Studies have reported interpersonal psychotherapy effective for major depression, which is generally acknowledged to have an important biological component. Yet, no studies have correlated a response to interpersonal psychotherapy with the synaptic processes thought to mediate antidepressant effects. Dr. Aldenhoff believes that previous attempts to link biological changes in the brain with responses to interpersonal psychotherapy may have failed because researchers have typically focused on changes within the synapse. He describes alternative sites where neuro-biological changes may mediate responses to interpersonal psychotherapy.
Dr. Aldenhoff noted that in looking at the dietary depletion of tryptophan, the amino acid precursor of serotonin (a marker for involvement of synaptic mechanisms in antidepressant response) a 1994 study failed to show an exacerbation of depression in patients deprived of dietary tryptophan. This negative finding might mean that the dysregulation of serotonergic neurotransmission thought to be involved in the pathophysiology of depression can occur at sites other than the synapse. Serotonin function may be one of several possible triggers for a cascade of neuro-chemical effects that result in a "final common pathway" that is associated with the "self-healing" processes that appear as an antidepressant response. Other reports show similar response rates in patients treated with antidepressants that predominantly affect neurotransmitters other than serotonin.
The final common intracellular pathway associated with antidepressant response may involve effects on intracellular calcium concentrations. Dr. Aldenhoff's group measured effects of the mitogen phytohemagglutinin on intracellular calcium levels in the lymphocytes of normal and depressed patients. In normal subjects, 40% of cells exhibited an oscillatory increase in intracellular calcium concentration, compared with 20% of cells from depressed patients. A subsequent study of 25 depressed patients and 25 healthy controls found normalizing effects on intracellular calcium concentrations following eight weeks of interpersonal therapy. Pharmacotherapy produced similar changes on intracellular calcium concentrations in a subgroup of patients with severe depression.
Another final common pathway may involve effects on gene expression, which is mediated in part by transcription factors such as the cyclic AMP response element-binding protein. Dr. Aldenhoff's group has found increased concentrations of this protein in patients treated with the antidepressants imipramine and fluoxetine. Increased concentrations of this binding protein also were found to increase in responders to an eight-week course of interpersonal psychotherapy. Non-responders showed no change in the concentration of this protein.
Dr. Aldenhoff and his colleagues acknowledge the need for longer-term studies to illuminate a possible relationship between antidepressant response and changes in the concentration of cyclic AMP element-binding protein.