Controversies regarding lithium-associated weight gain: case-control study of real-world drug safety data.

BACKGROUND: The impact of long-term lithium treatment on weight gain has been a controversial topic with conflicting evidence. We aim to assess reporting of weight gain associated with lithium and other mood stabilizers compared to lamotrigine which is considered free of metabolic adverse drug reactions (ADRs). METHODS: We conducted a case/non-case pharmacovigilance study using data from the AMSP project (German: "Arzneimittelsicherheit in der Psychiatrie"; i.e., Drug Safety in Psychiatry), which collects data on ADRs from patients treated in psychiatric hospitals in Germany, Austria, and Switzerland. We performed a disproportionality analysis of reports of weight gain (> 10% of baseline body weight) calculating reporting odds ratio (ROR). We compared aripiprazole, carbamazepine, lithium, olanzapine, quetiapine, risperidone, and valproate to lamotrigine. Additional analyses related to different mood stabilizers as reference medication were performed. We also assessed sex and age distributions of weight-gain reports. RESULTS: We identified a total of 527 cases of severe drug-induced weight gain representing 7.4% of all severe ADRs. The ROR for lithium was 2.1 (95%CI 0.9-5.1, p > 0.05), which did not reach statistical significance. Statistically significant disproportionate reporting of weight gain was reported for olanzapine (ROR: 11.5, 95%CI 4.7-28.3, p < 0.001), quetiapine (ROR: 3.4, 95%CI 1.3-8.4, p < 0.01), and valproate (ROR: 2.4, 95%CI 1.1-5.0, p = 0.03) compared to lamotrigine. Severe weight gain was more prevalent in non-elderly (< 65 years) than in elderly patients, with an ROR of 7.6 (p < 0.01) in those treated with lithium, and an ROR of 14.7 (p < 0.01) in those not treated with lithium. CONCLUSIONS: Our findings suggest that lithium is associated with more reports of severe weight gain than lamotrigine, although this difference did not reach statistical significance. However, lithium use led to fewer reports of severe weight gain than some alternative drugs for long-term medication (olanzapine, quetiapine, and valproate), which is consistent with recent studies. Monitoring of weight gain and metabolic parameters remains essential with lithium and its alternatives.

Dear Doctor Letters regarding citalopram and escitalopram: guidelines vs real-world data.

Dear Doctor Letters (DDLs, Direct Healthcare Professional Communications) from 2011 provided guidance regarding QTc-prolonging effects with risk of torsade de pointes during treatment with citalopram and escitalopram. This study examines the DDLs' effects on prescription behavior. Data from 8842 inpatients treated with citalopram or escitalopram with a primary diagnosis of major depressive disorder (MDD) were derived from a European pharmacovigilance study (Arzneimittelsicherheit in der Psychiatrie, AMSP) from 2001 to 2017. It was examined to what extent new maximum doses were adhered to and newly contraindicated combinations with QTc-prolonging drugs were avoided. In addition, the prescriptions of psychotropic drugs before and after DDLs were compared in all 43,480 inpatients with MDD in the data set. The proportion of patients dosed above the new limit decreased from 8 to 1% in patients ≤ 65 years and from 46 to 23% in patients > 65 years old for citalopram versus 14-5% and 47-31% for escitalopram. Combinations of es-/citalopram with other QTc-prolonging psychotropic drugs reduced only insignificantly (from 35.9 to 30.9%). However, the proportion of patients with doses of quetiapine > 150 mg/day substantially decreased within the combinations of quetiapine and es-/citalopram (from 53 to 35%). After the DDLs, prescription of citalopram decreased and of sertraline increased. The DDLs' recommendations were not entirely adhered to, particularly in the elderly and concerning combination treatments. This might partly be due to therapeutic requirements of the included population. Official warnings should consider clinical needs.

[Effect of the direct healthcare professional communication on citalopram and escitalopram drug utilization for inpatient treatment of anxiety disorders]. / Effekt der Rote-Hand-Briefe zu Citalopram und Escitalopram auf Verordnungszahlen bei der stationären Behandlung von Angsterkrankungen.

