The role of serotonin autoreceptor antagonism in major depression has been a matter of intense debate in recent years. On the basis of animal experiments, it has been suggested that the blockade of this autoreceptor with pindolol during concomitant treatment with selective serotonin reuptake inhibitors (SSRIs) would result in a rapid and augmented antidepressant effect, but it has also been argued that the possible augmenting effect of pindolol is due to the beta-blocking properties of this drug. Results from the first human studies have also been controversial. We used a national computer-based central register to study the cumulative incidence of the use of beta-adrenergic receptor antagonists and antidepressant drugs, as well as the point prevalence of disability pensions as a result of major affective disorders (296, DSM-III-R; F30-F34, ICD-10) at the end of a 3-year follow-up period. Our results from a very large database (total N = 30,485) indicate that the use of pindolol is associated with a marked reduction (from 29% to 52%) in the prevalence of disability pensions resulting from major affective disorders when compared with the use of other beta-adrenergic receptor antagonists. The use of pindolol was associated with a slightly lower rate of antidepressant use when compared with other beta-adrenergic receptor antagonists and especially when compared with propranolol. The results suggest that long-term therapy with pindolol treatment augments the pharmacologic effect of antidepressant drugs (especially SSRIs) among patients with major affective disorders. The finding that patients receiving pindolol have a lower prevalence of disability pensions resulting from major affective disorders indicates that the prevalence of severe treatment-resistant major affective disorders could be decreased markedly by using pindolol as the first-choice beta-adrenergic receptor antagonist in the treatment of cardiovascular diseases whenever possible among those patients who have experienced at least one depressive episode and are receiving antidepressant treatment.