Progression to Psychosis Increasingly Seen as Preventable

PITTSBURGH – Emerging evidence is leading to optimism that early interventions could prevent the onset of schizophrenia or reduce its impact on cognitive function.

Among psychiatric disorders, schizophrenia tends to manifest later in life than most, typically not until late adolescence or early adulthood. Yet, evidence suggests that brain changes actually occur much earlier in life among those destined to develop the disease, said Dr. Matcheri S. Keshavan, the Stanley Cobb Professor of Psychiatry at Harvard Medical School and vice-chair of public psychiatry at Beth Israel Deaconess Medical Center and the Massachusetts Mental Health Center, all in Boston.

Indeed, schizophrenia is increasingly being viewed as a neurodevelopmental disorder with psychosis as a late and potentially preventable stage of the illness (Nature 2010;468:187-93). Research is now investigating whether it is possible to detect these early signs and intervene before the onset of psychosis to minimize the impact of the disease, said Dr. Keshavan, who is also professor of psychiatry at the University of Pittsburgh.

The emergence of cognitive control and emotion regulation during adolescence are related to expansion of connectivity and fine-tuning of both excitatory and inhibitory neurotransmitter systems. At the same time, abstract thinking and executive function arise from increased efficiency at the expense of brain plasticity, or the ability of the brain to rewire itself in response to change. These processes might go haywire in those at risk for schizophrenia, and a combination of genetic and environmental factors could lead to a failure of inhibitory processes resulting in psychosis, he explained.

"Psychosis begins in adolescence, but schizophrenia really begins in childhood or even earlier. ... The risk-plasticity model of development of schizophrenia suggests several windows of opportunity for primary, secondary, and tertiary prevention," he said.

Several signs mark the early stages of disease. In one recent meta-analysis of 18 studies, individuals with schizophrenia demonstrated mean IQ scores of approximately half a standard deviation below those of healthy comparison subjects, years before the onset of psychotic symptoms (Am. J. Psychiatry 2008;165:579-87).

Certain biomarkers might help to identify those at risk. In a study from Dr. Keshavan’s work in Pittsburgh, at-risk relatives of schizophrenia patients who themselves had schizotypy performed less well on the Wisconsin Card Sort task, which assesses executive function, and showed age-related deficits on the oculomotor delayed response task, compared with non-schizotypal relatives and healthy controls (Prog. Neuropsychopharmacol. Biol. Psychiatry 2006;30:230-8).

Two follow-up studies showed gray matter losses evolving during the premorbid phase among high-risk relatives, compared with control relatives, in areas mediating social cognition and overlapping with cognitive deficits (Neuroimage 2011;54S1:S272-9 and Neuroimage 2011;54S1:S287-92).

Other data from Dr. Keshavan’s group at the University of Pittsburgh indirectly suggest that neurons do not appear to be lost in schizophrenia, but that a reduction in synaptic connectivity occurs leading to reduced brain plasticity (Schizophr. Res. 2010;119:47-51). Such a process might be reversible, he noted.

A variety of environmental factors have been implicated in triggering schizophrenia among individuals who already are genetically predisposed. These include obstetric complications (Ann. NY Acad. Sci. 2003;1008:269-75), exposure to the herpes simplex virus (Mol. Psychiatry 2007;12:105-13), and cannabis use (Schizophr. Res. 2008;99:1-6).

In a longitudinal study of 291 prodromal individuals who sought treatment, the risk of conversion to psychosis was 35% over 2.5 years. Five baseline features independently predicted conversion risk: A genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Algorithms combining two or three of these variables resulted in positive predictive power of 68%-80%, significantly greater than using prodromal criteria alone (Arch. Gen. Psychiatry 2008;65:28-37).

For individuals identified as being at high risk for progression to psychosis, studies are suggesting that use of a variety of pharmacologic and nonpharmacologic preventive interventions during the prodrome might be of benefit.

In a small randomized trial, 31 outpatients with prodromal symptoms of schizophrenia received 5-15 mg/day of olanzapine and 29 took placebo during a 1-year double-blind treatment period. No treatment was given in the subsequent year of follow-up. Although the difference in the rate of conversion during the treatment year was statistically insignificant, it was more than double in the placebo group – 38% vs. 16% with olanzapine (Am. J. Psychiatry 2006;163:790-9).

However, the olanzapine patients did gain significantly more weight (8.8 vs. 0.30kg), Dr. Keshavan noted.