BACKGROUND: In 2011, direct healthcare professional communication (DHPC) letters on citalopram and escitalopram were sent out to address the risk of QTc prolongation in the ECG. Healthcare professionals were informed about a reduction of the maximum recommended daily dose. Furthermore, a contraindication for QTc-prolonging co-medication was given. Previous studies noted that these instructions were implemented incompletely. AIM: For the first time, this study analyzed how the DHPC affected the prescription of citalopram and escitalopram in patients with anxiety disorders. METHODS: Drug utilization data from the project "Arzneimittelsicherheit in der Psychiatrie e. V." (AMSP) was used to examine whether the proportion of patients treated with a higher-than-recommended daily dose ("high dose") and the proportion of patients with QTc-prolonging co-medication would decrease post-DHPC (combined category of citalopram/escitalopram). RESULTS: Drug utilization data of n = 364 patients pre- and n = 262 patients post-DHPC were compared. The proportion of patients with high dose declined from 10.7% to 5.4% (p = 0.019). The proportion of patients with QTc-prolonging co-medication did not change significantly from pre- (54.7%) to post-DHPC (51.5%, p = 0.437). DISCUSSION: In accordance with previous studies, the proportion of high-dose patients decreased after DHPC publication while the proportion of patients with QTc-prolonging co-medication remained widely unchanged. The specific recommendation on daily dosage seems to have been better implemented than the broadly formulated contraindication of QTc-prolonging co-medication. Hence, DHPCs should be written precisely and give advice for specific clinical situations.

Pharmacological treatment of major depressive disorder according to severity in psychiatric inpatients: results from the AMSP pharmacovigilance program from 2001-2017.

The International Classification of Diseases (10th Version) categorizes major depressive disorder (MDD) according to severity. Guidelines provide recommendations for the treatment of MDD according to severity. Aim of this study was to assess real-life utilization of psychotropic drugs based on severity of MDD in psychiatric inpatients. Drug utilization data from the program "Drug Safety in Psychiatry" (German: Arzneimittelsicherheit in der Psychiatrie, AMSP) were analyzed according to the severity of MDD. From 2001 to 2017, 43,868 psychiatric inpatients with MDD were treated in participating hospitals. Most patients were treated with ≥ 1 antidepressant drug (ADD; 85.8% of patients with moderate MDD, 89.8% of patients with severe MDD, and 87.9% of patients with psychotic MDD). More severely depressed patients were more often treated with selective serotonin-norepinephrine reuptake inhibitors and mirtazapine and less often with selective serotonin reuptake inhibitors (p < 0.001 each). Use of antipsychotic drugs (APDs), especially second-generation APDs, increased significantly with severity (37.0%, 47.9%, 84.1%; p < 0.001 each). APD + ADD was the most used combination (32.8%, 43.6%, 74.4%), followed by two ADDs (26.3%, 29.3%, 24.9%). Use of lithium was minimal (3.3%, 6.1% ,7.1%). The number of psychotropic drugs increased with severity of MDD-patients with psychotic MDD had the highest utilization of psychotropic drugs (93.4%, 96.5%, 98.7%; p < 0.001). ADD monotherapy was observed to a lesser extent, even in patients with non-severe MDD (23.2%, 17.1%, 4.4%). Findings reveal substantial discrepancies between guideline recommendations and real-life drug utilization, indicating that guidelines may insufficiently consider clinical needs within the psychiatric inpatient setting.

Treatment of depression: Are psychotropic drugs appropriately dosed in women and in the elderly? Dosages of psychotropic drugs by sex and age in routine clinical practice.

