NPA 2015

LAS VEGAS – For many cannabis users who are trying to quit their habit, psychotherapy doesn’t seem to be enough, according to an expert.

“The addition of a pharmacological intervention might be helpful for [these people],” Dr. Frances R. Levin said at the annual psychopharmacology update held by the Nevada Psychiatric Association. “There are some promising medications out there, but we’re just at the beginning of this whole era of research.”

Yet, while the literature is nascent, both the problem and complexity of cannabis use are growing.

According to the Substance Abuse and Mental Health Services Administration, in 1993, only 7% of those seeking treatment for substance abuse were addicted to marijuana. In 2011, just under one-fifth of all substance abuse treatment patients wanted help quitting their cannabis use. Meanwhile, in that same time period, people seeking treatment for alcohol abuse went from 57% to 39%.

Part of the rise is tied to more adolescents using the drug, said Dr. Levin, who is the Kennedy-Leavy Professor of Clinical Psychiatry at Columbia University, New York. “They are certainly overrepresented.”

With nearly 20 million Americans who say they’ve used cannabis in the past month, it is the most widely used illicit drug in the country, according to the National Survey on Drug Use and Health. However, because some states and the District of Columbia recently have legalized the use of cannabis for recreational or medical purposes, or both, Dr. Levin said the drug’s illicit status is conditional. “What’s interesting is that it’s a growing problem. Ten percent of first-time users, 17% of first-time adolescent users, and 50% of daily users will develop cannabis use disorder.”

Of particular concern are synthetic cannabinoids, said Dr. Levin, who explained that the manufactured drugs are dissolved in acetone or alcohol, and then sprayed “indiscriminately” over dried plant materials, making the concentration of THC, the main psychoactive component of cannabis, hard to gauge. In addition, the synthetic version of the drug is a full, not partial agonist. “This makes them quite dangerous,” Dr. Levin said.

Manufacturers of the synthetic drug products largely have managed to stay a step ahead of regulation by constantly creating compounds that have yet to be scheduled by the Food and Drug Administration. Although the products are often packaged and marketed as herbal incense with names like “Spice” or “K-2”, the contents of the packages typically are smoked by adolescents and by those seeking to avoid failing drug tests since, according to Dr. Levin, synthetic cannabinoids also are undetectable on THC-based drug tests.

“Even though they are called ‘cannabinoid,’ these are a very different drug,” Dr. Levin said. Episodes of paranoia, anxiety, and tachycardia that sometimes last for months have been reported in case studies. “It’s very different from what happens from smoking marijuana,” she said.

Meanwhile, over the past few decades, marijuana proper also has undergone a transformation, in large part because of advances in the way in which growers can manipulate the various cannabinoids in the different plant strains. For example, Dr. Levin said that in Colorado, where the drug is legal, it is possible to purchase marijuana with specific cannabinoids at different concentration levels, developed to “reportedly induce certain types of psychoactive effects.”

Regardless of whether users choose the more designer drug options, Dr. Levin said that compared with the 1970s when the concentration of THC in marijuana that was smoked was typically 1%-3%, now “all bets are off,” because the potency and effects are much higher. “Kids getting into smoking marijuana today could be getting concentrations of 10, 20, maybe even 40%. We have a very different drug today that these kids, as well as the adults, are being exposed to.”

When the drug is ingested orally, such as in baked goods, the concentrations absorbed by the body can be even more, although the highs are less predictable and can last as much as three times longer as when it is smoked.

Currently, the only therapies available to those who want to quit are psychotherapies. Whether pharmacologic treatments can keep pace with the spread of the disorder is in question. “I want to be optimistic, but at the moment, we just have signals,” said Dr. Levin, who said the most promising pharmacotherapeutic approaches in humans to date include gabapentin, which has been used successfully to treat alcohol dependence, and N-acetylcysteine (NAC).

