THE NEUROBIOLOGIC ETIOLOGY of major affective disorders has remained obscure despite the intensive ongoing research efforts. Most of the research into the biochemical pathophysiology and the mechanisms of action of antidepressant drugs has focused on the function of postsynaptic serotonin (5-HT) and norepinephrine receptors. Selective 5-HT reuptake inhibitors (SSRIs) have become the most widely used antidepressant drugs in most of the world. Although SSRIs are extensively used and well-tolerated, they do have a delay of 2 to 3 weeks-like all other antidepressant drugs-between the onset of the treatment and the clinical improvement in the symptoms. Therefore, it is evident that recovery from depression is not directly attributable to the short-term blockade of 5-HT uptake by SSRIs. Animal studies have shown that short-term treatment with SSRIs increases the concentration of extracellular 5-HT in raphe nuclei, but not to the same extent in the projection areas such as the frontal cortex. [1-4] However, long-term treatment leads to marked increase in the 5-HT concentration in these projection areas. [5-7] It has been suggested that an increase of the extracellular 5-HT in the midbrain leads to the activation of somatodendritic 5-HT1A autoreceptors, which inhibit and reduce the 5-HT release increase in the cortical areas.  During long-term treatment with SSRIs, the autoreceptor becomes desensitized, and subsequently there is an increase in 5-HT release in the cortical areas. [7,9] On the basis of these observations, it can be assumed that concomitant use of a 5-HT (1A) antagonist with SSRI therapy should lead to an immediate increase of 5-HT release in the cortical areas and to a very rapid antidepressant effect. Experimental studies in animals have shown that 5-HT1A antagonists such as (-)-pindolol, (-)-tertatolol, and WAY-100635 potentiate the effect of SSRIs on 5-HT transmission. [8,10-12]
Open case studies in humans receiving concomitant pindolol and SSRI treatment have suggested that pindolol (7.5 mg/day) shortens the latency before there is a reduction of the symptoms and benefits patients with drug-resistant depression. [13,14] Data from a relatively large controlled trial indicate that the addition of pindolol to antidepressant treatment increases the effectiveness of fluoxetine,  trazodone,  and paroxetine therapy, [17-19] although data from other double-blind, placebo-controlled trials indicate that pindolol has no efficacy in hastening the clinical response in patients being treated with antidepressants. [20,21] Furthermore, it can been argued that even if pindolol does have positive effects, they are not necessarily attributable to 5-HT1A antagonism.  This argument is made on the basis of the theory that antidepressant response is mediated by the activation of postsynaptic 5-HT1A receptors, [23-25] and thus 5-HT1A antagonism of these receptors would counteract the benefits of increased 5-HT release into the synaptic cleft (although it has been shown that pindolol exerts its antagonistic activity selectively at somatodendritic 5-HT1A autoreceptors without altering the function of postsynaptic 5-HT1A receptors, at least in some forebrain regions).  Therefore, it has been suggested that the possible augmentation of antidepressant effects by pindolol is caused by the potentiation of [small beta, Greek]-adrenoreceptor down-regulation.  One can conclude that the role of 5-HT1A-autoreceptors in major affective disorders still remains controversial topic. It has been suggested that future studies should compare the efficacy of [small beta, Greek]-adrenergic receptor antagonists with similar intrinsic activity at [small beta, Greek]-adrenoreceptors but different affinities for the 5-HT1A receptor.  This has been investigated in a recent study which revealed that pindolol, but not metoprolol, accelerates the antidepressant effect of paroxetine. 
The computer-based Finnish national central register of The Social Insurance Institution provides one possibility to study associations between drug use, sick leave, and disability pensions in a very large population. The aim of this study was to test the hypothesis that the use of pindolol is associated with (1) lower cumulative incidence of antidepressant drug use (i.e., whether pindolol alone is having an antidepressant-like effect); (2) lower point prevalence of disability pensions resulting from major affective disorders in the end of the follow-up period; and especially (3) lower point prevalence of disability pensions resulting from major affective disorders among a subpopulation of patients treated with SSRIs when compared with the use of other [small beta, Greek]-adrenergic receptor antagonists lacking 5-HT1A antagonism properties. Because the study population was so large, it was possible to take into account matching for age, sex, and somatic health condition.