BACKGROUND: Several researchers have shown higher concentration-dose ratios of psychotropic drugs in women and the elderly. Therefore, lower dosages of psychotropic drugs may be recommended in women and the elderly. This study describes sex- and age-related dosage of psychotropic drugs prescribed to patients with major depressive disorder (MDD) in routine clinical practice. METHOD: Influence of sex and age on dosages are analysed for the 10 most commonly prescribed drugs in our dataset consisting of 32,082 inpatients with MDD. Data stems from the European drug safety program "Arzneimittelsicherheit in der Psychiatrie". The observed sex and age differences in prescriptions are compared to differences described in literature on age- and gender-related pharmacokinetics. RESULTS: Among patients over 65 years, a statistically significant decrease in dosages with increasing age (between 0.65% and 2.83% for each increasing year of age) was observed, except for zopiclone. However, only slight or no influence of sex-related adjustment of dosage in prescriptions was found. CONCLUSION: Age appears to influence adjustment of dosage in most psychotropic drugs, but to a lower extent than data on age-related pharmacokinetics suggests. Although literature also suggests that lower dosages of psychotropic drugs may be appropriate for females, this study found women are usually prescribed the same dosage as men.

Sex differences in pharmacological treatment of major depressive disorder: results from the AMSP pharmacovigilance program from 2001 to 2017.

Data on drug prescription for outpatients with major depressive disorder (MDD) suggest women are more likely to be treated with psychotropic drugs, while data on sex differences regarding pharmacological treatment of psychiatric inpatients are currently not available. Drug utilization data from the program "Drug Safety in Psychiatry" (German: Arzneimittelsicherheit in der Psychiatrie, AMSP) of 44,418 psychiatric inpatients with MDD were analyzed for sex differences between 2001 and 2017. Sex differences were analyzed using relative risks (RR) and 95% confidence intervals (95% CI). Time trends were analyzed by comparing the first (2001-2003) with the last time period (2015-2017). In general, men and women were equally likely to use psychotropic drugs. Monotherapy was more common in men. Women were more likely to utilize ≥ 4 psychotropic drugs. Antidepressant drugs (ADDs) were the most prescribed drug class. Men had a higher utilization of noradrenergic and specific serotonergic antidepressants (RR 1.15; 95% CI 1.12-1.19), especially mirtazapine (RR 1.16; 95% CI 1.12-1.19), but also of other ADDs such as bupropion (RR 1.50; 95% CI 1.35-1.68). Males had a slightly higher utilization of second-generation antipsychotic drugs (RR 1.06; 95% CI 1.03-1.09) and were less often treated with low-potency first-generation antipsychotic drugs (RR 0.86; 95% CI 0.83-0.90). Tranquilizing (e.g., benzodiazepines; RR 0.89; 95% CI 0.86-0.92) and hypnotic drugs (e.g., Z-drugs; RR 0.85; 95% CI 0.81-0.89) were less utilized in the treatment of male patients. Not all sex differences were stable over time. More sex differences were detectable in 2015-2017 than in 2001-2003. Findings suggest that certain psychotropic drugs are preferred in the treatment of men vs. women, however, sex differences found in this study are not as large as in ambulatory settings. To make evidence-based sex-specific recommendations in the treatment of MDD, differences in drug response and tolerability need to be further researched.

Time trends in pharmacological treatment of major depressive disorder: Results from the AMSP Pharmacovigilance Program from 2001-2017.

BACKGROUND: Currently available data on the prescription practice among patients with major depressive disorder (MDD) reflect the outpatient setting. This is the first study to provide information on time trends of psychotropic drug utilization in psychiatric inpatients. METHOD: Data stems from German-speaking psychiatric hospitals collected by the program "Drug Safety in Psychiatry" (Arzneimittelsicherheit in der Psychiatrie, AMSP) between 2001 and 2017. 44,418 psychiatric inpatients with MDD were included. Time trends in drug utilization were analyzed by comparing the first (2001-2003) and last time point (2015-2017) using risk ratios (RR). RESULTS: Antidepressant drugs (ADD) were the most used psychotropic drug class with utilization decreasing slightly from 2001-2003 (89.7%) to 2015-2017 (85.5%). Use of tricyclic ADDs showed the greatest decline (RR 0.35), while use of selective serotonin-noradrenaline reuptake inhibitors (RR 1.72) and "other ADDs" increased the most. Use of antipsychotic drugs (APD), especially second-generation antipsychotic drugs (RR 1.46), increased. Use of tranquilizing (RR 0.71) and hypnotic drugs (RR 0.43) both decreased. Most patients were treated with more than one psychotropic drug, most often ADD + APD, which was utilized more often in 2015-2017 (51.1%) than in 2001-2003 (45.1%; RR 1.13). Combination of two ADDs increased from 2001-2003 (24.5%) to 2015-2017 (33.0%; RR 1.35). LIMITATIONS: The cross-sectional design does not allow conclusions to be drawn about causal relationship of findings. Further, only certain clinical and sociodemographic data was available. CONCLUSION: Treatment of MDD has shown significant changes from 2001 to 2017.