Cognitive therapy (CT) is another potential approach. A randomized controlled trial compared CT over 6 months with monthly monitoring in 58 patients who met criteria for ultrahigh risk of developing a first episode of psychosis. Those receiving CT were less likely to be prescribed an antipsychotic medication over the subsequent 3 years. While CT did not affect transition to psychosis using two different measures, it did significantly reduce the likelihood of progression to psychosis after controlling for baseline cognitive factors (Schizophr. Bull. 2007;33:682-7).

Omega-3 fatty acids also have been investigated, based on evidence that their levels might be deficient in schizophrenia patients, leading to alterations in neurotransmission among other processes.

In a randomized, double-blind placebo-controlled trial, 81 adolescents and young adults with subthreshold psychosis received 1.2 g/d of omega-3 polyunsaturated fatty acids (PUFAs) for 12 weeks, followed by a 40-week monitoring period. At 12 months, 2 of 41 in the omega-3 group (4.9%) and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder, a significant difference (Arch. Gen. Psychiatry 2010;67:146-54).

The omega-3s also significantly reduced positive symptoms, negative symptoms, general symptoms, and improved functioning, compared with placebo, with no difference in the incidence of adverse effects between the treatment groups. "This finding suggests that the omega-3s prevented the transition to psychosis. If this is the case, it would be significant for young people at high risk of developing schizophrenia or other psychotic disorders," Dr. Keshavan said.

Antiviral agents also might have prevention potential. In an unpublished study by Dr. Konasale M. Prasad in Dr. Keshavan’s Pittsburgh group, valacyclovir in patients with schizophrenia produced a trend toward improvement in working memory.

And finally, evidence suggests that an integrated neurocognitive and social-cognitive rehabilitation program using cognitive enhancement therapy (CET) can positively affect cognitive and functional outcomes. A total of 58 early-course outpatients with schizophrenia or schizoaffective disorder were randomly assigned to CET or enriched supportive therapy, an illness management intervention using psychoeducation and applied coping strategies. After 2 years, CET moderately enhanced neurocognitive function. Strong differential effects on social cognition, cognitive style, and social adjustment composites remained at year 2 and also extended to measures of symptomatology, particularly negative symptoms (Psychiatr. Serv. 2009;60:1468-76).

The University of Pittsburgh authors, of whom Dr. Keshavan was again the principal investigator, concluded "CET appears to be an effective approach to the remediation of cognitive deficits in early schizophrenia that may help reduce disability in this population. The remediation of such deficits should be an integral component of early intervention programs treating psychiatrically stable schizophrenia outpatients."

Another study, currently in press, showed that gray matter density increased with CET compared to enriched supportive therapy at 1 year, Dr. Keshavan said.

"The summary is that there are many promising hypotheses and more research is needed to develop proof of concept," he concluded.

Dr. Keshavan disclosed that he receives grant/research support from GlaxoSmithKline.

PITTSBURGH – Emerging evidence is leading to optimism that early interventions could prevent the onset of schizophrenia or reduce its impact on cognitive function.

Among psychiatric disorders, schizophrenia tends to manifest later in life than most, typically not until late adolescence or early adulthood. Yet, evidence suggests that brain changes actually occur much earlier in life among those destined to develop the disease, said Dr. Matcheri S. Keshavan, the Stanley Cobb Professor of Psychiatry at Harvard Medical School and vice-chair of public psychiatry at Beth Israel Deaconess Medical Center and the Massachusetts Mental Health Center, all in Boston.

Indeed, schizophrenia is increasingly being viewed as a neurodevelopmental disorder with psychosis as a late and potentially preventable stage of the illness (Nature 2010;468:187-93). Research is now investigating whether it is possible to detect these early signs and intervene before the onset of psychosis to minimize the impact of the disease, said Dr. Keshavan, who is also professor of psychiatry at the University of Pittsburgh.

The emergence of cognitive control and emotion regulation during adolescence are related to expansion of connectivity and fine-tuning of both excitatory and inhibitory neurotransmitter systems. At the same time, abstract thinking and executive function arise from increased efficiency at the expense of brain plasticity, or the ability of the brain to rewire itself in response to change. These processes might go haywire in those at risk for schizophrenia, and a combination of genetic and environmental factors could lead to a failure of inhibitory processes resulting in psychosis, he explained.

