the other hand, the prescriptions of typical sedative antipsychotics in BPD patients slightly decreased between 2008 and 2011 (see Complementary Figure ii). Antidepressants were administered more frequently to BPD patients (65%) than to patients with schizophrenia (18%) or the overall patient population group (53%). As expected, patients with unipolar as well as bipolar depression received antidepressants more frequently (87% and 81%). The prescription rates of antidepressants for all analysed diagnoses remained steady during the investigated period. Among antidepressants, SSRIs were prescribed significantly more often for BPD (38%) than for schizophrenia (11%) or for the overall patient population group (28%, Table 2). There was no statistically significant difference in the prescription rate of SSRIs between BPD patients and patients with uni- or bipolar depression (40% and 37%). In contrast, SNRIs were prescribed less frequently in BPD patients (13%) than in patients with depression (24% and 27%, Table 2). The prescription rates for SSRIs remained stable for all diagnoses during the investigated period, whereas those for SNRIs in BPD, depression and the

overall patient population group steadily increased between 2001 and 2011. Anticonvulsants were prescribed significantly more often for BPD (29%) than for unipolar depression (14%), schizophrenia (15%) or the overall patient population group (21%). The prescription rates remained more or less constant for all the investigated diagnoses during the study period. Bipolar patients had the highest rates (53%). Within the class of anticonvulsants (Table 2) carbamazepine and valproic acid were prescribed significantly more often (6% and 13%) for BPD than for the other groups, with the exception of bipolar depression. BPD patients (5%) took lamotrigine significantly more often than patients with schizophrenia (1%) and as often as did patients of the other comparison groups, with the exception of bipolar depression, which had the highest rates (27%). These results indicate that that carbamazepine and valproic acid are apparently popular drugs for treating BPD patients. In summary, the following classes of drugs were prescribed significantly more often for BPD than for unipolar depression and schizophrenia: sedative typical low potency antipsychotics and anticonvulsants, and the single substances quetiapine, levomepromazine, chlorprothixene, carbamazepine and valproate. The prescription rates for BPD were most similar to those for bipolar depression. The median doses of these substances in BPD were similar to the median doses in the overall patient population group: 300 vs 400 mg/d for quetiapine, 100 vs 100 mg/d for levomepromazine, 100 vs 80 mg/d for chlorprothixene, 600 vs 600 mg/d for carbamazepine and 1200 vs 1200 mg/d for valproate, respectively.

Discussion This study found that 2.5% of the 88,793 patients hospitalised between 2001 and 2011 had been diagnosed to have BPD (see Table 1). Since only patients with a primary diagnosis of BPD were included the value is lower than the prevalence rates in some other in-patient populations (5– 10%, Leontieva and Gregory, 2013). The percentage of BPD diagnoses was noticeably higher in the group of female patients aged 18–40 (9.6%), reaching even 15% of females between the ages 21–25 (calculated from Table 2). Hence, the treatment of patients with BPD is quite relevant, not only to institutions highly specialised in personality disorders, but to psychiatric hospitals in general. Overall, the diagnosis of BPD was made considerably more often in females (87%); this is in agreement with current


