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Membrane phospholipids were measured in platelets of seven medication-free patients in the manic phase of bipolar affective disorder and seven healthy comparison subjects. The relative percentage of platelet membrane phosphatidylinositol-4,5-bisphosphate was significantly higher in the manic patients than in the comparison subjects. These results are consistent with an enhanced neuronal second messenger response after 5-hydroxytryptamine receptor stimulation followed by neurotransmitter release.

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OBJECTIVE: This investigation compared the efficacy of the monoamine oxidase inhibitor (MAOI) tranylcypromine with that of the tricyclic imipramine in the treatment of anergic bipolar depressive illness. METHOD: A controlled, double-blind comparison was used to study 56 outpatients who met operationalized criteria for anergic bipolar depression. Patients with bipolar I and II depression were equally distributed between comparison groups. Outcome was measured by the patient-rated Beck Depression Inventory and the clinician-rated Hamilton Rating Scale for Depression, Raskin Mania and Depression Scales, Clinical Global Impression Scale, and the Pittsburgh Reversed Vegetative Symptom Scale. Twenty-eight patients were treated with tranylcypromine and 28 with imipramine. Seventy-three percent of bipolar depressive patients screened for the study met criteria for anergic depression, consistent with previous findings from studies in bipolar illness that stretch back over 100 years. RESULTS: Tranylcypromine produced statistically significant superior outcome in terms of lower attrition, greater symptomatic improvement, and higher global response without increased risk of treatment-emergent hypomania or mania. CONCLUSIONS: The authors propose that the apparently superior efficacy of tranylcypromine in bipolar depression is specifically linked to anergia and reversed neurovegetative symptoms. Bipolar I and bipolar II patients had comparable outcomes, but bipolar I patients had a significantly greater risk of treatment-emergent mood swings. Although the relatively poor showing of imipramine warrants close scrutiny, these findings provide further documentation of the utility of MAOIs in patients presenting with anergia, motor retardation, hyperphagia, and/or hypersomnia.

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Few studies on the pharmacokinetics and plasma drug levels of monoamine oxidase (MAO) inhibitors have been performed, despite several decades of clinical use. Older MAO inhibitors such as tranylcypromine produce neuronal accumulation of neurotransmitter amines as a consequence of functionally irreversible MAO inhibition. Typically, these agents are cleared from the body rapidly, so plasma drug levels are not correlated with MAO inhibition. However, recent research has demonstrated that tranylcypromine can produce direct and reversible pharmacologic effects, as well as clinical mood effects, that appear more closely related to transient plasma tranylcypromine levels than to the degree of MAO inhibition. In addition, a new generation of reversible MAO inhibitors is now being introduced. The antidepressant actions of these latter agents will almost certainly be directly influenced by pharmacokinetic factors. This review summarizes the existing pharmacokinetic literature on tranylcypromine, phenelzine, moclobemide, and selegiline. These drugs and others like them promise to become increasingly important in modern psychopharmacologic practice.

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Because lithium is extruded from cells by means of coupled exchange for external sodium (Na+-Li+ countertransport), we hypothesized that clinical treatment with this agent could lead to significant augmentation of net cellular sodium influx. We therefore directly measured sodium influx in vitro using erythrocytes (RBCs) from 27 depressed bipolar patients. When cells were loaded with sufficient lithium to maximally stimulate Na+-Li+ countertransport activity (5.1 mmoles/1 RBCs), there was a significant 44% increase in mean sodium influx. To approximate clinical conditions more closely, we also studied sodium influx in a subset of eight subjects after loading cells with 0, 0.40, 0.66, and 1.55 mmoles lithium/1 RBCs. Over this range of lithium concentrations, sodium influx increased progressively. In separate experiments, we found that RBC sodium content measured in eight subjects did not change significantly during a 4-week course of lithium treatment. Thus, excess cellular sodium during such treatment may be extruded by increased activity of the membrane Na+-K+ pump, which has electrogenic properties and thereby could augment the membrane potential. In the nervous system, such an effect could stabilize cell membranes electrophysiologically, and possibly affect processes, such as behavioral sensitization or kindling, proposed to have a role in the development of recurrent affective disorders.

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