Pregabalin (PRG) is approved for the treatment of neuropathic pain, partial seizures, and generalized anxiety disorder in many countries. Supported by case reports and a few studies there is an ongoing debate on PRG's potential to cause addictive behaviors. Considering that PRG is currently under investigation for the treatment of benzodiazepine dependence and withdrawal as well as relapse prevention in alcohol dependence, assessment of PRG's abuse and dependence potential is indispensable. We report the case of a 38-year-old female patient with borderline personality disorder and past alcohol abuse who developed PRG abuse. The patient took up to 800 mg PRG per day, initially administered to treat unspecific anxiety, and experienced euphoric feelings after PRG intake. In the further course, she increased the daily PRG dosage and consulted other physicians to receive additional PRG prescriptions. During reduction of PRG, the patient developed a moderate withdrawal syndrome with vegetative symptoms. Because of the early detection of the developing PRG abuse (4 months after first application of PRG), the development of PRG dependence was prevented. This case illustrates the possibility of PRG to trigger the development of addictive behaviors and should encourage physicians to be very careful when administering PRG to patients with current or past substance-related disorders.

Agomelatine (AGM) was approved for the treatment of major depressive disorder (MDD) in adults by the European Medicines Agency (EMA) in February 2009. It is an analogue of melatonin and features a unique pharmacodynamic profile with agonism on both types of melatonergic receptors (MT1/MT2) and antagonism at serotonergic 5-HT2C receptors. There is, however, an ongoing debate regarding the efficacy and safety of this novel antidepressant agent, originally evoked by claims of a significant publication bias underlying the assessment of AGM being an effective antidepressant. Indeed, two recent comprehensive metaanalyses of published and unpublished clinical trials found evidence for a relevant publication bias. However, due to its statistically significant advantage over placebo based on the results of these metaanalyses AGM must be referred to as an effective antidepressant agent in the acute phase of MDD. However, the effect sizes of AGM in the treatment of MDD were evaluated as being small in comparison to other antidepressant agents. In addition, there is insufficient evidence for the efficacy of AGM in relapse prevention of MDD. Apart from efficacy issues, AGM appears to have the potential to exhibit severe hepatotoxicity (the EMA has identified AGM-associated "hepatotoxic reactions" as a new safety concern in September 2013) that is currently poorly understood. Considering these aspects, it seems inappropriate to evaluate AGM as an antidepressant agent of first choice. Nevertheless, its unique mechanism of action with particular sleep modulating effects may represent a specific treatment strategy for patients with particular characteristics; further studies with thorough characterization of patients are needed to test this hypothesis.

Hepatotoxicity related to antidepressive pharmacotherapy is a major safety concern, particularly considering that severe forms of hepatic failure with fatal outcome have been reported. Severe hepatotoxic adverse drug reactions were also reported for agomelatine (AGM), an antidepressive agent, which was approved for the treatment of major depressive disorder (MDD) in adults by the European Medicines Agency (EMA) in February 2009. Its general safety and tolerability profile appears to be favourable or similar in comparison to other antidepressants, particularly regarding metabolic aspects, sexual functioning, gastrointestinal side effects, and discontinuation phenomena. Epidemiology and pathophysiology of AGM-related hepatotoxicity are currently poorly understood. Pooled data from clinical trials indicate that patients treated with AGM demonstrate increased prevalence rates of elevated liver transaminases (> 3 x ULN; 1.34% on AGM 25 mg/day, 2.51% on AGM 50 mg/day) in comparison to placebo (0.5%). AGM-related hepatotoxic adverse drug reactions are unpredictable and usually occur as asymptomatic increases of liver enzymes, which develop during the first months of treatment and mostly recover after discontinuation of AGM-treatment or even on continued treatment. Liver injury due to AGM-related hepatotoxicity is mostly hepatocellular. The underlying mechanism appears to be idiosyncratic. Cholestatic or hypersensitivity reactions have not yet been reported. Some evidence suggests dose-dependence of AGM-related hepatotoxicity. In a recent post-authorisation opinion of the EMA, hepatotoxic reactions related to AGM were declared as an important identified risk and new contraindications for treatment with AGM were released (hypersensitivity to AGM, elevations of liver enzymes > 3 x ULN, hepatic impairment (not further specified), parallel use of potent CYP1A2 inhibitors). Considering these aspects, treatment with AGM must only be performed under strict accordance with the recently modified prescribing information. A final evaluation of AGM-related hepatotoxicity is currently not possible; further studies are necessary.