Caroline Helwick

AMSTERDAM – Visual processing abnormalities can be observed not only in schizophrenia but in persons at risk for psychosis, according to a study by investigators in the United Kingdom presented at the congress. “We wanted to clarify the importance of early visual deficits for the formation of cognitive deficits in the schizophrenia spectrum,” said Ivan Koychev, a doctoral candidate at the University of Manchester, Neuroscience and Psychiatry Unit.

“Our study confirmed that visual deficits are not due to the overt clinical phenotype, but are rather characteristic of the schizophrenia spectrum.”

Mr. Koychev and his colleagues carried out an event-related potential (ERP) study using a working memory task on volunteers exhibiting high and low levels of schizophrenia-like personality traits. The hypothesis was that the high schizotypes would have early visual deficits (P1 component reduction) and working memory similar to that observed in persons with schizophrenia and their first-degree relatives. They also hypothesized that the working memory deficits would be more pronounced on tasks that allow only short stimulus presentation, but would be more difficult to demonstrate in tasks that allow ample time for stimulus processing.

Participants completed a visual delayed discrimination task where they were shown stimuli briefly (400 ms), which they compared to target cues presented after a 6-second delay.

Researchers also recorded their performance on several tests of cognition.

The high schizotypal and low schizotypal (control) subjects did not differ in their reaction times to the task, which increased significantly with the working memory load (P less than .001). However, the performance on the task was significantly worse in the high schizotypes, as they identified correctly a lower number of target cues (P = .034), Mr. Koychev said.

“There was no difference in reaction times but their behavior was different in that the high schizotypes were recognizing fewer objects. We then asked if this was reflected in visual deficits, and we found reduced potential in the high schizotypes. This was true for encoding and retrieval. When subjects were shown images, the visual cortex did not respond as robustly,” he said in an interview.

The P1 ERP component was significantly reduced in the high schizotypes' sample, both in the encoding (P = .034; effect size, .0351) and retrieval (P = .029; effect size .353) phases of the task. None of the later components (N1, P2) was significantly different between the groups. The P1 abnormality in the schizotypal subjects was reflected by abnormalities in the alpha evoked oscillations (Neuropsychologia 2010;48:2205-17).

“Our study confirmed the hypothesis that the P1 component is reduced in individuals at risk of psychosis,” Dr. Koychev said.

AMSTERDAM – Visual processing abnormalities can be observed not only in schizophrenia but in persons at risk for psychosis, according to a study by investigators in the United Kingdom presented at the congress. “We wanted to clarify the importance of early visual deficits for the formation of cognitive deficits in the schizophrenia spectrum,” said Ivan Koychev, a doctoral candidate at the University of Manchester, Neuroscience and Psychiatry Unit.

“Our study confirmed that visual deficits are not due to the overt clinical phenotype, but are rather characteristic of the schizophrenia spectrum.”

Mr. Koychev and his colleagues carried out an event-related potential (ERP) study using a working memory task on volunteers exhibiting high and low levels of schizophrenia-like personality traits. The hypothesis was that the high schizotypes would have early visual deficits (P1 component reduction) and working memory similar to that observed in persons with schizophrenia and their first-degree relatives. They also hypothesized that the working memory deficits would be more pronounced on tasks that allow only short stimulus presentation, but would be more difficult to demonstrate in tasks that allow ample time for stimulus processing.

Participants completed a visual delayed discrimination task where they were shown stimuli briefly (400 ms), which they compared to target cues presented after a 6-second delay.

Researchers also recorded their performance on several tests of cognition.

The high schizotypal and low schizotypal (control) subjects did not differ in their reaction times to the task, which increased significantly with the working memory load (P less than .001). However, the performance on the task was significantly worse in the high schizotypes, as they identified correctly a lower number of target cues (P = .034), Mr. Koychev said.

“There was no difference in reaction times but their behavior was different in that the high schizotypes were recognizing fewer objects. We then asked if this was reflected in visual deficits, and we found reduced potential in the high schizotypes. This was true for encoding and retrieval. When subjects were shown images, the visual cortex did not respond as robustly,” he said in an interview.

The P1 ERP component was significantly reduced in the high schizotypes' sample, both in the encoding (P = .034; effect size, .0351) and retrieval (P = .029; effect size .353) phases of the task. None of the later components (N1, P2) was significantly different between the groups. The P1 abnormality in the schizotypal subjects was reflected by abnormalities in the alpha evoked oscillations (Neuropsychologia 2010;48:2205-17).

“Our study confirmed the hypothesis that the P1 component is reduced in individuals at risk of psychosis,” Dr. Koychev said.

AMSTERDAM – Visual processing abnormalities can be observed not only in schizophrenia but in persons at risk for psychosis, according to a study by investigators in the United Kingdom presented at the congress. “We wanted to clarify the importance of early visual deficits for the formation of cognitive deficits in the schizophrenia spectrum,” said Ivan Koychev, a doctoral candidate at the University of Manchester, Neuroscience and Psychiatry Unit.

“Our study confirmed that visual deficits are not due to the overt clinical phenotype, but are rather characteristic of the schizophrenia spectrum.”

Mr. Koychev and his colleagues carried out an event-related potential (ERP) study using a working memory task on volunteers exhibiting high and low levels of schizophrenia-like personality traits. The hypothesis was that the high schizotypes would have early visual deficits (P1 component reduction) and working memory similar to that observed in persons with schizophrenia and their first-degree relatives. They also hypothesized that the working memory deficits would be more pronounced on tasks that allow only short stimulus presentation, but would be more difficult to demonstrate in tasks that allow ample time for stimulus processing.

Participants completed a visual delayed discrimination task where they were shown stimuli briefly (400 ms), which they compared to target cues presented after a 6-second delay.

Researchers also recorded their performance on several tests of cognition.

The high schizotypal and low schizotypal (control) subjects did not differ in their reaction times to the task, which increased significantly with the working memory load (P less than .001). However, the performance on the task was significantly worse in the high schizotypes, as they identified correctly a lower number of target cues (P = .034), Mr. Koychev said.

“There was no difference in reaction times but their behavior was different in that the high schizotypes were recognizing fewer objects. We then asked if this was reflected in visual deficits, and we found reduced potential in the high schizotypes. This was true for encoding and retrieval. When subjects were shown images, the visual cortex did not respond as robustly,” he said in an interview.

The P1 ERP component was significantly reduced in the high schizotypes' sample, both in the encoding (P = .034; effect size, .0351) and retrieval (P = .029; effect size .353) phases of the task. None of the later components (N1, P2) was significantly different between the groups. The P1 abnormality in the schizotypal subjects was reflected by abnormalities in the alpha evoked oscillations (Neuropsychologia 2010;48:2205-17).

“Our study confirmed the hypothesis that the P1 component is reduced in individuals at risk of psychosis,” Dr. Koychev said.

AMSTERDAM – American ginseng significantly improved working-memory performance in a double-blind, placebo-controlled crossover study of healthy young adults presented at the congress.

The effects are distinct from those of Asian ginseng, and suggest that psychopharmacological properties dependcon the plant's ginsenoside profiles, said Andrew Scholey, Ph.D., professor of behavioral and brain sciences at the Brain Sciences Institute at Swinburne University, Melbourne, Australia.

Dr. Scholey, who led the study, said that previous studies have shown that Asian ginseng (Panax ginseng) lowers blood glucose, improves cognitive performance, and alleviates the mental fatigue that is associated with intense cognitive processing.

“American ginseng (Panax quinquefolius) shares Panax's glycemic properties, but no previous studies have been conducted to evaluate the capacity of American ginseng to modulate cognitive function,” said Dr. Scholey. “The availability of a highly standardized extract of P. quinquefolius (Cereboost) led us to evaluate its neurocognitive properties.”

The randomized trialsinvolved 32 healthy young adults. Subjects were assessed for acute mood, neurocognitive, and glycemic effects of three doses (100, 200, and 400 mg) of American ginseng (standardized to 10.65% ginsenosides). On study days, separated by at least a 7-day washout period, participants' mood, cognitive function, and blood glucose were measured at 1, 3, and 6 hours after administration of the ginseng.

To measure cognitive effects, investigators used the COMPASS (Computerized Mental Performance Assessment System) battery, which was developed to include tests that have proved sensitive to nutritional manipulations. COMPASS gauges performance on tasks of attention, working memory, secondary memory, and executive function.

The specific cognitive tests included word presentations, immediate word recall, picture presentations, face presentations, simple reaction times, choice reaction times, four-choice reaction times, Stroop color-word task, numeric working memory, alphabetic working memory, Corsi block-tapping task, N-back task, delayed word recall, delayed word recognition, delayed picture recognition, delayed face recognition, serial sevens subtraction task, serial threes subtraction task, and rapid visual information processing or Bakan task.

