Another source of evidence supporting the neurotrophic hypothesis of depression comes from studies of the direct effects of BDNF on emotional regulation. Direct infusion of BDNF into the midbrain, hippocampus, and lateral ventricles of rodents has an antidepressant-like effect in animal models. Moreover, all known classes of antidepressants are associated with an increase in BDNF levels in animal models with chronic (but not acute) administration. This increase in BDNF levels is consistently associated with increased neurogenesis in the hippocampus in these animal models. Other interventions thought to be effective in the treatment of major depression, including electroconvulsive therapy, also appear to robustly stimulate BDNF levels and hippocampus neurogenesis in animal models.
Human studies seem to support the animal data on the role of neurotrophic factors in stress states. Depression appears to be associated with a drop in BDNF levels in the cerebrospinal fluid and serum as well as with a decrease in tyrosine kinase receptor B activity. Conversely, administration of antidepressants increases BDNF levels in clinical trials and may be associated with an increase in hippocampus volume in some patients.
Much evidence supports the neurotrophic hypothesis of depression, but not all evidence is consistent with this concept. Animal studies in BDNF knockout mice have not always suggested an increase in depressive or anxious behaviors that would be expected with a deficiency of BDNF. In addition, some animal studies have found an increase in BDNF levels after some types of social stress and an increase rather than a decrease in depressive behaviors with lateral ventricle injections of BDNF.
A proposed explanation for the discrepant findings on the role of neurotrophic factors in depression is that there are polymorphisms for BDNF that may yield very different effects. Mutations in the BDNF gene have been found to be associated with altered anxiety and depressive behavior in both animal and human studies.
Thus, the neurotrophic hypothesis continues to be intensely investigated and has yielded new insights and potential targets in the treatment of MDD.
The monoamine hypothesis of depression (Figure 30–2) suggests that depression is related to a deficiency in the amount or function of cortical and limbic serotonin (5-HT), norepinephrine (NE), and dopamine (DA).
Evidence to support the monoamine hypothesis comes from several sources. It has been known for many years that reserpine treatment, which is known to deplete monoamines, is associated with depression in a subset of patients. Similarly, depressed patients who respond to serotonergic antidepressants such as fluoxetine often rapidly suffer relapse when given diets free of tryptophan, a precursor of serotonin synthesis. Patients who respond to noradrenergic antidepressants such as desipramine are less likely to relapse on a tryptophan-free diet. Moreover, depleting catecholamines in depressed patients who have previously responded to noradrenergic agents likewise tends to be associated with relapse. Administration of an inhibitor of norepinephrine synthesis is also associated with a rapid return of depressive symptoms in patients who respond to noradrenergic but not necessarily in patients who had responded to serotonergic antidepressants.
Another line of evidence supporting the monoamine hypothesis comes from genetic studies. A functional polymorphism exists for the promoter region of the serotonin transporter gene, which regulates how much of the transporter protein is available. Subjects who are homozygous for the s (short) allele may be more vulnerable to developing major depression and suicidal behavior in response to stress. In addition, homozygotes for the s allele may also be less likely to respond to and tolerate serotonergic antidepressants. Conversely, subjects with the l (long) allele tend to be more resistant to stress and may be more likely to respond to serotonergic antidepressants.