Data are encouraging on the efficacy of gabapentin in adults with cannabis use disorder from a 12-week, randomized double-blind trial of 50 adults given either placebo or 1,200 mg of gabapentin divided into three daily doses (Neuropsychopharmacology 2012;37:689-98). Although the study group did not suffer severe withdrawal and did decrease their overall cannabis use, the group did not necessarily achieve complete abstinence. However, the overall executive functions scores of the study group did improve. A puzzling drawback to the trial, said Dr. Levin, was the study’s notable attrition rate. “Only 36% made it to the end of the trial. We need to find out why there was such a high dropout rate.”

NAC is another potential avenue of efficacious pharmaceutical cannabis use treatment, based on several studies, including one in 116 adolescents given either 1,200 mg of NAC or placebo twice daily (Am. J. Psychiatry 2012;169:805-12). These treatments were combined with 10 minutes of talk therapy for the 8-week duration of the trial. In this trial, there was only a 40% attrition rate, and the study group was twice as likely as controls to turn in cannabinoid-free urine each week. The results have led to a multicenter National Institute on Drug Abuse–sponsored trial of 300 people and NAC along with paid urine tests, although Dr. Levin said she was curious how NAC would perform without the contingency management of having to pay for the urine. “That would have to be another study,” she noted.

Perhaps seeing partial cessation as a viable endpoint also might improve outcomes. It’s a larger question that has already come up for debate in studies of alcohol abuse where abject abstinence is not always the required outcome. It’s a point worth considering for cannabis use, said Dr. Levin, particularly when it can take weeks for cannabinoids to leave the urine. “Maybe continuous abstinence is too high a bar,” Dr. Levin said. “You talk to people who want to go from using all the time to maybe just smoking a joint at night. Who is to say that is the wrong outcome measure?”

Dr. Levin said she has received financial support from U.S. World Meds and GW Pharmaceuticals.

[email protected]                                                                     On Twitter @whitneymcknight

LAS VEGAS – For many cannabis users who are trying to quit their habit, psychotherapy doesn’t seem to be enough, according to an expert.

“The addition of a pharmacological intervention might be helpful for [these people],” Dr. Frances R. Levin said at the annual psychopharmacology update held by the Nevada Psychiatric Association. “There are some promising medications out there, but we’re just at the beginning of this whole era of research.”

Yet, while the literature is nascent, both the problem and complexity of cannabis use are growing.

According to the Substance Abuse and Mental Health Services Administration, in 1993, only 7% of those seeking treatment for substance abuse were addicted to marijuana. In 2011, just under one-fifth of all substance abuse treatment patients wanted help quitting their cannabis use. Meanwhile, in that same time period, people seeking treatment for alcohol abuse went from 57% to 39%.

Part of the rise is tied to more adolescents using the drug, said Dr. Levin, who is the Kennedy-Leavy Professor of Clinical Psychiatry at Columbia University, New York. “They are certainly overrepresented.”

With nearly 20 million Americans who say they’ve used cannabis in the past month, it is the most widely used illicit drug in the country, according to the National Survey on Drug Use and Health. However, because some states and the District of Columbia recently have legalized the use of cannabis for recreational or medical purposes, or both, Dr. Levin said the drug’s illicit status is conditional. “What’s interesting is that it’s a growing problem. Ten percent of first-time users, 17% of first-time adolescent users, and 50% of daily users will develop cannabis use disorder.”

Of particular concern are synthetic cannabinoids, said Dr. Levin, who explained that the manufactured drugs are dissolved in acetone or alcohol, and then sprayed “indiscriminately” over dried plant materials, making the concentration of THC, the main psychoactive component of cannabis, hard to gauge. In addition, the synthetic version of the drug is a full, not partial agonist. “This makes them quite dangerous,” Dr. Levin said.

Manufacturers of the synthetic drug products largely have managed to stay a step ahead of regulation by constantly creating compounds that have yet to be scheduled by the Food and Drug Administration. Although the products are often packaged and marketed as herbal incense with names like “Spice” or “K-2”, the contents of the packages typically are smoked by adolescents and by those seeking to avoid failing drug tests since, according to Dr. Levin, synthetic cannabinoids also are undetectable on THC-based drug tests.

