For the past 60 years, the standard of care has remained one-dimensional in this brain syndrome, even though the clinical and neurobiological complexities of schizophrenia are multidimensional. Dopamine D2 receptor antagonists, discovered serendipitously in the 1950s, have remained the mainstay of treatment, despite momentous insights about the neurodevelopmental and neurodegenerative processes of schizophrenia.
Why do we ignore abundant evidence that the brain in schizophrenia needs extensive structural repair, not simply a reduction in the activity of a single neurotransmitter in the mesolimbic dopamine tract? Perhaps the age-old dogmatic pessimism that neurodegeneration cannot be reversed has inhibited the field from attempting to escape the dopamine box, so to speak, and from developing innovative, even radical, approaches to repair of the brain of persons with schizophrenia.
But radical thinking is justified when dealing with a cruel brain syndrome that disables young adults in the prime of life.
We should exploit neuroprotective tactics
Several neuroprotective approaches to preventing or reversing the degenerative changes across brain regions in schizophrenia are now recognized. Indirect evidence exists for such interventions in animal models, but the results of few controlled human studies have been published.
Here are my proposals for using neuroprotective tactics to address the unmet need to repair the brain of patients ravaged by neurotoxic psychotic relapses.
Promote 100% adherence to antipsychotic therapy. The simplest tactic to protect the brain from atrophy in patients with schizophrenia is to use long-acting injectable antipsychotic agents immediately after the first psychotic episode. The risk of a psychotic relapse is far lower (7-fold lower, according to a study performed at the University of California, Los Angeles, that soon will be published) with an injectable medication than with oral medication in first-episode patients. Preventing psychotic episodes is, logically, the most important neuroprotective tactic.
Enhance neurogenesis. The brain has 2 neurogenic regions that produce progenitor cells (stem cells) that gradually mature and differentiate into neurons and glia. That is how the brain naturally replenishes itself throughout life. This adult neurogenesis process, carried out in the dentate gyrus of the hippocampus and in the subventricular zone, stops during psychosis but resumes when psychosis remits.
Second-generation antipsychotics (but not first-generation agents) stimulate neurogenesis in animals.1 Haloperidol, in fact, does the opposite—suppressing neurogenesis and causing neuronal death via 15 different molecular mechanisms (see my editorial, “Haloperidol clearly is neurotoxic. Should it be banned?,” in the July 2013 issue).
Other psychotropics also induce neurogenesis, including selective serotonin reuptake inhibitors (SSRIs), which increase hippocampal neurogenesis (atypical antipsychotics appear to increase neurogenesis in the subventricular zone).2 SSRIs often have been used in schizophrenia patients for 2 common comorbid conditions: depression and anxiety. These agents can help regenerate brain tissue, in addition to providing their approved therapeutic indications.
Lithium and valproate have been shown to be neuroprotective3 and to stimulate neurogenesis. Both are often used in schizoaffective disorder, bipolar type; they can exert a neuroprotective effect in addition to their clinical usefulness. The combination of an SSRI or lithium with a second-generation antipsychotic could be synergistic in turbocharging neurogenesis. This sounds like polypharmacy—but it is a rational approach that deserves to be put to the test.
Increase neurotrophins, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). When neurotrophin levels decline, the brain starts shrinking because of apoptosis. Psychosis lowers neurotrophins drastically—by approximately 60%. Atypical antipsychotics have been reported to increase the level of neurotrophins; haloperidol actually lowers those levels.4
Decrease inflammation. Psychosis has been shown to be associated with neuro-inflammation, as reflected in a surge of pro-inflammatory cytokines (released from activated microglia).5 A rise in interleukin-6, tumor necrosis factor-alpha, interferon-gamma, and other pro-inflammatory markers has been extensively documented in many studies.
With that observed rise in mind, several controlled studies have shown that adding an anti-inflammatory agent (aspirin, a nonsteroidal anti-inflammatory drug, a COX-2 inhibitor, or minocycline) to an antipsychotic can accentuate the therapeutic response, especially during a first episode of psychosis.6 Note also that second-generation antipsychotics have anti-inflammatory effects7 as well that might be part of their efficacy beyond blocking dopamine D2 receptors.
Decrease free radicals. Microglia are activated by psychosis to release free radicals, also known as reactive oxygen species; these include nitric oxide, superoxide, and peroxynitrate. All these species are destructive to brain tissue. Using an adjunctive strong antioxidant, such as N-acetyl cysteine,8 with an antipsychotic might help neutralize destructive effects of free radicals and protect the brain from tissue loss during a psychotic episode.
Avoid apoptosis inducers. Several substances can initiate programmed cell death (apoptosis), which is triggered during psychosis (believed to be caused by increased dopamine and, possibly, glutamate, activity) and which leads to brain atrophy. Patients with schizophrenia must be protected from these apoptosis inducers:
• lipid peroxidation products
• inflammatory cytokines.