Psychopharmacological Treatment of Schizophrenia Over Time in 30 908 Inpatients: Data From the AMSP Study.

BACKGROUND: Psychotropic drugs are the cornerstone of schizophrenia treatment, often requiring lifelong treatment. Data on pharmacotherapy in inpatient settings are lacking. METHODS: Prescription data of schizophrenic inpatients within the time period 2000-2015 were obtained from the database of the Drug Safety Program in Psychiatry (AMSP). Data were collected at 2 index dates per year; the prescription patterns and changes over time were analyzed. RESULTS: Among 30 908 inpatients (mean age 41.6 years, 57.8% males), the drug classes administered most often were antipsychotics (94.8%), tranquilizers (32%), antidepressants (16.5%), antiparkinsonians (16%), anticonvulsants (14.1%), hypnotics (8.1%), and lithium (2.1%). The use of second-generation antipsychotics significantly increased from 62.8% in 2000 to 88.9% in 2015 (P < .001), whereas the prescription of first-generation antipsychotics decreased from 46.6% in 2000 to 24.7% in 2015 (P < .001). The administration of long-acting injectable antipsychotics decreased from 15.2% in 2000 to 11.7% in 2015 (P = .006). Clopazine was the most often used antipsychotic, having been used for 21.3% of all patients. Polypharmacy rates (≥5 drugs) increased from 19% in 2000 to 26.5% in 2015. Psychiatric polypharmacy (≥3 psychotropic drugs) was present in 44.7% of patients. CONCLUSIONS: Combinations of antipsychotics and augmentation therapies with other drug classes are frequently prescribed for schizophrenic patients. Though treatment resistance and unsatisfactory functional outcomes reflect clinical necessity, further prospective studies are needed on real-world prescription patterns in schizophrenia to evaluate the efficacy and safety of this common practice.

Cutaneous adverse drug reactions to psychotropic drugs and their risk factors - a case-control study.

Cutaneous adverse drug reactions (CADRs) in patients with psychotropic drugs are common. Large studies on the relevant drugs and other risk factors are still scarce. 594 cases of severe CADRs ("cases") were compared with 8085 cases of other adverse drug reactions ("non-cases") documented in a pharmacovigilance program in psychiatry (AMSP) from 1993 to 2014. Logistic regression was carried out to determine risk factors and between-drug differences. CADRs were relatively more prevalent in patients treated with clomipramine, maprotiline, carbamazepine, lamotrigine, acamprosate, clomethiazole and disulfiram as well as with antidepressants and anticonvulsants as drug classes (p < 0.01). For these drugs, significantly more women were found in patients using maprotiline, lamotrigine (not carbamazepine) and in the groups of antidepressants, tricyclics and anticonvulsants (p < 0.01). Women were more vulnerable to CADRs (67% in cases and 56% in non-cases, p < 0.01). The significantly higher rate of CADRs in women was mainly observed under age of 50 years, i.e. during female reproductive years. In a multivariate logistic regression, female sex, the diagnostic group ICD F1 (substance abuse), maprotiline, carbamazepine, lamotrigine and clomethiazole were identified as risk factors of CADRs. The case/non-case approach allowed to identify risk factors based on empirical data rather than experts' evaluations. The new findings of substance abuse and clomethiazole as risk factors for CADRs have to be confirmed in further studies. Since CADRs can be life-threatening, it is important to be aware of risk factors, especially women during their reproductive period and with lamotrigine treatment.

