The catecholamine deficiency hypothesis of depression was essentially based on the incidental detection of iproniazide and imipramine. However, current findings favor noradrenergic overactivity, at least in the periphery. The incidental observation of acute behavioral inhibition by centrally active cholinomimetics like physostigmine suggested a cholinergic-adrenergic balance involved in the regulation of drive and mood. Indeed, cholinomimetics seem to have acute depressiogenic and antimanic properties and, conversely, anticholinergics some acute euphoriant activity. However, time course and dose-response relationships of drugs influencing mood and drive do not favor simple concepts of too much or too little activity of one or the other transmitter system. Cholinomimetics and psychostimulants show an acute mutual antagonism, the mechanism of which is obscure. In healthy volunteers clonidine and the putative antidepressant brofaromine did not influence the effects of physostigmine. Patients with mood disorders respond supersensitively to a cholinergic challenge in terms of behavior, neuroendocrine regulation and REM sleep induction. Thus, the anticholinergic properties of tricyclics might be relevant to their antidepressant activity. However, adjunctive treatment with the cholinolytic biperiden as compared to placebo did not enhance the antidepressant efficacy of mianserin or viloxazine. This is incompatible with cholinergic overactivity contributing to the depressive state. Physostigmine induces autonomous and endocrine responses reminiscent of stress reactions. Findings in healthy volunteers suggest relationships between the sensitivity to physostigmine and personality traits like irritability and emotional lability and passive stress coping strategies. Thus, the cholinergic supersensitivity in mood disorders might be related to some personality dimension like stress intolerance rather than the depressive state itself.