The study found, for the first time, cognitive and mood enhancements after the administration of American ginseng. Cognition-enhancing effects of the extract were observed across a range of cognitive parameters at a range of doses, reported Dr. Scholey, whose study was published recently (Psychopharamacology 2010 July 31 [doi:10.1007/s00213-010-1964-y]).

“The most striking finding was a significant improvement of working-memory performance,” Dr. Scholey reported. Compared with placebo, all doses of the extract were found to improve some aspect of cognition.

For all doses combined, a significant effect of treatment was observed for choice reaction time accuracy (P = .030), numeric working memory speed (P = .007), fspeed of alphabetic working memory (P = .04), andfoorsi block score (P = .041). These data represent enhancement effects predominantly on working-memory processes, and to some degree on short-term verbal declarative memory and attention, he said.

No significant baseline differences were found between conditions, showing that posttreatment effects were not attributable to differences in baseline performance, he added.

No differences were seen in blood glucose levels, which rules out the effects of glucose on insulin-mediated mechanisms.

In the published report, the investigators noted that the findings should be treated with a degree of caution. “Firstly, this is the first investigation into the neurocognitive effects of American ginseng. Clearly, the study needs at least partial replication, possibly with more focus on specific working-memory processes. Secondly, given the exploratory nature of the study, no adjustment was made for multiple comparisons,” he said. Further research is needed in other populations, such as in older individuals and those with cognitive problems.

The study was sponsored by Naturex, maker of Cereboost.

American ginseng roots enhanced cognition and mood at several doses.

Source ©Orchidpoet/iStockphoto

AMSTERDAM – American ginseng significantly improved working-memory performance in a double-blind, placebo-controlled crossover study of healthy young adults presented at the congress.

The effects are distinct from those of Asian ginseng, and suggest that psychopharmacological properties dependcon the plant's ginsenoside profiles, said Andrew Scholey, Ph.D., professor of behavioral and brain sciences at the Brain Sciences Institute at Swinburne University, Melbourne, Australia.

Dr. Scholey, who led the study, said that previous studies have shown that Asian ginseng (Panax ginseng) lowers blood glucose, improves cognitive performance, and alleviates the mental fatigue that is associated with intense cognitive processing.

“American ginseng (Panax quinquefolius) shares Panax's glycemic properties, but no previous studies have been conducted to evaluate the capacity of American ginseng to modulate cognitive function,” said Dr. Scholey. “The availability of a highly standardized extract of P. quinquefolius (Cereboost) led us to evaluate its neurocognitive properties.”

The randomized trialsinvolved 32 healthy young adults. Subjects were assessed for acute mood, neurocognitive, and glycemic effects of three doses (100, 200, and 400 mg) of American ginseng (standardized to 10.65% ginsenosides). On study days, separated by at least a 7-day washout period, participants' mood, cognitive function, and blood glucose were measured at 1, 3, and 6 hours after administration of the ginseng.

To measure cognitive effects, investigators used the COMPASS (Computerized Mental Performance Assessment System) battery, which was developed to include tests that have proved sensitive to nutritional manipulations. COMPASS gauges performance on tasks of attention, working memory, secondary memory, and executive function.

The specific cognitive tests included word presentations, immediate word recall, picture presentations, face presentations, simple reaction times, choice reaction times, four-choice reaction times, Stroop color-word task, numeric working memory, alphabetic working memory, Corsi block-tapping task, N-back task, delayed word recall, delayed word recognition, delayed picture recognition, delayed face recognition, serial sevens subtraction task, serial threes subtraction task, and rapid visual information processing or Bakan task.

The study found, for the first time, cognitive and mood enhancements after the administration of American ginseng. Cognition-enhancing effects of the extract were observed across a range of cognitive parameters at a range of doses, reported Dr. Scholey, whose study was published recently (Psychopharamacology 2010 July 31 [doi:10.1007/s00213-010-1964-y]).

“The most striking finding was a significant improvement of working-memory performance,” Dr. Scholey reported. Compared with placebo, all doses of the extract were found to improve some aspect of cognition.

For all doses combined, a significant effect of treatment was observed for choice reaction time accuracy (P = .030), numeric working memory speed (P = .007), fspeed of alphabetic working memory (P = .04), andfoorsi block score (P = .041). These data represent enhancement effects predominantly on working-memory processes, and to some degree on short-term verbal declarative memory and attention, he said.

No significant baseline differences were found between conditions, showing that posttreatment effects were not attributable to differences in baseline performance, he added.

No differences were seen in blood glucose levels, which rules out the effects of glucose on insulin-mediated mechanisms.

In the published report, the investigators noted that the findings should be treated with a degree of caution. “Firstly, this is the first investigation into the neurocognitive effects of American ginseng. Clearly, the study needs at least partial replication, possibly with more focus on specific working-memory processes. Secondly, given the exploratory nature of the study, no adjustment was made for multiple comparisons,” he said. Further research is needed in other populations, such as in older individuals and those with cognitive problems.

The study was sponsored by Naturex, maker of Cereboost.

American ginseng roots enhanced cognition and mood at several doses.

Source ©Orchidpoet/iStockphoto

AMSTERDAM – American ginseng significantly improved working-memory performance in a double-blind, placebo-controlled crossover study of healthy young adults presented at the congress.

The effects are distinct from those of Asian ginseng, and suggest that psychopharmacological properties dependcon the plant's ginsenoside profiles, said Andrew Scholey, Ph.D., professor of behavioral and brain sciences at the Brain Sciences Institute at Swinburne University, Melbourne, Australia.

Dr. Scholey, who led the study, said that previous studies have shown that Asian ginseng (Panax ginseng) lowers blood glucose, improves cognitive performance, and alleviates the mental fatigue that is associated with intense cognitive processing.

“American ginseng (Panax quinquefolius) shares Panax's glycemic properties, but no previous studies have been conducted to evaluate the capacity of American ginseng to modulate cognitive function,” said Dr. Scholey. “The availability of a highly standardized extract of P. quinquefolius (Cereboost) led us to evaluate its neurocognitive properties.”

The randomized trialsinvolved 32 healthy young adults. Subjects were assessed for acute mood, neurocognitive, and glycemic effects of three doses (100, 200, and 400 mg) of American ginseng (standardized to 10.65% ginsenosides). On study days, separated by at least a 7-day washout period, participants' mood, cognitive function, and blood glucose were measured at 1, 3, and 6 hours after administration of the ginseng.

To measure cognitive effects, investigators used the COMPASS (Computerized Mental Performance Assessment System) battery, which was developed to include tests that have proved sensitive to nutritional manipulations. COMPASS gauges performance on tasks of attention, working memory, secondary memory, and executive function.

The specific cognitive tests included word presentations, immediate word recall, picture presentations, face presentations, simple reaction times, choice reaction times, four-choice reaction times, Stroop color-word task, numeric working memory, alphabetic working memory, Corsi block-tapping task, N-back task, delayed word recall, delayed word recognition, delayed picture recognition, delayed face recognition, serial sevens subtraction task, serial threes subtraction task, and rapid visual information processing or Bakan task.

The study found, for the first time, cognitive and mood enhancements after the administration of American ginseng. Cognition-enhancing effects of the extract were observed across a range of cognitive parameters at a range of doses, reported Dr. Scholey, whose study was published recently (Psychopharamacology 2010 July 31 [doi:10.1007/s00213-010-1964-y]).

“The most striking finding was a significant improvement of working-memory performance,” Dr. Scholey reported. Compared with placebo, all doses of the extract were found to improve some aspect of cognition.

For all doses combined, a significant effect of treatment was observed for choice reaction time accuracy (P = .030), numeric working memory speed (P = .007), fspeed of alphabetic working memory (P = .04), andfoorsi block score (P = .041). These data represent enhancement effects predominantly on working-memory processes, and to some degree on short-term verbal declarative memory and attention, he said.

No significant baseline differences were found between conditions, showing that posttreatment effects were not attributable to differences in baseline performance, he added.

No differences were seen in blood glucose levels, which rules out the effects of glucose on insulin-mediated mechanisms.

In the published report, the investigators noted that the findings should be treated with a degree of caution. “Firstly, this is the first investigation into the neurocognitive effects of American ginseng. Clearly, the study needs at least partial replication, possibly with more focus on specific working-memory processes. Secondly, given the exploratory nature of the study, no adjustment was made for multiple comparisons,” he said. Further research is needed in other populations, such as in older individuals and those with cognitive problems.

The study was sponsored by Naturex, maker of Cereboost.

American ginseng roots enhanced cognition and mood at several doses.

Source ©Orchidpoet/iStockphoto

AMSTERDAM – American ginseng significantly improved working-memory performance in a double-blind, placebo-controlled crossover study of healthy young adults presented at the annual congress of the European College of Neuropsychopharmacology.

“This preliminary study has identified robust working-memory enhancement following the administration of American ginseng. These effects are distinct from those of Asian ginseng, and suggest that psychopharmacological properties depend critically on ginsenoside profiles,” said Andrew Scholey, Ph.D., professor of behavioral and brain sciences at the Brain Sciences Institute at Swinburne University, Melbourne, Australia.