Psychopharmacological treatment of 2195 in-patients published data: 84%, 86% and 80%, respectively (Haw and Stubbs, 2011; Pascual et al., 2010; Zanarini et al., 2001). A comparison of our data with the current recommendations of treatment guidelines (APA, 2001, 2005; Herpertz et al., 2007; NHMRC, 2012; NICE, 2009) revealed remarkably high percentage rates of drug treatment and polypharmacy. All guidelines primarily recommend psychotherapy as treatment, since a spate of evidence supports its efficacy in BPD. In contrast, there is either only minimal or moderate research-based evidence for the use of drugs in BPD or the recommendations for drugs are described as solely concensus-based and lacking good quality evidence. Proposals to use drugs together with psychological interventions have restricted them to adjunctive therapy (NHMRC, 2012) that is performed for only a short period of time (NICE, 2009) and is targeted to symptoms (Herpertz et al., 2007) or syndromes (APA, 2001, 2005), respectively. In our study population, only 10% of 2195 hospitalised BPD patients were not on psychotropic drugs. This is comparable to 6% in the out-patient population of the Spanish study (Pascual et al., 2010). In contrast, a distinctly higher proportion of patients were treated without psychotropic drugs (16 out of 79 BPD patients, i.e. 20%) in the British in-patient population (Haw and Stubbs, 2011). Polypharmacy with at least two psychotropic drugs was observed in 80% of the BPD patients of this study (83% in the Spanish data). Three or more psychiatric drugs were administered to 54% of BPD patients in our study, compared to 57% in the study of Pascual et al. (2010). Again, the treatment of the British patients (Haw and Stubbs, 2011) appeared to be more evidence-based: polypharmacy occurred in only 58% (Ztwo drugs) and 27% (Zthree drugs) of these patients. We found that a mean of 2.8 psychotropic drugs per patient was prescribed concomitantly, and a total of 4.0 drugs per patient, if non-psychotropic drugs were included in the analysis as well. These results are again similar to the out-patient data from Spain (Pascual et al., 2010) who calculated a mean of 2.7 psychotropic drugs. Moreover, intensive polypharmacy was also found in the AMSP project for patients with bipolar depression (Greil et al., 2012; Haeberle et al., 2012) and for all patients (Haueis et al., 2011). Comparison of the prescription rates of psychotropic drug classes and of single drugs found in this study with the results in other studies reveals largely agreement, but also some major discrepancies. For example, there were distinct differences in the use of benzodiazepines: 74% (Pascual et al., 2010) and 6% (Haw and Stubbs, 2011) in the Spanish and the British population, respectively. The data of our study showed that benzodiazepines were administered to 30% of the patients, an approximately intermediate value compared with those found in the other studies. The use of benzodiazepines has been strongly discouraged in patients with BPD due to increased disinhibition and suicidality (Gardner and Cowdry, 1985; Ripoll, 2012). Hence, the low rate of benzodiazepine use in the British population (Haw and Stubbs, 2011) appears to reflect an adherence to general treatment recommendations. Particularly noteworthy was the frequent use of typical antipsychotics with sedative properties such as levomepromazine and chlorprothixene, a prescription pattern that had not been described before. This class of drugs was prescribed

7 significantly more often to BPD patients (31% of the female patients aged 18 to 40 years) than to patients with unipolar or bipolar depression, schizophrenia, or the overall patient group. To the best of our knowledge, there is no published data available on the efficacy of levomepromazine for BPD. Reduced sleep problems may possibly be associated with its use, as patients with post-traumatic stress disorder receiving the drug reported this beneficial effect (Aukst-Margetic et al., 2004). The most frequently prescribed single drug substance in BPD patients in our study was quetiapine; its incidence rate was 22% (2001–2011) and 33% (2009–2011), respectively. In contrast, Haw and Stubbs (2011) reported only a 9% use of quetiapine (7 out of 79 patients). They described clozapine as “the only drug that works” in BPD (Haw and Stubbs, 2011); it caused “a major improvement in target symptoms” and was the most frequently prescribed drug (38%). In our study the prescription rate of clozapine was only 2%. Both quetiapine and clozapine may be preferred for their sedating properties and low propensity to induce extrapyramidal adverse effects. According to a Cochrane review, their use in BPD is based only on lower-level evidence studies (Lieb et al., 2010; Stoffers et al., 2010). Several open-label studies on quetiapine have reported positive effects on BPD (Belli et al., 2012; Bellino et al., 2006), and a recent 8-week placebo controlled study found less severe symptoms in BPD patients treated with an extended-release quetiapine formulation (Black et al., 2014). The frequent use of clozapine and quetiapine in a population of predominantly young women as in ours and the British study is of particular concern, especially since there is a high risk of weight gain and development of metabolic syndromes associated with use of either substance (Kahl et al., 2013). Moreover, regular blood cell monitoring is required during the administration of clozapine (Ferreri et al., 2004). Anticonvulsants as a group, as well as valproic acid and carbamazepine as single substances, were prescribed significantly more often in the BPD population than in the other investigated patient groups, with the exception of bipolar depression. Valproate was the most frequently used anticonvulsant in the British study (Haw and Stubbs, 2011), as well as in our study, in which 13% of the young female patients between ages 18 and 40 had been prescribed valproic acid. This finding is very important since valproic acid should generally not be prescribed to women of childbearing age. On the other hand, beneficial effects of moodstabilising anticonvulsants in BPD have been reported (Ingenhoven et al., 2010; Lieb et al., 2010; Stoffers et al., 2010), particularly for valproate semisodium (Hollander et al., 2005), lamotrigine (Leiberich et al., 2008; Tritt et al., 2005) and topiramate (Loew et al., 2006; Varghese et al., 2010), but not for carbamazepine (de la Fuente and Lotstra, 1994). Only 4% of BPD patients received lithium, although two earlier placebo-controlled studies had reported its efficacy (Links, 1990; Rifkin et al., 1972). High prescription rates of antidepressants (about 70%) were reported in previous studies (Haw and Stubbs, 2011; Pascual et al., 2010). SSRIs (in about 40% of all BPD patients) were the most commonly prescribed subclass of antidepressants, and were given to patients with BPD more frequently than to the overall group of patients and equally often to patients with depression (uni- and bipolar). On the other