Suicidal Ideation and Suicidal Behavior as Rare Adverse Events of Antidepressant Medication: Current Report from the AMSP Multicenter Drug Safety Surveillance Project.

Background: Suicidal ideations, suicide attempts, and fatal suicides are rare adverse drug reactions to antidepressant drugs, but they essentially are clinically relevant. Drawing on a larger dataset of the European drug surveillance program, the present naturalistic study updates a previous contribution (Stübner et al., 2010). Methods: First an analysis of the comprehensive data collected in 81 psychiatric hospitals from 1993 to 2014 by the European drug surveillance program Arzneimittelsicherheit in der Psychiatrie was made. All documented single cases of suicidal ideations or behavior judged as adverse drug reactions to antidepressant drugs were carefully assessed as to their clinical features and drug prescriptions. Results: Among 219,635 adult hospitalized patients taking antidepressant drugs under surveillance, 83 cases of suicidal adverse drug reactions occurred (0.04%): 44 cases of suicidal ideation, 34 attempted suicides, and 5 committed suicides were documented. Restlessness was present in 42 patients, ego-dystonic intrusive suicidal thoughts or urges in 39 patients, impulsiveness in 22 patients, and psychosis in 7 patients. Almost all adverse drug reactions occurred shortly after beginning antidepressant drug medication or increasing the dosage. Selective serotonin reuptake inhibitors caused a higher incidence of suicidal ideation and suicidal behavior as adverse drug reactions than noradrenergic and specific serotonergic antidepressants or tricyclic antidepressants, as did monotherapy consisting of one antidepressant drug, compared to combination treatments. Conclusions: The study supports the view that antidepressant drug-triggered suicidal ideation and suicidal behavior (primarily with selective serotonin reuptake inhibitors) are rare. Special clinical features (restlessness, ego-dystonic thoughts or urges, impulsiveness) may be considered as possible warning signs. A combination therapy might be preferable to antidepressant drug monotherapy when beginning treatment.

Use and safety of antiepileptic drugs in psychiatric inpatients-data from the AMSP study.

The psychiatric utilization patterns and risks of antiepileptic drugs (AEDs) were assessed by using data from the drug safety programme Arzneimittelsicherheit in der Psychiatrie over the time period 1993-2013. In a total of 432,215 patients, the main indications for AED use were acute mania, schizoaffective disorder, and schizophrenic and organic psychoses. Valproic acid (VPA) was the most common substance across all of those groups, reaching administration rates of up to 50% since 2005, at which time carbamazepine (CBZ) administration consistently dropped below a rate of 10%. Lamotrigine (LTG) and pregabalin (PGB) increased in relevance after 2005 and 2010, respectively (with administration rates of up to 9%), whereas oxcarbazepine (OXC) was least prevalent (<3%). The mean rates of severe adverse drug reactions (ADRs) ranged from 6 cases per 1000 patients treated (VPA) to 19/1000 (OXC) and were significantly lower with treatment with VPA compared to OXC and CBZ. Hyponatremia was the leading ADR during treatment with OXC; severe allergic skin reactions were most often observed during treatment with CBZ and LTG, and severe oedema was most common during treatment with PGB. Severe hyponatremia induced by OXC was observed significantly more often in female patients than in male patients.

Pharmacotherapy for obsessive compulsive disorder in clinical practice - Data of 842 inpatients from the International AMSP Project between 1994 and 2012.