“Even though they are called ‘cannabinoid,’ these are a very different drug,” Dr. Levin said. Episodes of paranoia, anxiety, and tachycardia that sometimes last for months have been reported in case studies. “It’s very different from what happens from smoking marijuana,” she said.

Meanwhile, over the past few decades, marijuana proper also has undergone a transformation, in large part because of advances in the way in which growers can manipulate the various cannabinoids in the different plant strains. For example, Dr. Levin said that in Colorado, where the drug is legal, it is possible to purchase marijuana with specific cannabinoids at different concentration levels, developed to “reportedly induce certain types of psychoactive effects.”

Regardless of whether users choose the more designer drug options, Dr. Levin said that compared with the 1970s when the concentration of THC in marijuana that was smoked was typically 1%-3%, now “all bets are off,” because the potency and effects are much higher. “Kids getting into smoking marijuana today could be getting concentrations of 10, 20, maybe even 40%. We have a very different drug today that these kids, as well as the adults, are being exposed to.”

When the drug is ingested orally, such as in baked goods, the concentrations absorbed by the body can be even more, although the highs are less predictable and can last as much as three times longer as when it is smoked.

Currently, the only therapies available to those who want to quit are psychotherapies. Whether pharmacologic treatments can keep pace with the spread of the disorder is in question. “I want to be optimistic, but at the moment, we just have signals,” said Dr. Levin, who said the most promising pharmacotherapeutic approaches in humans to date include gabapentin, which has been used successfully to treat alcohol dependence, and N-acetylcysteine (NAC).

Data are encouraging on the efficacy of gabapentin in adults with cannabis use disorder from a 12-week, randomized double-blind trial of 50 adults given either placebo or 1,200 mg of gabapentin divided into three daily doses (Neuropsychopharmacology 2012;37:689-98). Although the study group did not suffer severe withdrawal and did decrease their overall cannabis use, the group did not necessarily achieve complete abstinence. However, the overall executive functions scores of the study group did improve. A puzzling drawback to the trial, said Dr. Levin, was the study’s notable attrition rate. “Only 36% made it to the end of the trial. We need to find out why there was such a high dropout rate.”

NAC is another potential avenue of efficacious pharmaceutical cannabis use treatment, based on several studies, including one in 116 adolescents given either 1,200 mg of NAC or placebo twice daily (Am. J. Psychiatry 2012;169:805-12). These treatments were combined with 10 minutes of talk therapy for the 8-week duration of the trial. In this trial, there was only a 40% attrition rate, and the study group was twice as likely as controls to turn in cannabinoid-free urine each week. The results have led to a multicenter National Institute on Drug Abuse–sponsored trial of 300 people and NAC along with paid urine tests, although Dr. Levin said she was curious how NAC would perform without the contingency management of having to pay for the urine. “That would have to be another study,” she noted.

Perhaps seeing partial cessation as a viable endpoint also might improve outcomes. It’s a larger question that has already come up for debate in studies of alcohol abuse where abject abstinence is not always the required outcome. It’s a point worth considering for cannabis use, said Dr. Levin, particularly when it can take weeks for cannabinoids to leave the urine. “Maybe continuous abstinence is too high a bar,” Dr. Levin said. “You talk to people who want to go from using all the time to maybe just smoking a joint at night. Who is to say that is the wrong outcome measure?”

Dr. Levin said she has received financial support from U.S. World Meds and GW Pharmaceuticals.

[email protected]                                                                     On Twitter @whitneymcknight

LAS VEGAS – For many cannabis users who are trying to quit their habit, psychotherapy doesn’t seem to be enough, according to an expert.

“The addition of a pharmacological intervention might be helpful for [these people],” Dr. Frances R. Levin said at the annual psychopharmacology update held by the Nevada Psychiatric Association. “There are some promising medications out there, but we’re just at the beginning of this whole era of research.”

Yet, while the literature is nascent, both the problem and complexity of cannabis use are growing.