In Finland, data on disability pensions and the claims for reimbursement of costs for long-term drug use for severe diseases (such as hypertension, angina pectoris, and the most severe cases of major affective disorders) are available for the whole nation (population of 5,078,000 in 1995).  These data are filed in the computer-based central database of The Social Insurance Institution. We studied the cumulative incidence of the use of [small beta, Greek]-adrenergic receptor antagonists and antidepressant drugs (only those patients whose antidepressant treatment started after [small beta, Greek]-blocker were included) during the 3-year period as well as the point prevalence of disability pensions resulting from major affective disorders (296, DSM-III-R; F30-F34, ICD-10) at the end of the follow-up period. (The data on disability were filed on December 31, 1996.) The age-adjusted odds ratios (ORs) and 95% confidence intervals for these outcome measures were calculated using logistic regression analysis with pindolol group as the reference. The prevalence of disability pensions was further differentiated between patients receiving long-term fluoxetine or citalopram SSRI treatment and the rest of the patients receiving [small beta, Greek]-adrenergic receptor antagonists; of the latter, 7.5% received reimbursement of costs resulting from long-term antidepressant treatment (other than SSRIs). Fluoxetine and citalopram are the two most commonly prescribed antidepressant drugs in Finland; in 1995 they accounted for more than 50% of all antidepressant medication used.  This survey was performed in the population aged 15 to 65 years (3,401,000 in 1995  during the period from January 1, 1994, to December 31, 1996. The data were gathered from a random 7% sample (persons having their birthday on the 8th or 18th day of the month) of patients receiving long-term [small beta, Greek]-adrenergic receptor antagonist treatment. Because of the relatively small number of subjects in the pindolol group, additional data from all patients receiving pindolol without concomitant propranolol treatment (N = 11,231) were used to calculate the incidence of disability pensions among patients with pindolol. Unfortunately, this kind of large database was not available for other [small beta, Greek]-adrenergic receptor antagonists. The demographic data of the patients are presented in Table 1.
(Table 2) shows the cumulative incidences for antidepressant use. The results show that the incidence of overall antidepressant and SSRI use is slightly lower among patients receiving pindolol, but this difference reached statistical significance only when compared with propranolol concerning overall antidepressant use; concerning SSRI use, the difference was statistically significant only when compared with atenolol and propranolol. Table 3 shows the prevalence of disability pensions resulting from major affective disorders at the end of the follow-up period. The prevalence of disability pensions for patients taking pindolol was 29% (group with one or more [small beta, Greek]-blocker other than pindolol, propranolol, metoprolol, or atenolol) to 52% (propranolol and atenolol groups) lower than that of all other [small beta, Greek]-adrenergic receptor antagonists. The age-adjusted ORs for [small beta, Greek]-adrenergic receptor antagonists other than pindolol ranged from 1.45 (one or more other [small beta, Greek]-blocker) to 3.08 (propranolol). The difference between pindolol and the second-most beneficial specified [small beta, Greek]-blocker (metoprolol) was statistically significant concerning the prevalence of disability pensions (OR = 1.68, p = 0.0004). The differences between the pindolol group and all other groups remained significant even after Bonferroni correction, except for the group "one or more other [small beta, Greek]-blocker."
The prevalence of disability pensions among patients receiving an SSRI was 23% (compared with propranolol) to 65% (compared with atenolol) lower in the pindolol group. The ORs for the prevalence of disability pensions in all [small beta, Greek]-adrenergic receptor antagonist groups except for the propranolol group were higher among the subpopulation receiving SSRIs (ORs from 1.88 to 3.14) than among patients with no SSRI (ORs from 1.06 to 2.18). Thus, the beneficial effect associated with pindolol use was slightly more prominent in the SSRI subpopulation when compared with the effect in the rest of the population.