BACKGROUND: Specific treatment of obsessive compulsive disorder (OCD) is based on cognitive-behavioral therapy, serotonin reuptake inhibitors (SRIs) or their combination. Treatment strategies do not always follow evidence-based guidelines in outpatient settings. Data on pharmacotherapy in inpatient settings are lacking. METHODS: Prescription data for inpatients suffering from OCD in the time period 1994-2012 were obtained from the database of the Drug Safety Program in Psychiatry (AMSP). Data were collected on two index dates per year; the prescription patterns and changes over time were analysed. RESULTS: Of 842 patients 89.9% received at least one psychotropic drug and 67.6% a combination of at least two psychotropic drugs. The drug groups prescribed most often were antidepressants (78.0%), antipsychotics (46.7%), and tranquilizers (19.7%). In 58.0% of all cases selective serotonin reuptake inhibitors (SSRIs) were used as antidepressants, followed by tricyclic antidepressants (TCAs, 17.8%), mainly clomipramine (10.9%). Second-generation antipsychotics (SGAs) were administered in 37.8% of all cases, first-generation antipsychotics (FGAs) in 13.7%. While the use over time significantly increased for psychotropic drugs, antidepressants, antipsychotics, tranquilizers, SSRIs and SGAs, it remained stable for FGAs and decreased for TCAs. LIMITATIONS: Observational cross-sectional study without follow-up or additional information. CONCLUSIONS: In clinical practice, most OCD patients received pharmacological treatment. The high prescription rate of SSRIs and their preference over clomipramine as well as the augmentation of this therapy with SGAs comply with the guidelines. Administration of tranquilizers as well as sedative FGAs and the choice of single SGAs are not in line with expert recommendations.

Drug-Induced Liver Injury during Antidepressant Treatment: Results of AMSP, a Drug Surveillance Program.

BACKGROUND: Drug-induced liver injury is a common cause of liver damage and the most frequent reason for withdrawal of a drug in the United States. The symptoms of drug-induced liver damage are extremely diverse, with some patients remaining asymptomatic. METHODS: This observational study is based on data of Arzneimittelsicherheit in der Psychiatrie, a multicenter drug surveillance program in German-speaking countries (Austria, Germany, and Switzerland) recording severe drug reactions in psychiatric inpatients. Of 184234 psychiatric inpatients treated with antidepressants between 1993 and 2011 in 80 psychiatric hospitals, 149 cases of drug-induced liver injury (0.08%) were reported. RESULTS: The study revealed that incidence rates of drug-induced liver injury were highest during treatment with mianserine (0.36%), agomelatine (0.33%), and clomipramine (0.23%). The lowest probability of drug-induced liver injury occurred during treatment with selective serotonin reuptake inhibitors ([0.03%), especially escitalopram [0.01%], citalopram [0.02%], and fluoxetine [0.02%]). The most common clinical symptoms were nausea, fatigue, loss of appetite, and abdominal pain. In contrast to previous findings, the dosage at the timepoint when DILI occurred was higher in 7 of 9 substances than the median overall dosage. Regarding liver enzymes, duloxetine and clomipramine were associated with increased glutamat-pyruvat-transaminase and glutamat-oxalat-transaminase values, while mirtazapine hardly increased enzyme values. By contrast, duloxetine performed best in terms of gamma-glutamyl-transferase values, and trimipramine, clomipramine, and venlafaxine performed worst. CONCLUSIONS: Our findings suggest that selective serotonin reuptake inhibitors are less likely than the other antidepressants, examined in this study, to precipitate drug-induced liver injury, especially in patients with preknown liver dysfunction.

Second-generation antipsychotics in a tertiary care hospital: prescribing patterns, metabolic profiles, and drug interactions.

We carried out an observational study that analyzed population characteristics, metabolic profiles, potentially interacting pharmacotherapy, and related adverse events in second-generation antipsychotics (SGAs) users of a tertiary care hospital. Within our pharmacoepidemiological database derived from electronic medical records of 82,358 hospitalizations, we identified 1136 hospitalizations contributing 9165 patient-days with exposure to SGA. Blood pressure, blood glucose, lipids, and BMI had been documented in 97.7, 75.7, 24.6, and 77.4% of hospitalizations, respectively. Among these, the prevalence of hypertension, hyperglycemia, dyslipidemia, and BMI 30 kg/m or more was 36.9, 22.6, 61.1, and 23.1%, respectively. A total of 63.4, 70.8, and 37.1% of SGA users with hyperglycemia, dyslipidemia, and hypertension, respectively, received no pharmacotherapy for these conditions. We identified 614 patient-days with SGA plus formally contraindicated comedication and another 1066 patient-days with other high-risk combinations for QTc prolongation. Among those there was one case with associated neutropenia and four cases with abnormal QTc interval. However, specific monitoring for such adverse events was not documented in 45.5% of hospitalizations with contraindicated and 89.8% with high-risk QTc-prolonging combinations. Our study identified targets for improved monitoring and management in SGA users. These may be implemented as automated alerts into electronic prescribing systems and thereby efficiently support safer pharmacotherapy in clinical practice.