According to the Substance Abuse and Mental Health Services Administration, in 1993, only 7% of those seeking treatment for substance abuse were addicted to marijuana. In 2011, just under one-fifth of all substance abuse treatment patients wanted help quitting their cannabis use. Meanwhile, in that same time period, people seeking treatment for alcohol abuse went from 57% to 39%.

Part of the rise is tied to more adolescents using the drug, said Dr. Levin, who is the Kennedy-Leavy Professor of Clinical Psychiatry at Columbia University, New York. “They are certainly overrepresented.”

With nearly 20 million Americans who say they’ve used cannabis in the past month, it is the most widely used illicit drug in the country, according to the National Survey on Drug Use and Health. However, because some states and the District of Columbia recently have legalized the use of cannabis for recreational or medical purposes, or both, Dr. Levin said the drug’s illicit status is conditional. “What’s interesting is that it’s a growing problem. Ten percent of first-time users, 17% of first-time adolescent users, and 50% of daily users will develop cannabis use disorder.”

Of particular concern are synthetic cannabinoids, said Dr. Levin, who explained that the manufactured drugs are dissolved in acetone or alcohol, and then sprayed “indiscriminately” over dried plant materials, making the concentration of THC, the main psychoactive component of cannabis, hard to gauge. In addition, the synthetic version of the drug is a full, not partial agonist. “This makes them quite dangerous,” Dr. Levin said.

Manufacturers of the synthetic drug products largely have managed to stay a step ahead of regulation by constantly creating compounds that have yet to be scheduled by the Food and Drug Administration. Although the products are often packaged and marketed as herbal incense with names like “Spice” or “K-2”, the contents of the packages typically are smoked by adolescents and by those seeking to avoid failing drug tests since, according to Dr. Levin, synthetic cannabinoids also are undetectable on THC-based drug tests.

“Even though they are called ‘cannabinoid,’ these are a very different drug,” Dr. Levin said. Episodes of paranoia, anxiety, and tachycardia that sometimes last for months have been reported in case studies. “It’s very different from what happens from smoking marijuana,” she said.

Meanwhile, over the past few decades, marijuana proper also has undergone a transformation, in large part because of advances in the way in which growers can manipulate the various cannabinoids in the different plant strains. For example, Dr. Levin said that in Colorado, where the drug is legal, it is possible to purchase marijuana with specific cannabinoids at different concentration levels, developed to “reportedly induce certain types of psychoactive effects.”

Regardless of whether users choose the more designer drug options, Dr. Levin said that compared with the 1970s when the concentration of THC in marijuana that was smoked was typically 1%-3%, now “all bets are off,” because the potency and effects are much higher. “Kids getting into smoking marijuana today could be getting concentrations of 10, 20, maybe even 40%. We have a very different drug today that these kids, as well as the adults, are being exposed to.”

When the drug is ingested orally, such as in baked goods, the concentrations absorbed by the body can be even more, although the highs are less predictable and can last as much as three times longer as when it is smoked.

Currently, the only therapies available to those who want to quit are psychotherapies. Whether pharmacologic treatments can keep pace with the spread of the disorder is in question. “I want to be optimistic, but at the moment, we just have signals,” said Dr. Levin, who said the most promising pharmacotherapeutic approaches in humans to date include gabapentin, which has been used successfully to treat alcohol dependence, and N-acetylcysteine (NAC).

Data are encouraging on the efficacy of gabapentin in adults with cannabis use disorder from a 12-week, randomized double-blind trial of 50 adults given either placebo or 1,200 mg of gabapentin divided into three daily doses (Neuropsychopharmacology 2012;37:689-98). Although the study group did not suffer severe withdrawal and did decrease their overall cannabis use, the group did not necessarily achieve complete abstinence. However, the overall executive functions scores of the study group did improve. A puzzling drawback to the trial, said Dr. Levin, was the study’s notable attrition rate. “Only 36% made it to the end of the trial. We need to find out why there was such a high dropout rate.”