"Psychosis begins in adolescence, but schizophrenia really begins in childhood or even earlier. ... The risk-plasticity model of development of schizophrenia suggests several windows of opportunity for primary, secondary, and tertiary prevention," he said.

Several signs mark the early stages of disease. In one recent meta-analysis of 18 studies, individuals with schizophrenia demonstrated mean IQ scores of approximately half a standard deviation below those of healthy comparison subjects, years before the onset of psychotic symptoms (Am. J. Psychiatry 2008;165:579-87).

Certain biomarkers might help to identify those at risk. In a study from Dr. Keshavan’s work in Pittsburgh, at-risk relatives of schizophrenia patients who themselves had schizotypy performed less well on the Wisconsin Card Sort task, which assesses executive function, and showed age-related deficits on the oculomotor delayed response task, compared with non-schizotypal relatives and healthy controls (Prog. Neuropsychopharmacol. Biol. Psychiatry 2006;30:230-8).

Two follow-up studies showed gray matter losses evolving during the premorbid phase among high-risk relatives, compared with control relatives, in areas mediating social cognition and overlapping with cognitive deficits (Neuroimage 2011;54S1:S272-9 and Neuroimage 2011;54S1:S287-92).

Other data from Dr. Keshavan’s group at the University of Pittsburgh indirectly suggest that neurons do not appear to be lost in schizophrenia, but that a reduction in synaptic connectivity occurs leading to reduced brain plasticity (Schizophr. Res. 2010;119:47-51). Such a process might be reversible, he noted.

A variety of environmental factors have been implicated in triggering schizophrenia among individuals who already are genetically predisposed. These include obstetric complications (Ann. NY Acad. Sci. 2003;1008:269-75), exposure to the herpes simplex virus (Mol. Psychiatry 2007;12:105-13), and cannabis use (Schizophr. Res. 2008;99:1-6).

In a longitudinal study of 291 prodromal individuals who sought treatment, the risk of conversion to psychosis was 35% over 2.5 years. Five baseline features independently predicted conversion risk: A genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Algorithms combining two or three of these variables resulted in positive predictive power of 68%-80%, significantly greater than using prodromal criteria alone (Arch. Gen. Psychiatry 2008;65:28-37).

For individuals identified as being at high risk for progression to psychosis, studies are suggesting that use of a variety of pharmacologic and nonpharmacologic preventive interventions during the prodrome might be of benefit.

In a small randomized trial, 31 outpatients with prodromal symptoms of schizophrenia received 5-15 mg/day of olanzapine and 29 took placebo during a 1-year double-blind treatment period. No treatment was given in the subsequent year of follow-up. Although the difference in the rate of conversion during the treatment year was statistically insignificant, it was more than double in the placebo group – 38% vs. 16% with olanzapine (Am. J. Psychiatry 2006;163:790-9).

However, the olanzapine patients did gain significantly more weight (8.8 vs. 0.30kg), Dr. Keshavan noted.

Cognitive therapy (CT) is another potential approach. A randomized controlled trial compared CT over 6 months with monthly monitoring in 58 patients who met criteria for ultrahigh risk of developing a first episode of psychosis. Those receiving CT were less likely to be prescribed an antipsychotic medication over the subsequent 3 years. While CT did not affect transition to psychosis using two different measures, it did significantly reduce the likelihood of progression to psychosis after controlling for baseline cognitive factors (Schizophr. Bull. 2007;33:682-7).

Omega-3 fatty acids also have been investigated, based on evidence that their levels might be deficient in schizophrenia patients, leading to alterations in neurotransmission among other processes.

In a randomized, double-blind placebo-controlled trial, 81 adolescents and young adults with subthreshold psychosis received 1.2 g/d of omega-3 polyunsaturated fatty acids (PUFAs) for 12 weeks, followed by a 40-week monitoring period. At 12 months, 2 of 41 in the omega-3 group (4.9%) and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder, a significant difference (Arch. Gen. Psychiatry 2010;67:146-54).

The omega-3s also significantly reduced positive symptoms, negative symptoms, general symptoms, and improved functioning, compared with placebo, with no difference in the incidence of adverse effects between the treatment groups. "This finding suggests that the omega-3s prevented the transition to psychosis. If this is the case, it would be significant for young people at high risk of developing schizophrenia or other psychotic disorders," Dr. Keshavan said.