The use of pindolol per se was associated with a slightly lower rate of antidepressant use (especially compared with propranolol), which indicates that pindolol alone may have some beneficial effect on mood or that it may differ from other [small beta, Greek]-adrenergic receptor antagonists (especially propranolol) concerning the induction of iatrogenic depression. The latter explanation is unlikely because the use of pindolol was also associated with a slightly lower rate of antidepressant use when compared with atenolol, which is a hydrophilic agent and should have a very modest effect on mood. The possibility of pharmacokinetic interaction between pindolol and SSRIs cannot be ruled out because there are no published data on the possible effect of SSRIs on the plasma levels of pindolol. Pindolol was associated with a marked reduction in the prevalence of disability pensions resulting from major affective disorders at the end of the follow-up period. Because comprehensive data on the prevalence of disability pensions resulting from major affective disorders from patients with SSRI treatment but without concomitant [small beta, Greek]-adrenergic receptor antagonist treatment were not available, we had no "baseline" data for patients without [small beta, Greek]-blockers. However, we think that it is essential to match patients concerning their somatic health condition (because cardiovascular diseases are associated with an increased depression rate), and therefore, the best possible control group consists of patients with other [small beta, Greek]-adrenergic receptor antagonist treatments. Unfortunately we had no data on the use of other medications, other diagnoses, or other sociodemographic risk factors that may have had an effect on the incidence of depression.
It is possible that some properties other than 5-HT1A autoreceptor antagonism (such as the cost of the drug, slight intrinsic sympathomimetic activity, or its effects on lipid metabolism and bronchus obstruction) could account for these marked differences between pindolol and the other [small beta, Greek]-adrenergic receptor antagonists. Because pindolol is one of the least expensive [small beta, Greek]-adrenergic receptor antagonists available, it is not likely that differences in socioeconomic status would be significant. On the other hand, it is very difficult to find any association between the clinical profile of the patients receiving pindolol versus other [small beta, Greek]-blockers and their vulnerability to major depression. The lower prevalence of disability pensions resulting from major affective disorders among patients receiving pindolol suggests that pindolol augments antidepressant treatment and thus can decrease the prevalence of treatment-resistant major affective disorders that lead to disability pension. On the basis of the studies by Avorn and associates  and Thiessen and associates,  it can be assumed that a significant proportion of cases of major depression are in fact iatrogenic disorders induced by the [small beta, Greek]-adrenoreceptor blockade of lipophilic [small beta, Greek]-adrenergic receptor antagonists such as propranolol (but not by the treatment with hydrophilic [small beta, Greek]-adrenergic receptor antagonists such as atenolol). Therefore, it is probable that a specific 5-HT1A autoreceptor antagonist without affinity for the [small beta, Greek]-adrenoreceptor effect might have an even clearer beneficial antidepressant-augmenting effect than pindolol. Future studies should test whether such compounds (e.g., WAY-100635-like compounds) could be used in the augmentation of SSRI treatment.
In Finland, approximately 300,000 subjects (younger than 65 years) receive long-term [small beta, Greek]-adrenergic receptor antagonist treatment. Because the prevalence of disability pensions resulting from major affective disorders was approximately 30% to 50% lower in the pindolol group compared with that of patients receiving other [small beta, Greek]-adrenergic receptor antagonists (in the 7% sample), it can be estimated that in Finland, there would have been approximately 2,000 fewer cases of therapy-resistant major affective disorders requiring disability pension among the population younger than 65 years during the 3-year period had it been possible to replace other [small beta, Greek]-adrenergic receptor antagonists with pindolol. (If we assume that the incidence and the drug treatment of depression and cardiovascular diseases do not differ markedly between Finland and the United States, this would correspond to approximately 100,000 fewer cases of therapy-resistant major affective disorders in the United States.) Therefore, it can be argued that those patients who have experienced at least one depressive episode, are receiving antidepressant treatment, and require [small beta, Greek]-adrenergic receptor antagonist for cardiovascular disease should be treated with pindolol in preference to other [small beta, Greek]-adrenergic receptor antagonists if there is no absolute or relative contraindication (such as a recent myocardial infarction) against its use.
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