NAC is another potential avenue of efficacious pharmaceutical cannabis use treatment, based on several studies, including one in 116 adolescents given either 1,200 mg of NAC or placebo twice daily (Am. J. Psychiatry 2012;169:805-12). These treatments were combined with 10 minutes of talk therapy for the 8-week duration of the trial. In this trial, there was only a 40% attrition rate, and the study group was twice as likely as controls to turn in cannabinoid-free urine each week. The results have led to a multicenter National Institute on Drug Abuse–sponsored trial of 300 people and NAC along with paid urine tests, although Dr. Levin said she was curious how NAC would perform without the contingency management of having to pay for the urine. “That would have to be another study,” she noted.

Perhaps seeing partial cessation as a viable endpoint also might improve outcomes. It’s a larger question that has already come up for debate in studies of alcohol abuse where abject abstinence is not always the required outcome. It’s a point worth considering for cannabis use, said Dr. Levin, particularly when it can take weeks for cannabinoids to leave the urine. “Maybe continuous abstinence is too high a bar,” Dr. Levin said. “You talk to people who want to go from using all the time to maybe just smoking a joint at night. Who is to say that is the wrong outcome measure?”

Dr. Levin said she has received financial support from U.S. World Meds and GW Pharmaceuticals.

[email protected]                                                                     On Twitter @whitneymcknight

LAS VEGAS – By ignoring schizophrenia’s symptomatology and focusing instead on its biomarkers and other implicated factors, researchers are homing in on treatments and interventions for the disease, according to an expert.

“The developmental model of schizophrenia suggests ... the field is now moving toward treatments better targeted to causes,” Dr. Matcheri S. Keshavan said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Whitney McKnight/Frontline Medical News

Clinicians need to understand that the disease is not homogeneous but more like a syndrome that can present in a variety of ways, according to Dr. Keshavan, Stanley Cobb Professor of Psychiatry at Harvard Medical School, Boston.

The stars emerging in the constellation many researchers are now using to chart the disease’s etiology range from neurobiologic disruptions, to drug use, to genetics, and several other possible factors. Reductions in stress, preventing drug use, and proactive cognitive support, as well as the development of targeted pharmacologic interventions are all currently being explored as ways to mitigate the disease.

‘Pathophysiological hits’

Whereas an excess of dopamine and hypersensitive dopamine receptors in the limbic region of the brain previously were thought to increase the risk for schizophrenia, Dr. Keshavan said the latest thinking is that there also might be cortical dopamine deficits, leading to a variety of symptoms, including psychosis. “Too little cortical dopamine might account for cognitive impairments and medical symptoms, whereas too much limbic dopamine might account for psychosis,” Dr. Keshavan said.

Beyond dopamine dysfunction, Dr. Keshavan said he and others have observed that higher levels of brain glutamate in adolescents correlate with more schizotypal symptoms, leading him to consider that there might be a problem with cortical glutaminergic regulation.

The pathophysiology of these changes is still uncertain, but Dr. Keshavan said several novel pharmacologic intervention trials are now underway, including some intended to reverse cognitive deficits by targeting GABA allosteric modulators to help correct glutaminergic dysfunction.

Also occurring in adolescence, both preceding and during schizophrenia’s prodromal phase, is a depletion of gray matter in the brain, particularly in boys. Also, a decrease in the brain’s plasticity because of exaggerated synaptic pruning by the adolescent brain, an otherwise normal function, has been cited as a risk factor for schizophrenia. Additionally, research into disruptions of the adolescent’s maturing stress response system has shown that for some, prolonged periods of stress can lead to an imbalance of cortical cognitive control.

Such brain imbalances often are thought to be related to a series of “pathophysiological hits” as Dr. Keshavan called them.

“It’s possible that in the premorbid phase, there is already a failure in brain development which is followed by a steep decline [in its integrity] due to excessive pruning, and there might be a post-illness onset of decline as well. That might be related to neuroinflammation, excitotoxicity, oxidative stress, and antipsychotic effects.”