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hand, statistically the prescription rate of SNRIs for BPD was significantly lower than for depression (see Table 2). Only marginal data are currently available on the efficacy of the SNRIs venlafaxine and duloxetine in the treatment of BPD (Bellino et al., 2010; Markovitz and Wagner, 1995). In our study the SNRI venlafaxine (13% of all BPD patients) was the most frequently prescribed antidepressant between 2009 and 2011, followed by escitalopram (11%), mirtazapine and citalopram (both 10%). A recently published paper with questionnaire-based data (Knappich et al., 2014) on treatment preferences of German psychiatrists reported that the most frequently named antidepressants in the treatment of BPD in 2010 were the SSRIs escitalopram and citalopram. Interestingly, SNRIs were also mentioned as a treatment option by about 40% of the 141 surveyed psychiatrists. According to a Cochrane review, however, there is no evidence of effectiveness of any SSRI (Lieb et al., 2010). Hence, these authors recommended SSRIs only if the patient was experiencing a major depressive episode or another comorbid condition requiring treatment with antidepressants. Prescriping atypical antipsychotics increasingly and tricyclic antidepressants decreasingly over time as observed in this study reflects general trends in psychopharmacotherapy and has been described for depression also (Greil et al., 2012; Haeberle et al., 2012). The high prescription rates of atypical antipsychotics and of anticonvulsants found in our study correspond to the results of the Cochrane analysis, which determined some beneficial effects of SGAs (second generation antipsychotics) and mood stabilisers. However, to date there is only limited evidence supporting the frequent use of antidepressants (Stoffers et al., 2010). Similarly, Vita et al. (2011) conclude in their metaanalysis that treatment with mood stabilisers and antipsychotics may be effective for treating affective dysregulation and impulsive-behavioural dyscontrol. Antipsychotics were effective in reducing cognitive-perceptual symptoms. In contrast, antidepressants did not show any efficacy in treating BPD symptoms other than affective dysregulation. The major use of antidepressants observed in our study clearly contradicts the common recommendations. Limitations: Our study reported only on prescription rates in hospitalised patients. However, a comparison of our data set with the out-patient data from Spain (Pascual et al., 2010) revealed a pronounced similarity of the results, especially in terms of polypharmacy and the frequent use of psychotropic drugs. Thus, the recorded data may possibly also be similar in out-patient settings. Moreover, a substantial percentage of BPD out-patients were hospitalised at least once for psychiatric reasons (Zanarini et al., 2001) and continued their medications after discharge. A second limitation of our study is that the diagnoses were based on the records of clinicians and not further verified by structured interviews. Third, although comorbid conditions are very relevant in BPD (Zimmerman et al., 2013; Zimmerman and Morgan, 2013), e.g. depression as well as the various subsyndromes of BPD (APA, 2001; Vita et al., 2011), they are not covered in our data base. Since patients with prevailing symptoms of axis I diagnoses were not included, but only patients with a primary diagnosis of BPD, comorbidity may be less relevant than in other studies. Nevertheless, it is not clear, for what purpose the psychotropic drugs were prescribed. Finally, the duration of drug treatment and its effectiveness remained unknown.

Conclusion In the absence of evidence and specific recommendations in the current guidelines, clinicians have been making their treatment choices on the basis of the individual circumstances of each patient. Antipsychotic drugs with sedative profiles like quetiapine or mood-stabilising drugs like valproic acid are preferably used. SSRIs have also played an important role due to their efficacy in relieving depressive and affective dysregulation. In contrast, drugs such as lithium, which can be toxic if given in overdoses, is being avoided. To this day, any type of drug treatment used for BPD is off-label, and no drug has yet been officially approved for this indication. Treatment guidelines for BPD must include specific drug treatment recommendations based on robust evidence. Further clinical studies will still need to be conducted before this objective is achieved.