Photo credit: Orchidpoet/iStockphoto

Dr. Scholey, who led the study, said that previous studies have shown that Asian ginseng (Panax ginseng) lowers blood glucose, improves cognitive performance, and alleviates the mental fatigue that is associated with intense cognitive processing.

“American ginseng (Panax quinquefolius) shares Panax’s glycemic properties, but no previous studies have been conducted to evaluate the capacity of American ginseng to modulate cognitive function,” Dr. Scholey said. “The availability of a highly standardized extract of P. quinquefolius (Cereboost) led us to evaluate its neurocognitive properties in humans for the first time.”

The randomized, double-blind, placebo-controlled, crossover trial study involved 32 healthy young adults. Subjects were assessed for acute mood, neurocognitive, and glycemic effects of three doses (100, 200, and 400 mg) of American ginseng (standardized to 10.65% ginsenosides). On study days, separated by at least a 7-day washout period, participants’ mood, cognitive function, and blood glucose were measured at 1, 3, and 6 hours after administration of the ginseng.

To measure cognitive effects, investigators used the COMPASS (Computerized Mental Performance Assessment System) battery, which was developed to include tests that have proved sensitive to nutritional manipulations. COMPASS gauges performance on tasks of attention, working memory, secondary memory, and executive function.

The specific cognitive tests included word presentations, immediate word recall, picture presentations, face presentations, simple reaction times, choice reaction times, four-choice reaction times, Stroop color-word task, numeric working memory, alphabetic working memory, Corsi block-tapping task, N-back task, delayed word recall, delayed word recognition, delayed picture recognition, delayed face recognition, serial sevens subtraction task, serial threes subtraction task, and rapid visual information processing or Bakan task.

The study found, for the first time, cognitive and mood enhancements after the administration of American ginseng. Cognition-enhancing effects of the extract were observed across a range of cognitive parameters at a range of doses, reported Dr. Scholey, whose study was published recently (Psychopharamacology 2010 July 31 [doi:10.1007/s00213-010-1964-y]).

“The most striking finding was a significant improvement of working-memory performance,” Dr. Scholey reported. Compared with placebo, all doses of the extract were found to improve some aspect of cognition.

For all doses combined, a significant effect of treatment was observed for choice reaction time accuracy (P = .030), for numeric working memory speed (P = .007), for speed of alphabetic working memory (P = .04), and for Corsi block score (P = .041). These data represent enhancement effects predominantly on working-memory processes, and to some degree on short-term verbal declarative memory and attention, he said.

No significant baseline differences were found between conditions, showing that posttreatment effects were not attributable to differences in baseline performance, he added.

No differences were observed on blood glucose levels, which rules out any interpretation of the cognitive facilitation effects as being attributable to effects of glucose on insulin-mediated mechanisms. The lack of glycemic effects suggests that these effects can occur independently of changes in blood glucose, at least in healthy younger populations, Dr. Scholey said.

In the published report, the investigators noted that the findings should be treated with a degree of caution.

“Firstly, this is the first investigation into the neurocognitive effects of American ginseng. Clearly, the study needs at least partial replication, possibly with more focus on specific working-memory processes. Secondly, given the exploratory nature of the study, no adjustment was made for multiple comparisons,” he said. Further research is needed in other populations, such as in older individuals and those with cognitive problems.

Disclosures: The study was sponsored by Naturex, maker of Cereboost.

AMSTERDAM – American ginseng significantly improved working-memory performance in a double-blind, placebo-controlled crossover study of healthy young adults presented at the annual congress of the European College of Neuropsychopharmacology.

“This preliminary study has identified robust working-memory enhancement following the administration of American ginseng. These effects are distinct from those of Asian ginseng, and suggest that psychopharmacological properties depend critically on ginsenoside profiles,” said Andrew Scholey, Ph.D., professor of behavioral and brain sciences at the Brain Sciences Institute at Swinburne University, Melbourne, Australia.

Photo credit: Orchidpoet/iStockphoto

Dr. Scholey, who led the study, said that previous studies have shown that Asian ginseng (Panax ginseng) lowers blood glucose, improves cognitive performance, and alleviates the mental fatigue that is associated with intense cognitive processing.

“American ginseng (Panax quinquefolius) shares Panax’s glycemic properties, but no previous studies have been conducted to evaluate the capacity of American ginseng to modulate cognitive function,” Dr. Scholey said. “The availability of a highly standardized extract of P. quinquefolius (Cereboost) led us to evaluate its neurocognitive properties in humans for the first time.”

The randomized, double-blind, placebo-controlled, crossover trial study involved 32 healthy young adults. Subjects were assessed for acute mood, neurocognitive, and glycemic effects of three doses (100, 200, and 400 mg) of American ginseng (standardized to 10.65% ginsenosides). On study days, separated by at least a 7-day washout period, participants’ mood, cognitive function, and blood glucose were measured at 1, 3, and 6 hours after administration of the ginseng.

To measure cognitive effects, investigators used the COMPASS (Computerized Mental Performance Assessment System) battery, which was developed to include tests that have proved sensitive to nutritional manipulations. COMPASS gauges performance on tasks of attention, working memory, secondary memory, and executive function.

The specific cognitive tests included word presentations, immediate word recall, picture presentations, face presentations, simple reaction times, choice reaction times, four-choice reaction times, Stroop color-word task, numeric working memory, alphabetic working memory, Corsi block-tapping task, N-back task, delayed word recall, delayed word recognition, delayed picture recognition, delayed face recognition, serial sevens subtraction task, serial threes subtraction task, and rapid visual information processing or Bakan task.

The study found, for the first time, cognitive and mood enhancements after the administration of American ginseng. Cognition-enhancing effects of the extract were observed across a range of cognitive parameters at a range of doses, reported Dr. Scholey, whose study was published recently (Psychopharamacology 2010 July 31 [doi:10.1007/s00213-010-1964-y]).

“The most striking finding was a significant improvement of working-memory performance,” Dr. Scholey reported. Compared with placebo, all doses of the extract were found to improve some aspect of cognition.

For all doses combined, a significant effect of treatment was observed for choice reaction time accuracy (P = .030), for numeric working memory speed (P = .007), for speed of alphabetic working memory (P = .04), and for Corsi block score (P = .041). These data represent enhancement effects predominantly on working-memory processes, and to some degree on short-term verbal declarative memory and attention, he said.

No significant baseline differences were found between conditions, showing that posttreatment effects were not attributable to differences in baseline performance, he added.

No differences were observed on blood glucose levels, which rules out any interpretation of the cognitive facilitation effects as being attributable to effects of glucose on insulin-mediated mechanisms. The lack of glycemic effects suggests that these effects can occur independently of changes in blood glucose, at least in healthy younger populations, Dr. Scholey said.

In the published report, the investigators noted that the findings should be treated with a degree of caution.

“Firstly, this is the first investigation into the neurocognitive effects of American ginseng. Clearly, the study needs at least partial replication, possibly with more focus on specific working-memory processes. Secondly, given the exploratory nature of the study, no adjustment was made for multiple comparisons,” he said. Further research is needed in other populations, such as in older individuals and those with cognitive problems.

Disclosures: The study was sponsored by Naturex, maker of Cereboost.

AMSTERDAM – American ginseng significantly improved working-memory performance in a double-blind, placebo-controlled crossover study of healthy young adults presented at the annual congress of the European College of Neuropsychopharmacology.

“This preliminary study has identified robust working-memory enhancement following the administration of American ginseng. These effects are distinct from those of Asian ginseng, and suggest that psychopharmacological properties depend critically on ginsenoside profiles,” said Andrew Scholey, Ph.D., professor of behavioral and brain sciences at the Brain Sciences Institute at Swinburne University, Melbourne, Australia.

Photo credit: Orchidpoet/iStockphoto

Dr. Scholey, who led the study, said that previous studies have shown that Asian ginseng (Panax ginseng) lowers blood glucose, improves cognitive performance, and alleviates the mental fatigue that is associated with intense cognitive processing.

“American ginseng (Panax quinquefolius) shares Panax’s glycemic properties, but no previous studies have been conducted to evaluate the capacity of American ginseng to modulate cognitive function,” Dr. Scholey said. “The availability of a highly standardized extract of P. quinquefolius (Cereboost) led us to evaluate its neurocognitive properties in humans for the first time.”

The randomized, double-blind, placebo-controlled, crossover trial study involved 32 healthy young adults. Subjects were assessed for acute mood, neurocognitive, and glycemic effects of three doses (100, 200, and 400 mg) of American ginseng (standardized to 10.65% ginsenosides). On study days, separated by at least a 7-day washout period, participants’ mood, cognitive function, and blood glucose were measured at 1, 3, and 6 hours after administration of the ginseng.

To measure cognitive effects, investigators used the COMPASS (Computerized Mental Performance Assessment System) battery, which was developed to include tests that have proved sensitive to nutritional manipulations. COMPASS gauges performance on tasks of attention, working memory, secondary memory, and executive function.