Inflammation and genetics

If these so-called hits are implicated, Dr. Keshavan said it might be possible to remediate high levels of oxidative stress that otherwise can lead to toxicity, damaging neurons and mitochondria, and contributing to functional decline after the onset of illness.

Finding ways to reduce brain inflammation also could lead to treatment. “There is an increasing amount of evidence that shows proinflammatory cytokines like [interleukin-6] and tumor necrosis factor–alpha are increased in people who are psychotic or in the prodromal phase of the illness,” Dr. Keshavan said. “As they get better, their inflammation is reduced. Therefore, I think working with anti-inflammatory hormones could have value.”

The highly heritable nature of schizophrenia is long established, but recent genetic research has helped identify multiple etiologic factors, particularly when it comes to the implication of more common genes that have a small impact and rarer ones that have a greater effect. These discoveries have shown how several mental illnesses such as autism, bipolar disorder, and ADHD overlap, but the way in which they manifest is determined by how one’s genes are either triggered or influenced by the environment or by neurochemical influences. “The picture is becoming more and more clear that schizophrenia is not one disease,” Dr. Keshavan said. “It’s a combination of a lot of physiological processes.”

Predictors for the development of psychosis include a family history of psychosis, cognitive impairment, schizotypal symptoms, childhood trauma, and cannabis use, Dr. Keshavan said.

 Prevention may not be complicated

As the various etiologies of this disease are being mapped, so too are new approaches that combine existing and emerging therapies. For primary prevention and secondary interventions, Dr. Keshavan said that, particularly in those in whom a risk for the illness already has been identified, reducing stress, enhancing cognitive abilities, and preventing drug use was key. In the near future, he anticipates that these kinds of behavioral interventions will be combined with cognitive-behavioral therapies, along with dopamine blockers, neuroprotective agents, and glutaminergic modulation, and perhaps even fish oil for its omega-3 fatty acids, as well as common anti-inflammatory agents such as aspirin.

By seeing schizophrenia not as “one disease but one of heterogeneity, we can better classify, stratify, and divide and conquer it,” Dr. Keshavan said.

Dr. Keshavan disclosed he has financial relationships with Sunovion and Otsuka.

[email protected]

On Twitter @whitneymcknight

LAS VEGAS – By ignoring schizophrenia’s symptomatology and focusing instead on its biomarkers and other implicated factors, researchers are homing in on treatments and interventions for the disease, according to an expert.

“The developmental model of schizophrenia suggests ... the field is now moving toward treatments better targeted to causes,” Dr. Matcheri S. Keshavan said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Whitney McKnight/Frontline Medical News

Clinicians need to understand that the disease is not homogeneous but more like a syndrome that can present in a variety of ways, according to Dr. Keshavan, Stanley Cobb Professor of Psychiatry at Harvard Medical School, Boston.

The stars emerging in the constellation many researchers are now using to chart the disease’s etiology range from neurobiologic disruptions, to drug use, to genetics, and several other possible factors. Reductions in stress, preventing drug use, and proactive cognitive support, as well as the development of targeted pharmacologic interventions are all currently being explored as ways to mitigate the disease.

‘Pathophysiological hits’

Whereas an excess of dopamine and hypersensitive dopamine receptors in the limbic region of the brain previously were thought to increase the risk for schizophrenia, Dr. Keshavan said the latest thinking is that there also might be cortical dopamine deficits, leading to a variety of symptoms, including psychosis. “Too little cortical dopamine might account for cognitive impairments and medical symptoms, whereas too much limbic dopamine might account for psychosis,” Dr. Keshavan said.

Beyond dopamine dysfunction, Dr. Keshavan said he and others have observed that higher levels of brain glutamate in adolescents correlate with more schizotypal symptoms, leading him to consider that there might be a problem with cortical glutaminergic regulation.

The pathophysiology of these changes is still uncertain, but Dr. Keshavan said several novel pharmacologic intervention trials are now underway, including some intended to reverse cognitive deficits by targeting GABA allosteric modulators to help correct glutaminergic dysfunction.

