The question of when antidepressant drugs (AD) initiate significant clinical actions in depressed patients is still unsettled. Findings from early studies on whether there is a lag in the onset of therapeutic actions were in disagreement. More recent results with the selective serotonin reuptake inhibitors (SSRIs) and other new ADs indicate that clinical actions occur within the first 2 weeks. In this paper, evidence from efficacy studies with the ADs is reviewed and the methodologic and conceptual obstacles to achieving definitive results about the onset issue are analyzed. Depression, formerly viewed as a homogenous disorder, is now seen as heterogenous and multifaceted in structure. Such major structural components as anxiety and disturbed psychomotor functioning can be as significant to the core of the disorder as depressed mood itself. Further, the ADs have been shown to act initially on different facets of the clinical disorder which then result in multiple clinical actions, e.g., an initial reduction in anxiety followed by stimulation of motor activity. Data from the NIMH Collaborative Study of the Psychobiology of Depression are used to illustrate: (1) the componential structure of severe depressive disorder; (2) the sequence of change in the major behavioral components of the disorder associated with the tricyclic drugs; (3) the consequent "multiple" onsets of clinical actions; and (4) measurement of the clinical significance and visibility of the early behavioral changes. Recent results describing new behavioral and methodological approaches, the use of early clinical changes to predict outcome, and strategies for designing sound studies of onset are discussed.

Affect↗

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The lithium ratio as a guide to patient compliance.

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Adult↗

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Kinetics of erythrocyte lithium-sodium countertransport in patients with affective illness before and during lithium therapy.

Previous investigations have elucidated an erythrocyte lithium-sodium countertransport (LSC) system as the primary mechanism for extruding lithium from the cell, and this activity has been described in terms of Michaelis-Menten kinetics. In most clinical studies the maximum velocity (Vmax) of the LSC has been measured by estimating the rate of lithium efflux from lithium-loaded cells. To date, few studies have examined whether the affinity (Km) of the LSC for lithium might be altered in patients with affective disorders. In the present study we examined LSC kinetic parameters (Vmax, leak, Km, and in vitro lithium ratio) at baseline in 80 patients with affective disorder and 25 healthy control subjects, and after 6 weeks of lithium administration in 33 of the patients. No differences in Vmax were observed between any patient and control group, although Vmax was significantly lower in unipolar depressed men compared to bipolar men (P = 0.043). The affinity (Km) of the transport 'carrier' for lithium did not differentiate between patient and control groups. Chronic lithium administration caused a decreased Vmax in bipolar men (P = 0.015), an increase in the in vitro lithium ratio in bipolar men (P = 0.002) and bipolar women (P = 0.002), and a marginal increase in Km in bipolar men (P = 0.08) and bipolar women (P = 0.06). Although the present data do not demonstrate an underlying difference for Km between affectively ill patients and controls, they do indicate a decrease in the affinity of the transport 'carrier' for lithium after chronic lithium administration.

Adult↗

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Inhibitory effects of desmethylimipramine on the action of thyroxine on cardiac beta-receptors and myocardial phosphorylase.

The influence of chronic administration of desmethylimipramine (DMI) on the actions of thyroxine (T4) on rat heart was studied. Administration od DMI (10 mg/kg, i.p., twice daily) for 7 days did not alter the cardiac beta-adrenergic receptor density or the affinity for (-)[3H]dihydroalprenolol (3H-DHA) but diminished the activation of myocardial phosphorylase produced by isoproterenol. Chronic injections of T4 (500 microgram/rat) for 5 days caused an increase in the number of beta-adrenergic receptors in the heart and potentiated the stimulatory effect of isoproterenol on cardiac phosphorylase alpha activity. When DMI was administered concomitantly with T4, there was no increase in the density of myocardial beta-adrenergic receptors and the T4-induced potentiation of the activation of heart phosphorylase by isoproterenol was abolished. However, simultaneous treatment of the rats with DMI and TR4 did not diminish the positive chronotropic effect of T4. It was concluded that DMI, while not affecting the population of cardiac beta-adrenergic receptors by itself, prevents the increase in these receptors produced by T4 and obviates the T4-induced potentiation of phosphorylase activation by isoproterenol. That the tachycardia caused by T4 persists in hearts in which DMI has impeded the increase in myocardial beta-receptors suggests that the increase in heart rate is not dependent on cardiac beta-adrenergic receptor density.

Animals↗