Antiviral agents also might have prevention potential. In an unpublished study by Dr. Konasale M. Prasad in Dr. Keshavan’s Pittsburgh group, valacyclovir in patients with schizophrenia produced a trend toward improvement in working memory.

And finally, evidence suggests that an integrated neurocognitive and social-cognitive rehabilitation program using cognitive enhancement therapy (CET) can positively affect cognitive and functional outcomes. A total of 58 early-course outpatients with schizophrenia or schizoaffective disorder were randomly assigned to CET or enriched supportive therapy, an illness management intervention using psychoeducation and applied coping strategies. After 2 years, CET moderately enhanced neurocognitive function. Strong differential effects on social cognition, cognitive style, and social adjustment composites remained at year 2 and also extended to measures of symptomatology, particularly negative symptoms (Psychiatr. Serv. 2009;60:1468-76).

The University of Pittsburgh authors, of whom Dr. Keshavan was again the principal investigator, concluded "CET appears to be an effective approach to the remediation of cognitive deficits in early schizophrenia that may help reduce disability in this population. The remediation of such deficits should be an integral component of early intervention programs treating psychiatrically stable schizophrenia outpatients."

Another study, currently in press, showed that gray matter density increased with CET compared to enriched supportive therapy at 1 year, Dr. Keshavan said.

"The summary is that there are many promising hypotheses and more research is needed to develop proof of concept," he concluded.

Dr. Keshavan disclosed that he receives grant/research support from GlaxoSmithKline.

PITTSBURGH – Emerging evidence is leading to optimism that early interventions could prevent the onset of schizophrenia or reduce its impact on cognitive function.

Among psychiatric disorders, schizophrenia tends to manifest later in life than most, typically not until late adolescence or early adulthood. Yet, evidence suggests that brain changes actually occur much earlier in life among those destined to develop the disease, said Dr. Matcheri S. Keshavan, the Stanley Cobb Professor of Psychiatry at Harvard Medical School and vice-chair of public psychiatry at Beth Israel Deaconess Medical Center and the Massachusetts Mental Health Center, all in Boston.

Indeed, schizophrenia is increasingly being viewed as a neurodevelopmental disorder with psychosis as a late and potentially preventable stage of the illness (Nature 2010;468:187-93). Research is now investigating whether it is possible to detect these early signs and intervene before the onset of psychosis to minimize the impact of the disease, said Dr. Keshavan, who is also professor of psychiatry at the University of Pittsburgh.

The emergence of cognitive control and emotion regulation during adolescence are related to expansion of connectivity and fine-tuning of both excitatory and inhibitory neurotransmitter systems. At the same time, abstract thinking and executive function arise from increased efficiency at the expense of brain plasticity, or the ability of the brain to rewire itself in response to change. These processes might go haywire in those at risk for schizophrenia, and a combination of genetic and environmental factors could lead to a failure of inhibitory processes resulting in psychosis, he explained.

"Psychosis begins in adolescence, but schizophrenia really begins in childhood or even earlier. ... The risk-plasticity model of development of schizophrenia suggests several windows of opportunity for primary, secondary, and tertiary prevention," he said.

Several signs mark the early stages of disease. In one recent meta-analysis of 18 studies, individuals with schizophrenia demonstrated mean IQ scores of approximately half a standard deviation below those of healthy comparison subjects, years before the onset of psychotic symptoms (Am. J. Psychiatry 2008;165:579-87).

Certain biomarkers might help to identify those at risk. In a study from Dr. Keshavan’s work in Pittsburgh, at-risk relatives of schizophrenia patients who themselves had schizotypy performed less well on the Wisconsin Card Sort task, which assesses executive function, and showed age-related deficits on the oculomotor delayed response task, compared with non-schizotypal relatives and healthy controls (Prog. Neuropsychopharmacol. Biol. Psychiatry 2006;30:230-8).

Two follow-up studies showed gray matter losses evolving during the premorbid phase among high-risk relatives, compared with control relatives, in areas mediating social cognition and overlapping with cognitive deficits (Neuroimage 2011;54S1:S272-9 and Neuroimage 2011;54S1:S287-92).

Other data from Dr. Keshavan’s group at the University of Pittsburgh indirectly suggest that neurons do not appear to be lost in schizophrenia, but that a reduction in synaptic connectivity occurs leading to reduced brain plasticity (Schizophr. Res. 2010;119:47-51). Such a process might be reversible, he noted.