The specific cognitive tests included word presentations, immediate word recall, picture presentations, face presentations, simple reaction times, choice reaction times, four-choice reaction times, Stroop color-word task, numeric working memory, alphabetic working memory, Corsi block-tapping task, N-back task, delayed word recall, delayed word recognition, delayed picture recognition, delayed face recognition, serial sevens subtraction task, serial threes subtraction task, and rapid visual information processing or Bakan task.

The study found, for the first time, cognitive and mood enhancements after the administration of American ginseng. Cognition-enhancing effects of the extract were observed across a range of cognitive parameters at a range of doses, reported Dr. Scholey, whose study was published recently (Psychopharamacology 2010 July 31 [doi:10.1007/s00213-010-1964-y]).

“The most striking finding was a significant improvement of working-memory performance,” Dr. Scholey reported. Compared with placebo, all doses of the extract were found to improve some aspect of cognition.

For all doses combined, a significant effect of treatment was observed for choice reaction time accuracy (P = .030), for numeric working memory speed (P = .007), for speed of alphabetic working memory (P = .04), and for Corsi block score (P = .041). These data represent enhancement effects predominantly on working-memory processes, and to some degree on short-term verbal declarative memory and attention, he said.

No significant baseline differences were found between conditions, showing that posttreatment effects were not attributable to differences in baseline performance, he added.

No differences were observed on blood glucose levels, which rules out any interpretation of the cognitive facilitation effects as being attributable to effects of glucose on insulin-mediated mechanisms. The lack of glycemic effects suggests that these effects can occur independently of changes in blood glucose, at least in healthy younger populations, Dr. Scholey said.

In the published report, the investigators noted that the findings should be treated with a degree of caution.

“Firstly, this is the first investigation into the neurocognitive effects of American ginseng. Clearly, the study needs at least partial replication, possibly with more focus on specific working-memory processes. Secondly, given the exploratory nature of the study, no adjustment was made for multiple comparisons,” he said. Further research is needed in other populations, such as in older individuals and those with cognitive problems.

Disclosures: The study was sponsored by Naturex, maker of Cereboost.

Major Finding: Persons who received a new formulation of low-dose sublingual zolpidem for middle-of-the-night insomnia showed no potential for abuse of the drug in the form of dependency, tolerance, or rebound potential, compared with placebo recipients.

Data Source: A 4-week outpatient study of 146 subjects.

Disclosures: Dr. Roth has served as a consultant to Transept Pharmaceuticals Inc., the manufacturer of the sublingual formulation of zolpidem tartrate. He has also received research support from and had other relationships with numerous pharmaceutical companies.

AMSTERDAM — A sublingual 3.5-mg formulation of zolpidem tartrate is effective for middle-of-the-night insomnia, producing no tolerance, rebound, or increase in use over a 4-week period, a study has shown.

“Awakening during the night with difficulty falling back to sleep is a prevalent condition, and a PRN treatment for this is needed as it may decrease overall drug exposure,” said the study's coinvestigator, Thomas Roth, Ph.D., of Henry Ford Hospital, Detroit.

Zolpidem sublingual tablets 3.5 mg and 1.75 mg were developed for the treatment of insomnia that is characterized by difficulty returning to sleep after middle-of-the-night (MOTN) awakening.

The compound is formulated with binary buffers to promote buccal absorption of a portion of the drug. This facilitates bioavailability, resulting in a rapid return to sleep.

Previous studies have found that sublingual zolpidem significantly reduces sleep latency after MOTN dosing.

In a sleep laboratory study, sleep latency time was approximately 28 minutes with placebo but just 10 minutes with zolpidem 3.5 mg (Sleep 2008;31:1277–84).

“This is a reduced dose of zolpidem, and importantly it is a sublingual formulation so you achieve much faster blood levels to help you fall back asleep but you reduce the total blood level as compared to taking it prophylactically. The concern is that over time, people take more and more of the medication,” Dr. Roth said at the meeting.

The drug is currently under review by the Food and Drug Administration for MOTN awakening.

In a study designed to address possible abuse liability associated with PRN use of the drug, 75 outpatients received zolpidem and 71 patients received placebo; all were assessed for latency to sleep onset after MOTN dosing across a 4-week treatment period.

To address rebound potential, outcomes also were observed on the first night of nondosing after 1 or more nights of medication use. Dependence and tolerance also were examined.

The study found no evidence of residual sleepiness after MOTN dosing with zolpidem. Patients who received the drug actually reported greater alertness, compared with baseline. On a scale of 1–9 (with 9 being most alert), the mean score was 4.9 at baseline, increasing to 5.7 after zolpidem dosing. Scores in the placebo arm were 4.7 and 5.2, respectively.

Sleep quality also improved significantly. Mean scores were 4.7 at baseline and 5.8 after treatment with zolpidem, compared with 4.5 and 5.2, respectively, with placebo.

The study found no evidence for the development of tolerance to zolpidem's efficacy.

Latency to sleep onset improved over the first 2 weeks, and apparently stabilized by week 3, for both the active-treatment and placebo groups, suggesting a nonspecific trend toward improvement in outcome over time.

The response to the medication did not change across the entire treatment period, and drug use was not different between treatment and placebo groups, Dr. Roth reported.

In fact, weekly medication use showed a decline for both the active and placebo groups, with medication use during week 4 being significantly lower than during week 1 in both arms.

The mean number of tablets taken during weeks 1 and 4 were 4.9 and 4.0, respectively, for the zolpidem group and 4.9 and 4.3, respectively, for the placebo group. There was no evidence of rebound effects on sleep initiation or total sleep time on nondosing nights, regardless of the number of nights of continuous use.

On average, for nights during which zolpidem was not dosed, total sleep time was similar for the active and placebo groups.

Dr. Roth noted that the improvement over placebo of about 20 minutes is clinically meaningful.

“It doesn't sound impressive, but try sleeping 20 minutes less every night for 3 months — you'll be in a coma. The effect is cumulative. It's about 2 hours a week.”

Middle-of-the-night awakening with difficulty falling back to sleep is a prevalent condition.

Source ©iStockphoto/redmonkey8

Major Finding: Persons who received a new formulation of low-dose sublingual zolpidem for middle-of-the-night insomnia showed no potential for abuse of the drug in the form of dependency, tolerance, or rebound potential, compared with placebo recipients.

Data Source: A 4-week outpatient study of 146 subjects.

Disclosures: Dr. Roth has served as a consultant to Transept Pharmaceuticals Inc., the manufacturer of the sublingual formulation of zolpidem tartrate. He has also received research support from and had other relationships with numerous pharmaceutical companies.

AMSTERDAM — A sublingual 3.5-mg formulation of zolpidem tartrate is effective for middle-of-the-night insomnia, producing no tolerance, rebound, or increase in use over a 4-week period, a study has shown.

“Awakening during the night with difficulty falling back to sleep is a prevalent condition, and a PRN treatment for this is needed as it may decrease overall drug exposure,” said the study's coinvestigator, Thomas Roth, Ph.D., of Henry Ford Hospital, Detroit.

Zolpidem sublingual tablets 3.5 mg and 1.75 mg were developed for the treatment of insomnia that is characterized by difficulty returning to sleep after middle-of-the-night (MOTN) awakening.

The compound is formulated with binary buffers to promote buccal absorption of a portion of the drug. This facilitates bioavailability, resulting in a rapid return to sleep.

Previous studies have found that sublingual zolpidem significantly reduces sleep latency after MOTN dosing.

In a sleep laboratory study, sleep latency time was approximately 28 minutes with placebo but just 10 minutes with zolpidem 3.5 mg (Sleep 2008;31:1277–84).

“This is a reduced dose of zolpidem, and importantly it is a sublingual formulation so you achieve much faster blood levels to help you fall back asleep but you reduce the total blood level as compared to taking it prophylactically. The concern is that over time, people take more and more of the medication,” Dr. Roth said at the meeting.

The drug is currently under review by the Food and Drug Administration for MOTN awakening.

In a study designed to address possible abuse liability associated with PRN use of the drug, 75 outpatients received zolpidem and 71 patients received placebo; all were assessed for latency to sleep onset after MOTN dosing across a 4-week treatment period.

To address rebound potential, outcomes also were observed on the first night of nondosing after 1 or more nights of medication use. Dependence and tolerance also were examined.

The study found no evidence of residual sleepiness after MOTN dosing with zolpidem. Patients who received the drug actually reported greater alertness, compared with baseline. On a scale of 1–9 (with 9 being most alert), the mean score was 4.9 at baseline, increasing to 5.7 after zolpidem dosing. Scores in the placebo arm were 4.7 and 5.2, respectively.

Sleep quality also improved significantly. Mean scores were 4.7 at baseline and 5.8 after treatment with zolpidem, compared with 4.5 and 5.2, respectively, with placebo.