Psychopharmacological treatment of 1650 in-patients with acute mania-data from the AMSP study.

BACKGROUND: Several studies have analyzed prescription patterns for bipolar disorder, but few have for acute mania. Treatment strategies in this complex domain change over time and do not always follow evidence-based guidelines. METHODS: Prescription data of in-patients suffering from acute mania in the time period from 2005 to 2012 were obtained from the database of the Drug Safety Program in Psychiatry (Institut für Arzneimittelsicherheit in der Psychiatrie; AMSP). Data were collected on two index dates per year. Changes over time were analyzed comparing the time periods 2005/06 and 2011/12. RESULTS: Among 1650 patients (mean ±SD; age: 48.9±14.91 years; 53.1% females) 54.1% received anticonvulsants, 74.5% second-generation antipsychotics (SGAs), 17.8% first-generation antipsychotics (FGAs), 29.1% lithium, 44.1% benzodiazepines and 14.5% antidepressants. Prescription of SGAs increased from 70% to 79% (p=0.005), while prescription of FGAs and anticonvulsants decreased from 19% to 13% (p<0.05) and 59% to 46% (p<0.001), respectively. Only 30% of patients received monotherapy with one mood stabilizer. We observed an impact of gender, age and psychotic symptoms on treatment strategy. 36.8% of the women≤40 years received valproate. LIMITATIONS: Follow-up data are missing and no differentiation between acute and maintenance treatments could be made due to the cross-sectional design. Additionally, our findings do not necessarily translate to outpatients or to other countries. CONCLUSIONS: Combination therapies represent standard clinical practice. Though many results reflect clinical necessity, the high number of antidepressant prescriptions or valproate use in women of child-bearing age should be judged critically. Further prospective studies should focus on real-world prescription practice in acute mania to evaluate efficacy and safety of common practice. This paper is dedicated to Prof. Dr. Hanns Hippius on the occasion of his 90th birthday.

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

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%≥2, and 54%≥3 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, 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.

Cardiovascular adverse reactions during antidepressant treatment: a drug surveillance report of German-speaking countries between 1993 and 2010.

BACKGROUND: Antidepressants (ADs) are known to have the potential to cause various cardiovascular adverse drug reactions (ADRs). The tricyclic antidepressants (TCAs) were first revealed to be a possible source of cardiovascular ADRs. In recent years, newer classes of ADs were also suggested to have a higher risk of cardiovascular adverse effects. In particular, the selective serotonin reuptake inhibitors (SSRIs) were suspected to have the potential to induce QTc interval prolongation, and therefore increase the risk of ventricular arrhythmia. This descriptive study is based on the continuous pharmacovigilance program of German-speaking countries (Austria, Germany, and Switzerland), the Arzneimittelsicherheit in der Psychiatrie (AMSP), which assesses severe ADRs occurring in clinical routine situations. METHODS: Of 169,278 psychiatric inpatients treated with ADs between 1993 and 2010, 198 cases of cardiovascular ADRs (0.12%) were analyzed. RESULTS: Our study showed that the incidence rates of cardiovascular ADRs were highest during treatment with monoamine oxidase inhibitors (0.27%), TCAs (0.15%), and serotonin noradrenaline reuptake inhibitors (0.14%); the risk of occurring during treatment with SSRIs (0.08%) was significantly lower. The noradrenergic and specific serotonergic AD mirtazapine (0.07%) had a significantly lower risk of cardiovascular ADRs than all other ADs. Severe hypotension was the most frequent ADR, followed by hypertension, arrhythmia, and in some rare cases heart failure. CONCLUSIONS: Despite certain limitations due to the AMSP study design, our observations on cardiovascular ADRs can contribute to a better knowledge of the cardiovascular risk profiles of antidepressants in the clinical routine setting. However, prospective studies are needed to verify our findings.

