Whereas the BDNF hypothesis predicts that agents directly promoting BDNF function might be as clinically effective as antidepressants, currently no such compounds are available. Perhaps targeting the small molecules that regulate BDNF or other neurotrophic factors might prove useful.23 This has led investigators back to CREB proteins and the cAMP second messenger system. The BDNF gene is induced in vitro and in vivo by CREB proteins. Virtually all antidepressants increase levels of CREB protein expression and function in several brain regions, including the hippocampus. Inhibitors of phosphodiesterases (PDEs), the enzymes that degrade cAMP also raise levels of CREB proteins; this drug strategy is being pursued.23 For example, rolipram, a phosphodiesterase 4 inhibitor, shows some antidepressant effectiveness,24 although it has too many adverse effects (emesis, sedation) for use in humans.
A variety of other clinical and experimental findings seem to support the hypothesis that dysfunction of the system controlling neuronal plasticity or remodeling contributes to the pathophysiology of mood disorders. For example, a recent study that used high-resolution MRI found greater cortical gray matter density in lithium(Drug information on lithium)-treated patients with bipolar disorder than in controls,25 whereas previous studies in untreated patients with bipolar disorder showed decreases of gray matter density in the same anterior limbic areas.
Studies of patients with bipolar disorder also show abnormalities in intracellular signal transduction (ie, second messenger systems). These include alterations in cAMP26 and another second messenger system involving protein kinase C signaling27 and the phosphatidylinositol pathway.28 In addition, intracellular calcium signaling systems, which are important in intracellular second messenger systems, showed differences in patients with bipolar disorder versus controls. It also has been shown that serotonin-induced intraplatelet calcium mobilization is enhanced in bipolar disorder.29
Other studies suggest that the intracellular calcium signaling system is a common mechanism by which diverse mood stabilizer medications (eg, lithium, valproic acid, carbamazepine(Drug information on carbamazepine)) may work in bipolar disorder.30 That a mood stabilizer's therapeutic effects (such as an antidepressant medication's effects) are often slow fits nicely with this model of their impact on second messengers, transcription factors, gene expression, and BDNF- mediated neuronal stabilization.31
In practical terms, the importance and ubiquity of second messenger systems, including PDEs, means that they are associated with a wide variety of diseases (not just affective illnesses). PDEs are being actively investigated for use in dementia and other memory disorders. Specific PDE inhibitors (such as rolipram) are being actively studied for their activity in immunomodulation—researchers are looking for impact on autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, diabetes mellitus, Crohn disease, and ulcerative colitis. Because of their involvement with inflammatory and immunomodulatory responses, asthma and chronic obstructive pulmonary disease are also being investigated.32 There is even a recent report that demonstrated some potential for rolipram as an antipsychotic agent.33GENETIC STUDIES
Further confirmation of the neurogenic hypothesis may come directly from genetic studies. Gene variations encountered in DNA samples of groups of affectively ill patients are being reproduced in genetic knockout mice. Using special techniques, molecular biologists create similar abnormalities in mice by introducing or removing a specific gene variation into a mouse's genome. The effects on overall animal behavior, hippocampal architecture, monoamine production, synaptic transmission, second messengers, cAMP, intracellular calcium, protein kinase, BDNF, and so on are then compared with behavior, brain architecture, and biochemical findings in control, "wild type" mice.
Some caution must accompany this type of investigation, since depres-sion is a complex phenomenon in which many genes may be involved. Nongenetic factors are likely to be involved as well, including psychological factors (eg, chronic stress, interpersonal loss, bereavement, blows to self-esteem) or medical disorders (eg, thyroid or adrenal abnormalities, diabetes, collagen(Drug information on collagen) disorders, Parkinson disease). Specifically, it is known from epidemiological studies that only 30% to 50%34 of the risk for depression is genetic.34,35
It is also not clear whether it makes sense to completely separate out unipolar major depressive disorder from a bipolar affective illness. The 2 disorders have some familial relationship, since rates of major depressive disorder are elevated in relatives of patients with bipolar disorder. However, they are not the same condition, and twin studies of patients with bipolar disorder show greater likelihood of bipolar disorder than unipolar disorder in the other twin.
Another type of genetic study begins with a known neurotrophin, such as BDNF, and looks toward identification of the spectrum of genes associated with its effects on synaptic plasticity.36 These studies start with an analysis of cell cultures of hippocampal neurons and look for increased expression of various genes within minutes and hours of adding BDNF. In addition, BDNF-induced gene transcripts also may be followed with in vivo animal studies. In recent studies, the loss of BDNF in genetically modified mice seemed to attenuate antidepressant efficacy, providing further support for the neurotrophin hypothesis of depression.37 There is also preliminary evidence that BDNF polymorphisms or mutations are asso- ciated with human mood disorders.38
Obviously, many other genetic approaches are possible. Linking genes to second messengers, neurotrophins, changing brain architecture and function, and behavior and affect is not simple, but progress is likely.CONCLUSION
Of necessity, what I have outlined is sketchy and oversimplified. However, there is much new evidence from multiple investigations and approaches in humans and animals to suggest that the effectiveness of SSRIs and other antidepressants (as well as mood stabilizers) lies not just with direct effects on synaptic transmission, but (more important) with what happens intracellularly in receiving neurons. Evidence is accumulating that complex effects within neurons exposed to amplified signaling affect the receiving neuron's nucleus and DNA. Genes are turned on, leading to adaptive changes, including neurogenesis, and synaptic growth leading to beneficial changes within important brain areas, such as the hippocampus.
Understanding affective illness as a brain problem (although one influenced by stress and other environmental impacts) will very likely result in new treatments. These will probably include new medications that use novel mechanisms of action that will enhance the functioning of an adaptable and ever-changing brain.