Role of funding source This study was supported by an unrestricted grant to René Bridler from the Swiss Society of Drug Safety in Psychiatry (SGAMSP). The AMSP Drug Safety Program is based on non-profit associations in the German-speaking countries Germany, Austria and Switzerland. During the last decades, almost all pharmaceutical companies involved in CNS research contributed financial support. Since 1993 educational and research grants have been given by the following pharmaceutical companies to the three local non-profit associations of the AMSP. Austrian companies: AESCA Pharma GmbH, AstraZeneca Österreich GmbH, Boehringer Ingelheim Austria, Bristol-Myers Squibb GmbH, CSC Pharmaceuticals GmbH, Eli Lilly GmbH, Germania Pharma GmbH, GlaxoSmithKline Pharma GmbH, Janssen-Cilag Pharma GmbH, Lundbeck GmbH, Novartis Pharma GmbH, Pfizer Med Inform, Servier Austria GmbH, Wyeth Lederle Pharma GmbH. German companies: Abbott GmbH & Co. KG, AstraZeneca GmbH, Aventis Pharma Deutschland GmbH GE-O/R/N, Bayer Vital GmbH & Co. KG, Boehringer Mannheim GmbH, Bristol-Myers-Squibb, Ciba Geigy GmbH, Desitin Arzneimittel GmbH, Duphar Pharma GmbH & Co. KG, Eisai GmbH, esparma GmbH Arzneimittel, GlaxoSmithKline Pharma GmbH & Co. KG, Hoffmann-La Roche AG Medical Affairs, Janssen-Cilag GmbH, Janssen Research Foundation, Knoll Deutschland GmbH, Lilly Deutschland GmbH Niederlassung Bad Homburg, Lundbeck GmbH & Co. KG, Novartis Pharma GmbH, Nordmark Arzneimittel GmbH, Organon GmbH, Otsuka-Pharma Frankfurt, Pfizer GmbH, Pharmacia & Upjohn GmbH, Promonta Lundbeck Arzneimittel, Rhone-Poulenc Rohrer, Sanofi-Synthelabo GmbH, Sanofi-Aventis Deutschland, Schering AG, SmithKlineBeecham Pharma GmbH, Solvay Arzneimittel GmbH, Synthelabo Arzneimittel GmbH, Dr Wilmar Schwabe GmbH & Co., Thiemann Arzneimittel GmbH, Troponwerke GmbH & Co. KG, Upjohn GmbH, Wander Pharma GmbH, Wyeth-Pharma GmbH. Swiss companies: AHP (Schweiz) AG, AstraZeneca AG, BristolMyers Squibb AG, Desitin Pharma GmbH, Eli Lilly (Suisse) S.A., Essex Chemie AG, GlaxoSmithKline AG, Janssen-Cilag AG, Lundbeck (Suisse) AG, Mepha Schweiz AG/Teva, MSD Merck Sharp & Dohme AG, Organon AG, Pfizer AG, Pharmacia, Sandoz Pharmaceuticals AG, Sanofi-Aventis (Suisse) S.A., Sanofi-Synthe´labo SA, Servier SA, SmithKlineBeecham AG, Solvay Pharma AG, Vifor SA, Wyeth AHP (Suisse) AG, Wyeth Pharmaceuticals AG. Almost all pharmaceutical companies involved in CNS research contribute financial support to the three associations, but they have no influence on the publication


Psychopharmacological treatment of 2195 in-patients

Contributions RB initiated the study, supported the development of the study concept and revised various versions of the manuscript. AH extracted the data from the AMSP data pool, performed the statistical analyses and checked various versions of the manuscript. STM supported the performance of the statistical analyses and revised various versions of the manuscript. KC supported the development of the study concept and revised various versions of the manuscript. RG and ST, as the project coordinators of AMSP, counselled the analyses and the interpretation of the data and revised the final version of the manuscript. SK supported the study concept, data acquisition and their interpretation and reviewed the manuscript critically. WG developed the concept and revised the various versions of the manuscript. All authors contributed to and approved the final manuscript.

Conflict of interest R. Bridler received a speaker's fee from Servier and unrestricted educational grants from Janssen and MSD. A. Häberle and S.T. Müller have no competing interests. K. Cattapan was a member of the advisory boards of Janssen and Lundbeck, and received a speaker's fee from Servier. R. Grohmann and S. Toto are both in the project management of AMSP. RG received a speaker's fee from Pfizer. S. Kasper received grant/research support from Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Lundbeck, Organon, Sepracor and Servier; Furthermore, he has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Lundbeck, Merck Sharp and Dome (MSD), Novartis, Organon, Pfizer, Schwabe, Sepracor, and Servier; and has served on speakers' bureaux for Angelini, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, Pfizer, Pierre Fabre, Schwabe, Sepracor, Wyeth and Servier. W. Greil has been a member of an advisory board for Lundbeck and has received speaker's fees from AstraZeneca, Lundbeck and the Lundbeck Institute.

Acknowledgements The authors would like to thank all hospitals and staff that participate in the AMSP project for contributing to the data collection. We also thank Ms. Christel Apfelbaum for assisting with the literature searches and for proof-reading the manuscript as well as Judy Benson for copyediting the manuscript.

Appendix A.

Supporting information

Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/ j.euroneuro.2015.03.017.

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