Also occurring in adolescence, both preceding and during schizophrenia’s prodromal phase, is a depletion of gray matter in the brain, particularly in boys. Also, a decrease in the brain’s plasticity because of exaggerated synaptic pruning by the adolescent brain, an otherwise normal function, has been cited as a risk factor for schizophrenia. Additionally, research into disruptions of the adolescent’s maturing stress response system has shown that for some, prolonged periods of stress can lead to an imbalance of cortical cognitive control.

Such brain imbalances often are thought to be related to a series of “pathophysiological hits” as Dr. Keshavan called them.

“It’s possible that in the premorbid phase, there is already a failure in brain development which is followed by a steep decline [in its integrity] due to excessive pruning, and there might be a post-illness onset of decline as well. That might be related to neuroinflammation, excitotoxicity, oxidative stress, and antipsychotic effects.”

Inflammation and genetics

If these so-called hits are implicated, Dr. Keshavan said it might be possible to remediate high levels of oxidative stress that otherwise can lead to toxicity, damaging neurons and mitochondria, and contributing to functional decline after the onset of illness.

Finding ways to reduce brain inflammation also could lead to treatment. “There is an increasing amount of evidence that shows proinflammatory cytokines like [interleukin-6] and tumor necrosis factor–alpha are increased in people who are psychotic or in the prodromal phase of the illness,” Dr. Keshavan said. “As they get better, their inflammation is reduced. Therefore, I think working with anti-inflammatory hormones could have value.”

The highly heritable nature of schizophrenia is long established, but recent genetic research has helped identify multiple etiologic factors, particularly when it comes to the implication of more common genes that have a small impact and rarer ones that have a greater effect. These discoveries have shown how several mental illnesses such as autism, bipolar disorder, and ADHD overlap, but the way in which they manifest is determined by how one’s genes are either triggered or influenced by the environment or by neurochemical influences. “The picture is becoming more and more clear that schizophrenia is not one disease,” Dr. Keshavan said. “It’s a combination of a lot of physiological processes.”

Predictors for the development of psychosis include a family history of psychosis, cognitive impairment, schizotypal symptoms, childhood trauma, and cannabis use, Dr. Keshavan said.

 Prevention may not be complicated

As the various etiologies of this disease are being mapped, so too are new approaches that combine existing and emerging therapies. For primary prevention and secondary interventions, Dr. Keshavan said that, particularly in those in whom a risk for the illness already has been identified, reducing stress, enhancing cognitive abilities, and preventing drug use was key. In the near future, he anticipates that these kinds of behavioral interventions will be combined with cognitive-behavioral therapies, along with dopamine blockers, neuroprotective agents, and glutaminergic modulation, and perhaps even fish oil for its omega-3 fatty acids, as well as common anti-inflammatory agents such as aspirin.

By seeing schizophrenia not as “one disease but one of heterogeneity, we can better classify, stratify, and divide and conquer it,” Dr. Keshavan said.

Dr. Keshavan disclosed he has financial relationships with Sunovion and Otsuka.

[email protected]

On Twitter @whitneymcknight

LAS VEGAS – By ignoring schizophrenia’s symptomatology and focusing instead on its biomarkers and other implicated factors, researchers are homing in on treatments and interventions for the disease, according to an expert.

“The developmental model of schizophrenia suggests ... the field is now moving toward treatments better targeted to causes,” Dr. Matcheri S. Keshavan said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Whitney McKnight/Frontline Medical News

Clinicians need to understand that the disease is not homogeneous but more like a syndrome that can present in a variety of ways, according to Dr. Keshavan, Stanley Cobb Professor of Psychiatry at Harvard Medical School, Boston.

The stars emerging in the constellation many researchers are now using to chart the disease’s etiology range from neurobiologic disruptions, to drug use, to genetics, and several other possible factors. Reductions in stress, preventing drug use, and proactive cognitive support, as well as the development of targeted pharmacologic interventions are all currently being explored as ways to mitigate the disease.

