Beyond dopamine: Brain repair tactics in schizophrenia

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:
   • amphetamine
   • cocaine
   • Cannabis
   • lipid peroxidation products
   • inflammatory cytokines.

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.

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:
   • amphetamine
   • cocaine
   • Cannabis
   • lipid peroxidation products
   • inflammatory cytokines.

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.

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:
   • amphetamine
   • cocaine
   • Cannabis
   • lipid peroxidation products
   • inflammatory cytokines.

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.