The study found no evidence for the development of tolerance to zolpidem's efficacy.

Latency to sleep onset improved over the first 2 weeks, and apparently stabilized by week 3, for both the active-treatment and placebo groups, suggesting a nonspecific trend toward improvement in outcome over time.

The response to the medication did not change across the entire treatment period, and drug use was not different between treatment and placebo groups, Dr. Roth reported.

In fact, weekly medication use showed a decline for both the active and placebo groups, with medication use during week 4 being significantly lower than during week 1 in both arms.

The mean number of tablets taken during weeks 1 and 4 were 4.9 and 4.0, respectively, for the zolpidem group and 4.9 and 4.3, respectively, for the placebo group. There was no evidence of rebound effects on sleep initiation or total sleep time on nondosing nights, regardless of the number of nights of continuous use.

On average, for nights during which zolpidem was not dosed, total sleep time was similar for the active and placebo groups.

Dr. Roth noted that the improvement over placebo of about 20 minutes is clinically meaningful.

“It doesn't sound impressive, but try sleeping 20 minutes less every night for 3 months — you'll be in a coma. The effect is cumulative. It's about 2 hours a week.”

Middle-of-the-night awakening with difficulty falling back to sleep is a prevalent condition.

Source ©iStockphoto/redmonkey8

Major Finding: Persons who received a new formulation of low-dose sublingual zolpidem for middle-of-the-night insomnia showed no potential for abuse of the drug in the form of dependency, tolerance, or rebound potential, compared with placebo recipients.

Data Source: A 4-week outpatient study of 146 subjects.

Disclosures: Dr. Roth has served as a consultant to Transept Pharmaceuticals Inc., the manufacturer of the sublingual formulation of zolpidem tartrate. He has also received research support from and had other relationships with numerous pharmaceutical companies.

AMSTERDAM — A sublingual 3.5-mg formulation of zolpidem tartrate is effective for middle-of-the-night insomnia, producing no tolerance, rebound, or increase in use over a 4-week period, a study has shown.

“Awakening during the night with difficulty falling back to sleep is a prevalent condition, and a PRN treatment for this is needed as it may decrease overall drug exposure,” said the study's coinvestigator, Thomas Roth, Ph.D., of Henry Ford Hospital, Detroit.

Zolpidem sublingual tablets 3.5 mg and 1.75 mg were developed for the treatment of insomnia that is characterized by difficulty returning to sleep after middle-of-the-night (MOTN) awakening.

The compound is formulated with binary buffers to promote buccal absorption of a portion of the drug. This facilitates bioavailability, resulting in a rapid return to sleep.

Previous studies have found that sublingual zolpidem significantly reduces sleep latency after MOTN dosing.

In a sleep laboratory study, sleep latency time was approximately 28 minutes with placebo but just 10 minutes with zolpidem 3.5 mg (Sleep 2008;31:1277–84).

“This is a reduced dose of zolpidem, and importantly it is a sublingual formulation so you achieve much faster blood levels to help you fall back asleep but you reduce the total blood level as compared to taking it prophylactically. The concern is that over time, people take more and more of the medication,” Dr. Roth said at the meeting.

The drug is currently under review by the Food and Drug Administration for MOTN awakening.

In a study designed to address possible abuse liability associated with PRN use of the drug, 75 outpatients received zolpidem and 71 patients received placebo; all were assessed for latency to sleep onset after MOTN dosing across a 4-week treatment period.

To address rebound potential, outcomes also were observed on the first night of nondosing after 1 or more nights of medication use. Dependence and tolerance also were examined.

The study found no evidence of residual sleepiness after MOTN dosing with zolpidem. Patients who received the drug actually reported greater alertness, compared with baseline. On a scale of 1–9 (with 9 being most alert), the mean score was 4.9 at baseline, increasing to 5.7 after zolpidem dosing. Scores in the placebo arm were 4.7 and 5.2, respectively.

Sleep quality also improved significantly. Mean scores were 4.7 at baseline and 5.8 after treatment with zolpidem, compared with 4.5 and 5.2, respectively, with placebo.

The study found no evidence for the development of tolerance to zolpidem's efficacy.

Latency to sleep onset improved over the first 2 weeks, and apparently stabilized by week 3, for both the active-treatment and placebo groups, suggesting a nonspecific trend toward improvement in outcome over time.

The response to the medication did not change across the entire treatment period, and drug use was not different between treatment and placebo groups, Dr. Roth reported.

In fact, weekly medication use showed a decline for both the active and placebo groups, with medication use during week 4 being significantly lower than during week 1 in both arms.

The mean number of tablets taken during weeks 1 and 4 were 4.9 and 4.0, respectively, for the zolpidem group and 4.9 and 4.3, respectively, for the placebo group. There was no evidence of rebound effects on sleep initiation or total sleep time on nondosing nights, regardless of the number of nights of continuous use.

On average, for nights during which zolpidem was not dosed, total sleep time was similar for the active and placebo groups.

Dr. Roth noted that the improvement over placebo of about 20 minutes is clinically meaningful.

“It doesn't sound impressive, but try sleeping 20 minutes less every night for 3 months — you'll be in a coma. The effect is cumulative. It's about 2 hours a week.”

Middle-of-the-night awakening with difficulty falling back to sleep is a prevalent condition.

Source ©iStockphoto/redmonkey8

Major Finding: GSK researchers have developed a “filtering” approach that will eliminate study centers with high placebo response rates and enrich the effect of active drug treatment, thus yielding more accurate results of clinical trials.

Data Source: The studies were conducted and models developed by GSK investigators.

Disclosures: Dr. Merlo-Pich is a full-time employee of GlaxoSmithKline.

AMSTERDAM – Novel trial designs can be used to reduce the high placebo response seen in clinical trials of antidepressants and thus increase the efficiency of those trials, according to a drug development scientist who proposed a “filtering” approach at the congress.

“We have found that the response to placebo is the strongest factor in a failed clinical trial,” said Dr. Emilio Merlo-Pich, of the Centre of Excellence for External Drug Discovery, GlaxoSmithKline (GSK) in Verona, Italy, who spoke at a session called “The Placebo in Psychiatry.”

The placebo response trumps other reasons proposed to explain the high clinical trial failure rate for novel antidepressants, he said, including trial design features, heterogeneity of the study population, site-subject interactions, and low assay sensitivity related to clinical rating scale deficiencies.

Randomized clinical trial (RCT) outcomes can be improved by learning from past experience and using clinical databases and trial modeling, Dr. Merlo-Pich said. He and his colleagues have proposed an approach to improving RCTs using data to assess the role of recruitment centers and the problem of signal detection.

“Our study supports the implementation of prior-driven data preprocessing into RCT protocols to attenuate their failure rate, leading to a more efficient antidepressant drug discovery,” he said.

A meta-analysis of 52 RCTs indicated that placebo change from baseline to the end of study strongly affects the detection of active treatment superiority (J. Nerv. Ment. Dis. 2003;191:211-8). A statistically significant positive correlation was seen between placebo response magnitude and the advantage of antidepressants over placebo (P less than .0001). Only 21% of antidepressant treatment arms in trials with high placebo responses (more than a 30% mean change from baseline) showed superiority over placebo, compared with 74% in trials with a lower placebo response.

For the present study, a meta-analysis was conducted on nine GSK clinical trials, including 3,953 subjects with major depressive disorder, 1,197 of whom were exposed to placebo and 2,756 who had received antidepressants. The placebo response (reduction in depression score) varied highly according to the center.

A sensitivity analysis indicated that the placebo response by center was relevant for the detection of a treatment effect and for the success of the whole trial, Dr. Merlo-Pich reported. Placebo responses that are “too high” or “too low” generate noise within an RCT, he explained.

“We found that the placebo response can be so strong as to prevent any detection of a signal of pharmacologic effects, even if one is present. Therefore, the performance of each recruitment center is critical for the success of the whole trial,” he said. “In spite of training, recruitment centers manage protocols differently and handle patients differently, and this introduces bias. In fact, we have found the majority of the treatment effect depends on the center's performance.”

Based on the level of the placebo response, the investigators classified individual centers as “informative” or “noninformative.” This classification was associated with the probability of detecting a signal of a clinically relevant treatment effect. The number of “informative” centers per study is relevant for the clinical trial outcome. “If you have enough informative centers, there is a higher probability of a positive trial,” he said.

In the study, only 60% of centers in the GSK database were classified as informative based on their specific level of placebo response, he reported.

Using this information, Dr. Merlo-Pich and his colleagues then ranked the centers' performance, varying from 0 (high background noise and no chance to detect a treatment effect) to 100 (low noise and optimal condition for detecting a treatment effect). They then applied a “band-pass filter preprocessing approach” prior to statistical analysis as an enrichment strategy to single out the informative study population, reduce the noise, and improve the outcomes.

A clinical trial simulation was conducted to assess the performance of this “filtering” approach. The result was that the proportion of failed RCTs was reduced from 50% to 10%, he reported.

