Adverse drug reactions in psychiatry.

A workshop at the Congress of the Swiss Society of Psychiatry and Psychotherapy focused on the adverse effects of psychotropic drugs. The interest was great: Already ten minutes before the start the hall was fully occupied. Important aspects of psychiatric drug therapy were explained by Prof. Gregor Hasler, MD, Head of the Department of Molecular Psychiatry, University Hospital of Psychiatry and Psychotherapy Bern, and Prof. Stefan Russmann, MD, drugsafety.ch and Boston University School of Public Health, Department of Epidemiology.

Patients in psychiatric care often receive multiple psychotropic medications at the same time, plus additional medications for non-psychiatric comorbidities. This polypharmacy also implies a high risk of adverse drug reactions (ADRs). Recognizing and successfully managing these requires good knowledge regarding indications, dosing, interactions, and special challenges of psychiatric pharmacotherapy (e.g., off-label use, QT prolongation, metabolic side effects, etc.). There is a large interindividual variability in the interactions. The consequences of interactions include loss of efficacy, relative overdose, and amplification of ADRs, as explained with two case examples.

Case 1: Metoprolol and paroxetine

A 53-year-old woman taking 100 mg of metoprolol daily for hypertension is prescribed an additional 20 mg of paroxetine, after which she complains of fatigue and dizziness. Her pulse rate is 50/min, and her systolic blood pressure is below 100 mmHg. The reason for these complaints: Due to an interaction, the beta blocker is overdosed. Metoprolol is predominantly degraded via CYP2D6, and paroxetine acts as a potent inhibitor of CYP2D6. There are several approaches to solve the problem: another beta-blocker without interaction with CYP2D6, an antihypertensive of a different class, another antidepressant, or reduction of the metoprolol dose with control of blood pressure and heart rate. It is also important to check the indication for the prescribed drugs.

Case 2: Simvastatin and clarithromycin

A 50-year-old woman taking simvastatin is receiving clarithromycin for pneumonia. She then complains of muscle pain and her urine is dark in color – a diagnosis of rhabdomyolysis is made. Plasma concentrations of simvastatin are tenfold higher than normal. This is due to a pharmacokinetic interaction: simvastatin is metabolized mainly via CYP3A4, and macrolide antibiotics inhibit CYP3A4 to varying degrees. Since the metabolization of the statin is inhibited, a higher plasma concentration results – this is particularly pronounced since simvastatin has a bioavailability of only 5%. This means that 95% of the simvastatin taken is usually subject to the first-pass-effect. If this is now reduced by half, 47.5% of the simvastatin taken enters the circulation instead of the usual 5%, which quickly leads to a relevant overdose.

Improve pharmacovigilance

In the Swiss pharmacovigilance system, physicians who observe ADRs are the primary reporters. The speakers urged primary care providers to report new ADRs with newly introduced drugs in particular, for example to the clinical pharmacology departments of university hospitals or, in the psychiatric field, to the Swiss Society for Drug Safety in Psychiatry (SGAMSP, http://amsp.de/category/kat-foerder vereine/kat-foerderverein-sgamsp). Computer-assisted options for identifying and preventing medication errors are also becoming increasingly important. For example, an important tool for estimating interactions is www.mediq.ch.

Tips for practice

When oral contraceptives are taken at the same time as antiepileptic drugs or St. John’s wort preparations, there is a risk that the effect of the contraceptives will decrease. In the case of St. John’s wort, for example, this results in spotting. For this reason, patients of childbearing age must be properly instructed regarding contraception when prescribed these medications.
Zolpidem (^Stilnox®) is very often responsible for emergencies, especially in the elderly, because it is relatively overdosed and the patient falls as a result of sedation. For this reason, the dosage should be halved in patients over 65 years of age.
There is a risk for serotonin syndrome when combining serotoninergic drugs (e.g., SSRIs, SNRIs, triptans, tramadol, atypical neuroleptics, antiepileptics, MAO inhibitors, etc.). Typical symptoms include sweating, muscle twitching, palpitations, nausea, diarrhea, agitation, and confusion.
St. John’s wort is a popular medicine, but it is not completely harmless despite its herbal origin. The use of St. John’s wort is contraindicated when taking, for example, cytostatics, immunosuppressants, antiretroviral agents or anticoagulants of the coumarin type!
Among the most commonly prescribed medications, many have a sedating effect – and thus corresponding ADRs. Prof. Hasler called for the use of less sedating agents, for example, not to prescribe a sleeping pill in addition to an antidepressant.
Antipsychotic polypharmacy is often dangerous. For individuals taking more than one antipsychotic, the 10-year survival rate decreases by a factor of 2.4. The combination of antipsychotics usually does not work, but causes cognitive deficits.