Hyponatraemia (HN) can be a life-threatening medical condition which may lead to severe neurological and psychiatric symptoms. The AMSP (Arzneimittelsicherheit in der Psychiatrie) is a multicentre drug surveillance programme that assesses severe or new adverse drug reactions during psychopharmacological treatment in psychiatric inpatients. We report on a total of 263 864 psychiatric inpatients monitored from 1993 to 2007 in 80 psychiatric hospitals in Germany, Switzerland and Austria. During this period plasma sodium levels below 130 mmol/l (severe HN according to AMSP) were reported in 93 patients (relative frequency 0.04%). On average, the plasma sodium levels of all cases were 119.7 mmol/l (±5.8 s.d.); median 121 mmol/l (range 104-129 mmol/l). Patients who showed no clinical signs (n=65, 70%) had a mean sodium level of 121.3 mmol/l (±5.0 s.d.); median 122 mmol/l (range 114-129 mmol/l). By contrast, patients with clinical symptoms (n=28, 30%) had a mean sodium level of 116.0 mmol/l (±6.0 s.d.); median 117 mmol/l (range 104-125 mmol/l). HN was mainly observed during treatment with selective serotonin reuptake inhibitors (SSRIs) (0.06%), Serotonin noradrenaline reuptake inhibitors (SNRIs) (0.08%), carbamazepine (0.10%) and oxcarbazepine (1.29%); the highest rate was found for oxcarbazepine. Antipsychotics, mirtazapine and tricyclic antidepressants were only rarely involved in HN (0.003-0.005%). Combinations of several drugs known to induce HN significantly increased the risk of HN, e.g. more than 10-fold for SSRI+diuretics+ACE inhibitors (0.37%) vs. SSRI given alone (0.02%). This is clinically relevant because such combinations, e.g. SSRI+diuretics may occur especially in elderly patients, who are in general at higher risk of developing HN.

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The AMSP (Arzneimittelsicherheit in der Psychiatrie) study is a new program for continuous assessment of adverse drug reactions (ADR) in psychiatric inpatients under naturalistic conditions of routine clinical treatment. It is based on the preceding drug surveillance study AMUP (Arzneimittelüberwachung in der Psychiatrie). Currently, 29 hospitals are participating in the study. This paper reports on the methods of the AMSP study and the first findings on the comparative risks of tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRI) . Data assessment is restricted to "severe" ADR as defined in the study protocol. Drug use is estimated from reference day data. From 1993 to 1997, 896 cases of severe ADR were observed in 48,564 patients (1.84%). SSRI and the new substances mirtazapine and venlafaxine were increasingly used as antidepressants (AD), but TCA were still the most common AD in 1997 (52.1% of all AD patients). Similar rates of ADR were observed for SSRI and TCA (1.7% and 1.5%, respectively, for all cases, 0.9% and 1.0%, respectively, only for cases rated as probable). However, different types of ADR occurred with the two AD subgroups; whereas toxic delirium and increased liver enzymes were the most frequent ADR related toTCA, nondelirious psychic and neurologic ADR predominated with SSRI. The duration of inpatient treatment was considerably longer in patients who experienced an ADR due to TCA or SSRI than in those who did not. The AMSP study promises to contribute greatly to drug safety by providing the relative frequencies of severe ADR from a large-scale database and by improving our knowledge of ADR.

Medical charts of 387 in-patients (schizophrenia n = 284, tardive dyskinesia, TD, n = 48), were analyzed to evaluate efficacy and adverse effects of clozapine. These patients were previously treated with between two and four other neuroleptics and were either therapy resistant or had severe side effects. Schizophrenic patients were treated with clozapine for 48 +/- 35 (TD 49 +/- 40) days, dosage was 189 +/- 119 (TD 220 +/- 176) mg. Four per cent showed worsening, 13% no change, 38% slight improvement, 42% marked improvement and 3% nearly total reduction of symptoms. In TD, 44% showed marked improvement, but only in 17% the drug was superior to previous neuroleptics. Adverse effects occurred in 56% of patients. Most frequent were sedation (17%), EEG alterations (16%), increase of liver enzymes (8%), hypotension (7%), hypersalivation (5%), fever (5%), ECG alterations (4%), tachycardia (3%), gastro-intestinal (3%) and delirious states (2%). A gradual increase in dosage seems to considerably reduce the incidence of some side effects. Clozapine treatment had to be discontinued because of severe side effects in 5.9%. In none of these patients did serious complications such as agranulocytosis occur. Only EEG alterations were significantly related to clozapine dosage (P less than 0.0005). At dismissal, most patients continued to receive clozapine; only in 22% (TD 20%) was it replaced by another neuroleptic. Thus, the ratio benefit/risk of clozapine treatment seems to be satisfactory in most of the negatively selected patients. Nevertheless, a gradual increase in dosage and careful control of hematological and other variables is highly recommended.

Monotherapy with antidepressants and any use of tricyclic AD and venlafaxine still has a considerable prevalence in bipolar depression, but this is controversial due to the reported risk of treatment emergent affective switches. Triple and quadruple therapy is not evidence-based but increasingly used in clinical practice. This may reflect an attempt to overcome treatment failure, and further studies should evaluate efficacy and safety of this common practice.

Based on a careful literature search a review is presented of the history, background, concepts and current use of comedication and polypharmacy in psychiatry. The pros and cons of comedication and polypharmacy are presented, as well as their apparent increase in recent times. Possible reasons for the increase of comedication/polypharmacy are described. Both the potential advantages as well as the potential risks are discussed. The one sided view that all comedication/polypharmacy is nothing but problematic is questioned. Comedication/polypharmacy seems to be, among others, the current answer to the well-known limited efficacy and effectiveness of current monotherapy treatment strategies.

Adverse effects related to clozapine were assessed within a post-marketing drug surveillance program, the AMUP study, in two university psychiatric departments. In a randomly selected sample of patients (intensive drug monitoring) ADRs of any type were observed in 76% of clozapine-treated inpatients. Sedation, hypersalivation, increase in transaminases, and EEG changes were most frequently observed, but only rarely required changes in therapy. In 8.1% of 959 patients exposed to clozapine in the total inpatient population of the participating hospitals ADR led to withdrawal of clozapine; in 3.9% reactions judged as severe and potentially life-threatening occurred. Among these latter toxic delirium prevailed. In addition, four cases of severe cardiovascular and respiratory dysregulation were observed with the combination of clozapine and benzodiazepines. These cases and one case of sudden death under clozapine and haloperidol treatment are presented in some detail. The results obtained for clozapine are compared to data from this drug surveillance program for other neuroleptics.

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.