In implementing the model, the researchers define a-priori per-protocol high and low enrichment criteria to be applied at the end of treatment and before the statistical analysis. This identifies the noninformative centers to be eliminated, leaving the informative centers for the per-protocol efficacy analysis.

“We believe we can apply this approach to any clinical trial. This will maximize our investment and enhance patient exposure to promising new compounds,” he concluded.

Disclosures: Dr. Merlo-Pich is a full-time employee of GlaxoSmithKline.

Placebo responses that are 'too high' or 'too low' generate noise within a randomized clinical trial.

Source DR. MERLO-PICH

Major Finding: GSK researchers have developed a “filtering” approach that will eliminate study centers with high placebo response rates and enrich the effect of active drug treatment, thus yielding more accurate results of clinical trials.

Data Source: The studies were conducted and models developed by GSK investigators.

Disclosures: Dr. Merlo-Pich is a full-time employee of GlaxoSmithKline.

AMSTERDAM – Novel trial designs can be used to reduce the high placebo response seen in clinical trials of antidepressants and thus increase the efficiency of those trials, according to a drug development scientist who proposed a “filtering” approach at the congress.

“We have found that the response to placebo is the strongest factor in a failed clinical trial,” said Dr. Emilio Merlo-Pich, of the Centre of Excellence for External Drug Discovery, GlaxoSmithKline (GSK) in Verona, Italy, who spoke at a session called “The Placebo in Psychiatry.”

The placebo response trumps other reasons proposed to explain the high clinical trial failure rate for novel antidepressants, he said, including trial design features, heterogeneity of the study population, site-subject interactions, and low assay sensitivity related to clinical rating scale deficiencies.

Randomized clinical trial (RCT) outcomes can be improved by learning from past experience and using clinical databases and trial modeling, Dr. Merlo-Pich said. He and his colleagues have proposed an approach to improving RCTs using data to assess the role of recruitment centers and the problem of signal detection.

“Our study supports the implementation of prior-driven data preprocessing into RCT protocols to attenuate their failure rate, leading to a more efficient antidepressant drug discovery,” he said.

A meta-analysis of 52 RCTs indicated that placebo change from baseline to the end of study strongly affects the detection of active treatment superiority (J. Nerv. Ment. Dis. 2003;191:211-8). A statistically significant positive correlation was seen between placebo response magnitude and the advantage of antidepressants over placebo (P less than .0001). Only 21% of antidepressant treatment arms in trials with high placebo responses (more than a 30% mean change from baseline) showed superiority over placebo, compared with 74% in trials with a lower placebo response.

For the present study, a meta-analysis was conducted on nine GSK clinical trials, including 3,953 subjects with major depressive disorder, 1,197 of whom were exposed to placebo and 2,756 who had received antidepressants. The placebo response (reduction in depression score) varied highly according to the center.

A sensitivity analysis indicated that the placebo response by center was relevant for the detection of a treatment effect and for the success of the whole trial, Dr. Merlo-Pich reported. Placebo responses that are “too high” or “too low” generate noise within an RCT, he explained.

“We found that the placebo response can be so strong as to prevent any detection of a signal of pharmacologic effects, even if one is present. Therefore, the performance of each recruitment center is critical for the success of the whole trial,” he said. “In spite of training, recruitment centers manage protocols differently and handle patients differently, and this introduces bias. In fact, we have found the majority of the treatment effect depends on the center's performance.”

Based on the level of the placebo response, the investigators classified individual centers as “informative” or “noninformative.” This classification was associated with the probability of detecting a signal of a clinically relevant treatment effect. The number of “informative” centers per study is relevant for the clinical trial outcome. “If you have enough informative centers, there is a higher probability of a positive trial,” he said.

In the study, only 60% of centers in the GSK database were classified as informative based on their specific level of placebo response, he reported.

Using this information, Dr. Merlo-Pich and his colleagues then ranked the centers' performance, varying from 0 (high background noise and no chance to detect a treatment effect) to 100 (low noise and optimal condition for detecting a treatment effect). They then applied a “band-pass filter preprocessing approach” prior to statistical analysis as an enrichment strategy to single out the informative study population, reduce the noise, and improve the outcomes.

A clinical trial simulation was conducted to assess the performance of this “filtering” approach. The result was that the proportion of failed RCTs was reduced from 50% to 10%, he reported.

In implementing the model, the researchers define a-priori per-protocol high and low enrichment criteria to be applied at the end of treatment and before the statistical analysis. This identifies the noninformative centers to be eliminated, leaving the informative centers for the per-protocol efficacy analysis.

“We believe we can apply this approach to any clinical trial. This will maximize our investment and enhance patient exposure to promising new compounds,” he concluded.

Disclosures: Dr. Merlo-Pich is a full-time employee of GlaxoSmithKline.

Placebo responses that are 'too high' or 'too low' generate noise within a randomized clinical trial.

Source DR. MERLO-PICH

Major Finding: GSK researchers have developed a “filtering” approach that will eliminate study centers with high placebo response rates and enrich the effect of active drug treatment, thus yielding more accurate results of clinical trials.

Data Source: The studies were conducted and models developed by GSK investigators.

Disclosures: Dr. Merlo-Pich is a full-time employee of GlaxoSmithKline.

AMSTERDAM – Novel trial designs can be used to reduce the high placebo response seen in clinical trials of antidepressants and thus increase the efficiency of those trials, according to a drug development scientist who proposed a “filtering” approach at the congress.

“We have found that the response to placebo is the strongest factor in a failed clinical trial,” said Dr. Emilio Merlo-Pich, of the Centre of Excellence for External Drug Discovery, GlaxoSmithKline (GSK) in Verona, Italy, who spoke at a session called “The Placebo in Psychiatry.”

The placebo response trumps other reasons proposed to explain the high clinical trial failure rate for novel antidepressants, he said, including trial design features, heterogeneity of the study population, site-subject interactions, and low assay sensitivity related to clinical rating scale deficiencies.

Randomized clinical trial (RCT) outcomes can be improved by learning from past experience and using clinical databases and trial modeling, Dr. Merlo-Pich said. He and his colleagues have proposed an approach to improving RCTs using data to assess the role of recruitment centers and the problem of signal detection.

“Our study supports the implementation of prior-driven data preprocessing into RCT protocols to attenuate their failure rate, leading to a more efficient antidepressant drug discovery,” he said.

A meta-analysis of 52 RCTs indicated that placebo change from baseline to the end of study strongly affects the detection of active treatment superiority (J. Nerv. Ment. Dis. 2003;191:211-8). A statistically significant positive correlation was seen between placebo response magnitude and the advantage of antidepressants over placebo (P less than .0001). Only 21% of antidepressant treatment arms in trials with high placebo responses (more than a 30% mean change from baseline) showed superiority over placebo, compared with 74% in trials with a lower placebo response.

For the present study, a meta-analysis was conducted on nine GSK clinical trials, including 3,953 subjects with major depressive disorder, 1,197 of whom were exposed to placebo and 2,756 who had received antidepressants. The placebo response (reduction in depression score) varied highly according to the center.

A sensitivity analysis indicated that the placebo response by center was relevant for the detection of a treatment effect and for the success of the whole trial, Dr. Merlo-Pich reported. Placebo responses that are “too high” or “too low” generate noise within an RCT, he explained.

“We found that the placebo response can be so strong as to prevent any detection of a signal of pharmacologic effects, even if one is present. Therefore, the performance of each recruitment center is critical for the success of the whole trial,” he said. “In spite of training, recruitment centers manage protocols differently and handle patients differently, and this introduces bias. In fact, we have found the majority of the treatment effect depends on the center's performance.”

Based on the level of the placebo response, the investigators classified individual centers as “informative” or “noninformative.” This classification was associated with the probability of detecting a signal of a clinically relevant treatment effect. The number of “informative” centers per study is relevant for the clinical trial outcome. “If you have enough informative centers, there is a higher probability of a positive trial,” he said.

In the study, only 60% of centers in the GSK database were classified as informative based on their specific level of placebo response, he reported.

Using this information, Dr. Merlo-Pich and his colleagues then ranked the centers' performance, varying from 0 (high background noise and no chance to detect a treatment effect) to 100 (low noise and optimal condition for detecting a treatment effect). They then applied a “band-pass filter preprocessing approach” prior to statistical analysis as an enrichment strategy to single out the informative study population, reduce the noise, and improve the outcomes.

A clinical trial simulation was conducted to assess the performance of this “filtering” approach. The result was that the proportion of failed RCTs was reduced from 50% to 10%, he reported.

In implementing the model, the researchers define a-priori per-protocol high and low enrichment criteria to be applied at the end of treatment and before the statistical analysis. This identifies the noninformative centers to be eliminated, leaving the informative centers for the per-protocol efficacy analysis.

“We believe we can apply this approach to any clinical trial. This will maximize our investment and enhance patient exposure to promising new compounds,” he concluded.