A variety of environmental factors have been implicated in triggering schizophrenia among individuals who already are genetically predisposed. These include obstetric complications (Ann. NY Acad. Sci. 2003;1008:269-75), exposure to the herpes simplex virus (Mol. Psychiatry 2007;12:105-13), and cannabis use (Schizophr. Res. 2008;99:1-6).

In a longitudinal study of 291 prodromal individuals who sought treatment, the risk of conversion to psychosis was 35% over 2.5 years. Five baseline features independently predicted conversion risk: A genetic risk for schizophrenia with recent deterioration in functioning, higher levels of unusual thought content, higher levels of suspicion/paranoia, greater social impairment, and a history of substance abuse. Algorithms combining two or three of these variables resulted in positive predictive power of 68%-80%, significantly greater than using prodromal criteria alone (Arch. Gen. Psychiatry 2008;65:28-37).

For individuals identified as being at high risk for progression to psychosis, studies are suggesting that use of a variety of pharmacologic and nonpharmacologic preventive interventions during the prodrome might be of benefit.

In a small randomized trial, 31 outpatients with prodromal symptoms of schizophrenia received 5-15 mg/day of olanzapine and 29 took placebo during a 1-year double-blind treatment period. No treatment was given in the subsequent year of follow-up. Although the difference in the rate of conversion during the treatment year was statistically insignificant, it was more than double in the placebo group – 38% vs. 16% with olanzapine (Am. J. Psychiatry 2006;163:790-9).

However, the olanzapine patients did gain significantly more weight (8.8 vs. 0.30kg), Dr. Keshavan noted.

Cognitive therapy (CT) is another potential approach. A randomized controlled trial compared CT over 6 months with monthly monitoring in 58 patients who met criteria for ultrahigh risk of developing a first episode of psychosis. Those receiving CT were less likely to be prescribed an antipsychotic medication over the subsequent 3 years. While CT did not affect transition to psychosis using two different measures, it did significantly reduce the likelihood of progression to psychosis after controlling for baseline cognitive factors (Schizophr. Bull. 2007;33:682-7).

Omega-3 fatty acids also have been investigated, based on evidence that their levels might be deficient in schizophrenia patients, leading to alterations in neurotransmission among other processes.

In a randomized, double-blind placebo-controlled trial, 81 adolescents and young adults with subthreshold psychosis received 1.2 g/d of omega-3 polyunsaturated fatty acids (PUFAs) for 12 weeks, followed by a 40-week monitoring period. At 12 months, 2 of 41 in the omega-3 group (4.9%) and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder, a significant difference (Arch. Gen. Psychiatry 2010;67:146-54).

The omega-3s also significantly reduced positive symptoms, negative symptoms, general symptoms, and improved functioning, compared with placebo, with no difference in the incidence of adverse effects between the treatment groups. "This finding suggests that the omega-3s prevented the transition to psychosis. If this is the case, it would be significant for young people at high risk of developing schizophrenia or other psychotic disorders," Dr. Keshavan said.

Antiviral agents also might have prevention potential. In an unpublished study by Dr. Konasale M. Prasad in Dr. Keshavan’s Pittsburgh group, valacyclovir in patients with schizophrenia produced a trend toward improvement in working memory.

And finally, evidence suggests that an integrated neurocognitive and social-cognitive rehabilitation program using cognitive enhancement therapy (CET) can positively affect cognitive and functional outcomes. A total of 58 early-course outpatients with schizophrenia or schizoaffective disorder were randomly assigned to CET or enriched supportive therapy, an illness management intervention using psychoeducation and applied coping strategies. After 2 years, CET moderately enhanced neurocognitive function. Strong differential effects on social cognition, cognitive style, and social adjustment composites remained at year 2 and also extended to measures of symptomatology, particularly negative symptoms (Psychiatr. Serv. 2009;60:1468-76).

The University of Pittsburgh authors, of whom Dr. Keshavan was again the principal investigator, concluded "CET appears to be an effective approach to the remediation of cognitive deficits in early schizophrenia that may help reduce disability in this population. The remediation of such deficits should be an integral component of early intervention programs treating psychiatrically stable schizophrenia outpatients."

Another study, currently in press, showed that gray matter density increased with CET compared to enriched supportive therapy at 1 year, Dr. Keshavan said.

"The summary is that there are many promising hypotheses and more research is needed to develop proof of concept," he concluded.

Dr. Keshavan disclosed that he receives grant/research support from GlaxoSmithKline.