Novel Targets, Novel Meds for Depression and Bipolar

To start, neurotransmitters, particularly the three we are familiar with, are only a small part of the picture in mood disorders, with the new and old generation antidepressants that target them representing at best a partial remedy for many patients. Other places to look involve a number of processes vital to cellular function rather than just mood, separate but interrelated, including:

• Neurotrophins - proteins that mediate neuron survival, inhibit cell death, and modulate synaptic neurotransmitter activity, which include nerve growth factor and brain-derived nerve growth factor (BDNF). It is believed these are secreted from the neuron and bind to specific tyrosine kinase (Trk) postsynaptic receptors. BDNF also acts as both an excitatory and inhibitory molecule through different mechanisms.
• Bcl-2 is a neuroprotective protein whose numbers are multiplied by a cellular signaling cascade that begins with nerve growth factor acting through several intermediate steps on the chemical pathway, MAP kinase. Increased bcl-2 protects neurons from ischemia, free radicals, excessive glutamate, and other catastrophes. The protein may also promote nerve cell growth and regeneration.
• The cAMP-CREB cascade is a signaling pathway that acts on BDNF and plays a role in neurogenesis - new cell growth - in the hippocampus. According to Manji et al, "it is quite plausible that alterations in hippocampal neurogenesis are fundamental to the clinical syndrome of depression."

Dr Manji and other scientists such as Ron Duman PhD at Yale have discovered that antidepressants or lithium indirectly enhanced one or more of the above processes in rats, leading researchers to speculate that much of the benefit of our medications may lie well downstream of the three neurotransmitters we know so well. This raises the possibility of formulating compounds with a direct action on novel targets, as well as taking a second look at what we already have in the stockpile.

One such target could be PDE, the enzyme responsible for breaking down cAMP. One "PDE inhibitor," rolipram, already exists, with rapid onset of action but with burdensome side effects. Second generation drugs are in development. Also under investigation is BDNF, experimentally administered to patients with ALS. A gleam in the eyes of researchers are “bcl-2 enhancers.” Pramipexole, a Parkinson’s drug acting mainly on dopamine, has also been found to increase bcl-2 in several brain areas, and shows antidepressant effects, according to preliminary studies. Larger studies at the NIMH are underway.

The trouble with current antidepressant treatment, the authors conclude, lies in the faulty assumption that our cell circuitry is intact and will faithfully relay meds-enhanced neurotransmitter activity to their intended targets. In fact, we are discovering just the opposite, that some of our brain cells take the kind of physical beating that necessitates “both trophic and neurochemical support” to restore neuronal connectivity and molecular signaling.

One day, cAMP, bcl-2, BDNF, and the rest may be as familiar to us as serotonin is today, not as academic curiosities, but as the targets of new drugs that promise to radically improve our lives. Bring on the CREBzac.