Disclosures: Dr. Merlo-Pich is a full-time employee of GlaxoSmithKline.

Placebo responses that are 'too high' or 'too low' generate noise within a randomized clinical trial.

Source DR. MERLO-PICH

AMSTERDAM – Circadian dysfunction can greatly affect brain function – impairing behavior, cognition, and affect – and can be improved with a “chronotherapeutic” approach, according to Anna Wirz-Justice, Ph.D., one of the leading researchers in the field.

Dr. Wirz-Justice, professor emeritus at the center for chronobiology at Psychiatric University Clinics in Basel, Switzerland, coauthored the treatment manual, “Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy” (Basel: Karger, 2009).

“In the treatment of affective disorders, chronotherapeutics offers a new synthesis of nonpharmacologic interventions designed to accelerate remission. Combining it with concomitant or follow-up medications shows great promise,” said Dr. Wirz-Justice, who has led numerous investigative studies in the field and lectured on the role of circadian rhythms in affective disorders at the congress.

Circadian rhythms are directed by a master biological block in the suprachiasmatic nucleus (SCN) as well as circadian oscillators in all brain regions and peripheral tissues. The SCN is synchronized daily by environmental signals, mainly light. Receiving information on lighting conditions directly from the retina, the SCN drives secretion of melatonin and regulates peripheral “clocks,” whose outputs modulate the SCN through feedback or feed-forward effects.

Specific circadian genes such as CLOCK, BMAL1, and PER are responsible for the main SCN “clock-working” machinery.

New interest in the role of circadian dysregulation in psychiatric disorders has arisen from the finding that a mutation in a core circadian clock gene induces hyperactivity, decreased sleep, and mania-like behavior in mice.

“Animal studies were the key development that brought the field to its present exciting position, by suggesting that 'clock genes' are directing the circadian rhythms in all physiological processes,” Dr. Wirz-Justice said.

Clinical Impact on Disorders

In healthy individuals, physiological and biochemical variables such as body temperature, cortisol and melatonin, thyroid-stimulating hormone, norepinephrine and serotonin exhibit circadian rhythms.

However, in patients who have affective disorders, many of these rhythms are disturbed in phase and amplitude.

For instance, in major depressive disorder (MDD), most patients present with sleep disturbances and altered circadian rhythms, including hormonal secretion, cardiac function, and body temperature.

Sleep disruption is a major symptom in depression and is often the factor prompting depressed persons to seek medical help.

Synchronizing impaired circadian rhythms through “chronotherapeutics” – improving sleep or paradoxically staying awake most of the night – can be extremely helpful in treating patients with MDD and bipolar disorder, Dr. Wirz-Justice said, but the approach is not limited to depression.

In addition to major depression (seasonal and nonseasonal), chronotherapeutics indications include bipolar disorder, premenstrual dysphoric disorder and depression during pregnancy, bulimia nervosa, attention-deficit/hyperactivity disorder, dementia, Parkinson's disease, and shift-work and jet-lag disturbances, according to Dr. Wirz-Justice.

“Light therapy has been used to resynchronize disturbed sleep schedules back to a more normal pattern. Light is also an effective antidepressant, acting on many of the same neurotransmitter systems and brain structures as antidepressant drugs,” she said.

“The new message is that light therapy is not just for seasonal affective disorder but for all forms of depression and for many other disorders,” she added.

“As an adjuvant to antidepressants in unipolar depressive patients or to lithium in bipolar patients, morning light hastens and potentiates the antidepressant response. Light therapy shows benefit even for patients with chronic depression of 2 years or more and provides a viable alternative for patients who refuse, resist, or cannot tolerate medication,” Dr. Wirz-Justice said.

Elements of chronotherapy include light therapy, dark therapy or blue-blocking sunglasses, wake therapy (total or partial sleep deprivation in the second half of the night), phase advance of the sleep-wake cycle, and exogenously administered melatonin.

Sleep Deprivation and Dark Therapy

A 1-night sleep deprivation, or “wake therapy,” is the most rapid antidepressant known, according to Dr. Wirz-Justice. A single night's sleep deprivation induces brain changes similar to those that result from many weeks of antidepressant drugs (Curr. Pharm. Des. 2009;15:2637-49).

“Approximately 60% of patients, independent of diagnostic subtypes, respond with marked improvement within hours,” she said. “Mostly, however, they relapse after recovery sleep, which indicates how important wakefulness must be. We have found you can prevent relapse by combining daily light therapy with antidepressants or lithium or a short phase advance of sleep over 3 days.”

Dark therapy (defined as keeping patients in a dark setting and extending rest-sleep for periods of 10-14 hours) has yielded positive results in controlling symptoms in acute mania and calming rapid-cycling bipolar patients in the manic phase, she said.

Since this approach is impractical, an alternative that is being investigated is the use of blue-blocking sunglasses. Blue is the wavelength to which the circadian system is particularly sensitive. Thus, by blocking this range in the light spectrum one can induce “circadian darkness” while not impairing vision, she explained.

Dr. Wirz-Justice is advocating wider use of these techniques in psychiatry and their incorporation into residency programs. “In clinical practice, there is still r

“In clinical practice, there is still rather widespread ignorance about circadian sleep disturbances and chronotherapeutics in spite of the significant evidence base,” she said.

“Enterprising doctors should try this out, and the techniques should be taught in residency programs.”

Disclosures: Dr. Wirz-Justice reported no potential conflicts of interest.

For more information on chronotherapeutics, check out the Center for Environmental Therapeutics' Web site at

www.chronotherapeutics.org

AMSTERDAM – Circadian dysfunction can greatly affect brain function – impairing behavior, cognition, and affect – and can be improved with a “chronotherapeutic” approach, according to Anna Wirz-Justice, Ph.D., one of the leading researchers in the field.

Dr. Wirz-Justice, professor emeritus at the center for chronobiology at Psychiatric University Clinics in Basel, Switzerland, coauthored the treatment manual, “Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy” (Basel: Karger, 2009).

“In the treatment of affective disorders, chronotherapeutics offers a new synthesis of nonpharmacologic interventions designed to accelerate remission. Combining it with concomitant or follow-up medications shows great promise,” said Dr. Wirz-Justice, who has led numerous investigative studies in the field and lectured on the role of circadian rhythms in affective disorders at the congress.

Circadian rhythms are directed by a master biological block in the suprachiasmatic nucleus (SCN) as well as circadian oscillators in all brain regions and peripheral tissues. The SCN is synchronized daily by environmental signals, mainly light. Receiving information on lighting conditions directly from the retina, the SCN drives secretion of melatonin and regulates peripheral “clocks,” whose outputs modulate the SCN through feedback or feed-forward effects.

Specific circadian genes such as CLOCK, BMAL1, and PER are responsible for the main SCN “clock-working” machinery.

New interest in the role of circadian dysregulation in psychiatric disorders has arisen from the finding that a mutation in a core circadian clock gene induces hyperactivity, decreased sleep, and mania-like behavior in mice.

“Animal studies were the key development that brought the field to its present exciting position, by suggesting that 'clock genes' are directing the circadian rhythms in all physiological processes,” Dr. Wirz-Justice said.

Clinical Impact on Disorders

In healthy individuals, physiological and biochemical variables such as body temperature, cortisol and melatonin, thyroid-stimulating hormone, norepinephrine and serotonin exhibit circadian rhythms.

However, in patients who have affective disorders, many of these rhythms are disturbed in phase and amplitude.

For instance, in major depressive disorder (MDD), most patients present with sleep disturbances and altered circadian rhythms, including hormonal secretion, cardiac function, and body temperature.

Sleep disruption is a major symptom in depression and is often the factor prompting depressed persons to seek medical help.

Synchronizing impaired circadian rhythms through “chronotherapeutics” – improving sleep or paradoxically staying awake most of the night – can be extremely helpful in treating patients with MDD and bipolar disorder, Dr. Wirz-Justice said, but the approach is not limited to depression.

In addition to major depression (seasonal and nonseasonal), chronotherapeutics indications include bipolar disorder, premenstrual dysphoric disorder and depression during pregnancy, bulimia nervosa, attention-deficit/hyperactivity disorder, dementia, Parkinson's disease, and shift-work and jet-lag disturbances, according to Dr. Wirz-Justice.

“Light therapy has been used to resynchronize disturbed sleep schedules back to a more normal pattern. Light is also an effective antidepressant, acting on many of the same neurotransmitter systems and brain structures as antidepressant drugs,” she said.

“The new message is that light therapy is not just for seasonal affective disorder but for all forms of depression and for many other disorders,” she added.

“As an adjuvant to antidepressants in unipolar depressive patients or to lithium in bipolar patients, morning light hastens and potentiates the antidepressant response. Light therapy shows benefit even for patients with chronic depression of 2 years or more and provides a viable alternative for patients who refuse, resist, or cannot tolerate medication,” Dr. Wirz-Justice said.

