Apoptosis can be inhibited by maintaining high levels of neurotrophic factors. Atypical, but not typical, antipsychotics increase levels of neurotrophins, such as NGF and BDNF.4 In addition, the Bcl-2 family of proteins inhibits apoptosis,9 and drugs such as lithium and valproate can induce Bcl-2 and protect against apoptosis and neuronal loss.3
Restore white-matter integrity. Numerous studies using diffusion tensor imaging have revealed that myelin is reduced or lacks integrity in schizophrenia. This results in loss of critical connectivity among brain regions, which might explain psychotic and cognitive symptoms. One possible way to repair white matter, which becomes more damaged after multiple psychotic episodes, is to use drugs indicated to treat the demyelinating disorder multiple sclerosis. Antagonists of LINGO-1, a negative regulator of axonal myelination, are a prominent possibility; a recent study reported altered signaling of LINGO-1 in schizophrenia.10
Decrease excessive glutamate. Because glutamate is neurotoxic and might contribute to brain-tissue loss during psychosis, it is important to reduce glutamate activity in schizophrenia. Lamotrigine and valproate are both known to do that.11 Several studies indicate that adjunctive lamotrigine might be helpful in schizophrenia.12
Inhibit caspase-3, also known as the “death cascade,” which is involved in brain-tissue loss. Eicosapentaenoic acid is an omega-3 fatty acid that inhibits caspase-3. Interestingly, omega-3 levels in patients with schizophrenia are significantly lower than in healthy subjects.13 Lithium also can inhibit caspase-3.
Do these proposals sound radical?
Most of the recommendations I’ve made here are not employed in the clinical practice of psychiatry. These ideas must be put to the test in controlled clinical trials.
The crux of my argument is that we need to think outside the “dopamine box” and focus on brain repair if we are to make progress in reversing, even preventing, neurodegeneration and clinical deterioration in this disabling brain syndrome. Just as cancer often is treated with rational polypharmacy, schizophrenia might need a similar approach. To vanquish schizophrenia—a goal that has eluded us—it is imperative to pursue radically novel and disruptive therapeutic strategies. The ideas I’ve listed here sound the call that the quest to repair the brain in schizophrenia must begin, and soon.