Age and adverse drug reactions from psychopharmacological treatment: data from the AMSP drug surveillance programme in Switzerland.

QUESTION UNDER STUDY: The frequency of severe adverse drug reactions (ADRs) from psychotropic drugs was investigated in hospitalised psychiatric patients in relation to their age. Specifically, the incidence of ADRs in patients up to 60 years was compared to that of patients older than 60 years. METHODS: Prescription rates of psychotropic drugs and reports of severe ADRs were collected in psychiatric hospitals in Switzerland between 2001 and 2010. The data stem from the drug surveillance programme AMSP. RESULTS: A total of 699 patients exhibited severe ADRs: 517 out of 28,282 patients up to 60 years (1.8%); 182 out of 11,446 elderly patients (1.6%, ns). Logistic regression analyses showed a significantly negative relationship between the incidence of ADRs and patients' age in general and in particular for weight gain, extrapyramidal motor system (EPMS) symptoms, increased liver enzymes and galactorrhoea. A significantly negative relationship was observed for age and the dosages of olanzapine, quetiapine, risperidone, valproic acid and lamotrigine. When comparing age groups, frequency of ADRs was lower in general for antipsychotic drugs and anticonvulsants, in particular for valproic acid in the elderly. Weight gain was found to be lower in the elderly for antipsychotic drugs, in particular for olanzapine. For the group of mood-stabilising anticonvulsants (carbamazepine, lamotrigine and valproic acid) the elderly exhibited a lower incidence of reported allergic skin reactions. CONCLUSION: The results suggest that for psychiatric inpatients the incidence of common severe ADRs (e.g., weight gain or EPMS symptoms) arising from psychotropic medication decreases with the age of patients.

Comparative performance of two drug interaction screening programmes analysing a cross-sectional prescription dataset of 84,625 psychiatric inpatients.

BACKGROUND: Clinical decision support software (CDSS) solutions can automatically identify drug interactions and thereby aim to improve drug safety. However, data on the comparative performance of different CDSS to detect and appropriately classify interactions in real-life prescription datasets is limited. OBJECTIVE: The aim of this study was to compare the results from two different CDSS analysing the pharmacotherapy of a large population of psychiatric inpatients for drug interactions. METHODS: We performed mass analyses of cross-sectional patient-level prescriptions from 84,625 psychiatric inpatients using two CDSS - MediQ and ID PHARMA CHECK(®). Interactions with the highest risk ratings and the most frequent ratings were reclassified according to the Zurich Interaction System (ZHIAS), a multidimensional classification that incorporates the OpeRational ClassificAtion of Drug Interactions (ORCA) and served as a reference standard. RESULTS: MediQ reported 6,133 unique interacting combinations responsible for 270,617 alerts affecting 63,454 patients. ID PHARMA CHECK(®) issued 5,400 interactions and 157,489 alerts in 48,302 patients. Only 2,154 unique interactions were identified by both programmes, but overlap increased with higher risk rating. MediQ reported high-risk interactions in 2.5 % of all patients, compared with 5 % according to ID PHARMA CHECK(®). The positive predictive value for unique major alerts to be (provisionally) contraindicated according to ORCA was higher for MediQ (0.63) than for either of the two ID PHARMA CHECK(®) components (0.42 for hospINDEX and 0.30 for ID MACS). MediQ reported more interactions, and ID PHARMA CHECK(®) tended to classify interactions into a higher risk class, but overall both programmes identified a similar number of (provisionally) contraindicated interactions according to ORCA criteria. Both programmes identified arrhythmia as the most frequent specific risk associated with interactions in psychiatric patients. CONCLUSIONS: CDSS can be used for mass-analysis of prescription data and thereby support quality management. However, in clinical practice CDSS impose an overwhelming alert burden on the prescriber, and prediction of clinical relevance remains a major challenge. Only a small subset of yet to be determined alerts appears suitable for automated display in clinical routine.