of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients. Agomelatine appears to cause fewer sexual side effects and discontinuation effects than paroxetine. Common (1–10% incidence) adverse effects include Hyperhidrosis (excess sweating that is not proportionate to the ambient temperature) Abdominal pain Nausea Vomiting Diarrhea Constipation Back pain Fatigue Increased ALAT and ASAT (liver enzymes) Headache Dizziness Somnolence Insomnia Migraine Anxiety Uncommon (0.1–1%) adverse effects include Paraesthesia (abnormal sensations [e.g. itching, burning, tingling, etc.] due to malfunctioning of the peripheral nerves) Blurred vision Eczema Pruritus (itching) Urticaria Agitation Irritability Restlessness Aggression Nightmares Abnormal dreams Rare (0.01–0.1%) adverse effects include Mania Hypomania Suicidal ideation Suicidal behaviour Hallucinations Steatohepatitis Increased GGT and/or alkaline phosphatase Liver failure Jaundice Erythematous rash Face oedema and angioedema Weight gain or loss, which tends to be less significant than with SSRIs Dependence and withdrawal No dosage tapering is needed on treatment discontinuation. Agomelatine has no abuse potential as measured in healthy volunteer studies. Overdose Agomelatine is expected to be relatively safe in overdose. Interactions Agomelatine is a substrate of CYP1A2, CYP2C9 and CYP2C19. Inhibitors of these enzymes, e.g. the SSRI antidepressant fluvoxamine, reduce its clearance and can therefore lead to an increase in agomelatine exposure. There is also the potential for agomelatine to interact with alcohol to increase the risk of hepatotoxicity. Pharmacology Pharmacodynamics Agomelatine is a melatonin receptor agonist (MT1 (Ki 0.1 nM) and MT2 (Ki = 0.12 nM)) and serotonin 5-HT2C (Ki = 631 nM) and 5-HT2B receptor (Ki = 660 nM) antagonist. Binding studies indicate that it has no effect on monoamine uptake and no affinity for adrenergic, histamine, cholinergic, dopamine, and benzodiazepine receptors, nor other serotonin receptors. Agomelatine resynchronizes circadian rhythms in animal models of delayed sleep phase syndrome. By antagonizing 5-HT2C, it disinhibits/increases noradrenaline and dopamine release specifically in the frontal cortex. Therefore, it is sometimes classified as a norepinephrine–dopamine disinhibitor. It has no influence on the extracellular levels of serotonin. Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase-shifting properties; it induces a phase advance of sleep, body temperature decline, and melatonin onset. Antagonism of 5-HT2B is putatively an antidepressant