‘Pathophysiological hits’

Whereas an excess of dopamine and hypersensitive dopamine receptors in the limbic region of the brain previously were thought to increase the risk for schizophrenia, Dr. Keshavan said the latest thinking is that there also might be cortical dopamine deficits, leading to a variety of symptoms, including psychosis. “Too little cortical dopamine might account for cognitive impairments and medical symptoms, whereas too much limbic dopamine might account for psychosis,” Dr. Keshavan said.

Beyond dopamine dysfunction, Dr. Keshavan said he and others have observed that higher levels of brain glutamate in adolescents correlate with more schizotypal symptoms, leading him to consider that there might be a problem with cortical glutaminergic regulation.

The pathophysiology of these changes is still uncertain, but Dr. Keshavan said several novel pharmacologic intervention trials are now underway, including some intended to reverse cognitive deficits by targeting GABA allosteric modulators to help correct glutaminergic dysfunction.

Also occurring in adolescence, both preceding and during schizophrenia’s prodromal phase, is a depletion of gray matter in the brain, particularly in boys. Also, a decrease in the brain’s plasticity because of exaggerated synaptic pruning by the adolescent brain, an otherwise normal function, has been cited as a risk factor for schizophrenia. Additionally, research into disruptions of the adolescent’s maturing stress response system has shown that for some, prolonged periods of stress can lead to an imbalance of cortical cognitive control.

Such brain imbalances often are thought to be related to a series of “pathophysiological hits” as Dr. Keshavan called them.

“It’s possible that in the premorbid phase, there is already a failure in brain development which is followed by a steep decline [in its integrity] due to excessive pruning, and there might be a post-illness onset of decline as well. That might be related to neuroinflammation, excitotoxicity, oxidative stress, and antipsychotic effects.”

Inflammation and genetics

If these so-called hits are implicated, Dr. Keshavan said it might be possible to remediate high levels of oxidative stress that otherwise can lead to toxicity, damaging neurons and mitochondria, and contributing to functional decline after the onset of illness.

Finding ways to reduce brain inflammation also could lead to treatment. “There is an increasing amount of evidence that shows proinflammatory cytokines like [interleukin-6] and tumor necrosis factor–alpha are increased in people who are psychotic or in the prodromal phase of the illness,” Dr. Keshavan said. “As they get better, their inflammation is reduced. Therefore, I think working with anti-inflammatory hormones could have value.”

The highly heritable nature of schizophrenia is long established, but recent genetic research has helped identify multiple etiologic factors, particularly when it comes to the implication of more common genes that have a small impact and rarer ones that have a greater effect. These discoveries have shown how several mental illnesses such as autism, bipolar disorder, and ADHD overlap, but the way in which they manifest is determined by how one’s genes are either triggered or influenced by the environment or by neurochemical influences. “The picture is becoming more and more clear that schizophrenia is not one disease,” Dr. Keshavan said. “It’s a combination of a lot of physiological processes.”

Predictors for the development of psychosis include a family history of psychosis, cognitive impairment, schizotypal symptoms, childhood trauma, and cannabis use, Dr. Keshavan said.

 Prevention may not be complicated

As the various etiologies of this disease are being mapped, so too are new approaches that combine existing and emerging therapies. For primary prevention and secondary interventions, Dr. Keshavan said that, particularly in those in whom a risk for the illness already has been identified, reducing stress, enhancing cognitive abilities, and preventing drug use was key. In the near future, he anticipates that these kinds of behavioral interventions will be combined with cognitive-behavioral therapies, along with dopamine blockers, neuroprotective agents, and glutaminergic modulation, and perhaps even fish oil for its omega-3 fatty acids, as well as common anti-inflammatory agents such as aspirin.

By seeing schizophrenia not as “one disease but one of heterogeneity, we can better classify, stratify, and divide and conquer it,” Dr. Keshavan said.

Dr. Keshavan disclosed he has financial relationships with Sunovion and Otsuka.

[email protected]

On Twitter @whitneymcknight