Elements of chronotherapy include light therapy, dark therapy or blue-blocking sunglasses, wake therapy (total or partial sleep deprivation in the second half of the night), phase advance of the sleep-wake cycle, and exogenously administered melatonin.

Sleep Deprivation and Dark Therapy

A 1-night sleep deprivation, or “wake therapy,” is the most rapid antidepressant known, according to Dr. Wirz-Justice. A single night's sleep deprivation induces brain changes similar to those that result from many weeks of antidepressant drugs (Curr. Pharm. Des. 2009;15:2637-49).

“Approximately 60% of patients, independent of diagnostic subtypes, respond with marked improvement within hours,” she said. “Mostly, however, they relapse after recovery sleep, which indicates how important wakefulness must be. We have found you can prevent relapse by combining daily light therapy with antidepressants or lithium or a short phase advance of sleep over 3 days.”

Dark therapy (defined as keeping patients in a dark setting and extending rest-sleep for periods of 10-14 hours) has yielded positive results in controlling symptoms in acute mania and calming rapid-cycling bipolar patients in the manic phase, she said.

Since this approach is impractical, an alternative that is being investigated is the use of blue-blocking sunglasses. Blue is the wavelength to which the circadian system is particularly sensitive. Thus, by blocking this range in the light spectrum one can induce “circadian darkness” while not impairing vision, she explained.

Dr. Wirz-Justice is advocating wider use of these techniques in psychiatry and their incorporation into residency programs. “In clinical practice, there is still r

“In clinical practice, there is still rather widespread ignorance about circadian sleep disturbances and chronotherapeutics in spite of the significant evidence base,” she said.

“Enterprising doctors should try this out, and the techniques should be taught in residency programs.”

Disclosures: Dr. Wirz-Justice reported no potential conflicts of interest.

For more information on chronotherapeutics, check out the Center for Environmental Therapeutics' Web site at

www.chronotherapeutics.org

AMSTERDAM – Circadian dysfunction can greatly affect brain function – impairing behavior, cognition, and affect – and can be improved with a “chronotherapeutic” approach, according to Anna Wirz-Justice, Ph.D., one of the leading researchers in the field.

Dr. Wirz-Justice, professor emeritus at the center for chronobiology at Psychiatric University Clinics in Basel, Switzerland, coauthored the treatment manual, “Chronotherapeutics for Affective Disorders: A Clinician's Manual for Light and Wake Therapy” (Basel: Karger, 2009).

“In the treatment of affective disorders, chronotherapeutics offers a new synthesis of nonpharmacologic interventions designed to accelerate remission. Combining it with concomitant or follow-up medications shows great promise,” said Dr. Wirz-Justice, who has led numerous investigative studies in the field and lectured on the role of circadian rhythms in affective disorders at the congress.

Circadian rhythms are directed by a master biological block in the suprachiasmatic nucleus (SCN) as well as circadian oscillators in all brain regions and peripheral tissues. The SCN is synchronized daily by environmental signals, mainly light. Receiving information on lighting conditions directly from the retina, the SCN drives secretion of melatonin and regulates peripheral “clocks,” whose outputs modulate the SCN through feedback or feed-forward effects.

Specific circadian genes such as CLOCK, BMAL1, and PER are responsible for the main SCN “clock-working” machinery.

New interest in the role of circadian dysregulation in psychiatric disorders has arisen from the finding that a mutation in a core circadian clock gene induces hyperactivity, decreased sleep, and mania-like behavior in mice.

“Animal studies were the key development that brought the field to its present exciting position, by suggesting that 'clock genes' are directing the circadian rhythms in all physiological processes,” Dr. Wirz-Justice said.

Clinical Impact on Disorders

In healthy individuals, physiological and biochemical variables such as body temperature, cortisol and melatonin, thyroid-stimulating hormone, norepinephrine and serotonin exhibit circadian rhythms.

However, in patients who have affective disorders, many of these rhythms are disturbed in phase and amplitude.

For instance, in major depressive disorder (MDD), most patients present with sleep disturbances and altered circadian rhythms, including hormonal secretion, cardiac function, and body temperature.

Sleep disruption is a major symptom in depression and is often the factor prompting depressed persons to seek medical help.

Synchronizing impaired circadian rhythms through “chronotherapeutics” – improving sleep or paradoxically staying awake most of the night – can be extremely helpful in treating patients with MDD and bipolar disorder, Dr. Wirz-Justice said, but the approach is not limited to depression.

In addition to major depression (seasonal and nonseasonal), chronotherapeutics indications include bipolar disorder, premenstrual dysphoric disorder and depression during pregnancy, bulimia nervosa, attention-deficit/hyperactivity disorder, dementia, Parkinson's disease, and shift-work and jet-lag disturbances, according to Dr. Wirz-Justice.

“Light therapy has been used to resynchronize disturbed sleep schedules back to a more normal pattern. Light is also an effective antidepressant, acting on many of the same neurotransmitter systems and brain structures as antidepressant drugs,” she said.

“The new message is that light therapy is not just for seasonal affective disorder but for all forms of depression and for many other disorders,” she added.

“As an adjuvant to antidepressants in unipolar depressive patients or to lithium in bipolar patients, morning light hastens and potentiates the antidepressant response. Light therapy shows benefit even for patients with chronic depression of 2 years or more and provides a viable alternative for patients who refuse, resist, or cannot tolerate medication,” Dr. Wirz-Justice said.

Elements of chronotherapy include light therapy, dark therapy or blue-blocking sunglasses, wake therapy (total or partial sleep deprivation in the second half of the night), phase advance of the sleep-wake cycle, and exogenously administered melatonin.

Sleep Deprivation and Dark Therapy

A 1-night sleep deprivation, or “wake therapy,” is the most rapid antidepressant known, according to Dr. Wirz-Justice. A single night's sleep deprivation induces brain changes similar to those that result from many weeks of antidepressant drugs (Curr. Pharm. Des. 2009;15:2637-49).

“Approximately 60% of patients, independent of diagnostic subtypes, respond with marked improvement within hours,” she said. “Mostly, however, they relapse after recovery sleep, which indicates how important wakefulness must be. We have found you can prevent relapse by combining daily light therapy with antidepressants or lithium or a short phase advance of sleep over 3 days.”

Dark therapy (defined as keeping patients in a dark setting and extending rest-sleep for periods of 10-14 hours) has yielded positive results in controlling symptoms in acute mania and calming rapid-cycling bipolar patients in the manic phase, she said.

Since this approach is impractical, an alternative that is being investigated is the use of blue-blocking sunglasses. Blue is the wavelength to which the circadian system is particularly sensitive. Thus, by blocking this range in the light spectrum one can induce “circadian darkness” while not impairing vision, she explained.

Dr. Wirz-Justice is advocating wider use of these techniques in psychiatry and their incorporation into residency programs. “In clinical practice, there is still r

“In clinical practice, there is still rather widespread ignorance about circadian sleep disturbances and chronotherapeutics in spite of the significant evidence base,” she said.

“Enterprising doctors should try this out, and the techniques should be taught in residency programs.”

Disclosures: Dr. Wirz-Justice reported no potential conflicts of interest.

For more information on chronotherapeutics, check out the Center for Environmental Therapeutics' Web site at

www.chronotherapeutics.org

Major Finding: Persons who received a new formulation of low-dose sublingual zolpidem for middle-of-the-night insomnia showed no potential for abuse of the drug in the form of dependency, tolerance, or rebound potential, compared with placebo recipients.

Data Source: A 4-week outpatient study of 146 subjects.

Disclosures: Dr. Roth has served as a consultant to Transept Pharmaceuticals Inc., the manufacturer of the sublingual formulation of zolpidem tartrate. He has also received research support from and had other relationships with numerous pharmaceutical companies.

AMSTERDAM – A sublingual 3.5-mg formulation of zolpidem tartrate is effective for middle-of-the-night insomnia, producing no tolerance, rebound, or increase in use over 4 weeks, investigators reported at the congress.

“Awakening during the night with difficulty falling back to sleep is a prevalent condition, and a p.r.n. treatment for this is needed as it may decrease overall drug exposure,” said the study's coinvestigator, Thomas Roth, Ph.D., of Henry Ford Hospital, Detroit.

Zolpidem sublingual tablets 3.5 mg and 1.75 mg were developed for the treatment of insomnia that is characterized by difficulty returning to sleep after middle-of-the-night (MOTN) awakening. The compound is formulated with binary buffers to promote buccal absorption of a portion of the drug. This facilitates bioavailability, resulting in a rapid return to sleep. Previous studies have found that sublingual zolpidem significantly reduces sleep latency after MOTN dosing. In a sleep laboratory study, sleep latency time was approximately 28 minutes with placebo but just 10 minutes with zolpidem 3.5 mg (Sleep 2008;31:1277-84).

“This is a reduced dose of zolpidem, and importantly it is a sublingual formulation so you achieve much faster blood levels to help you fall back asleep but you reduce the total blood level as compared to taking it prophylactically. The concern is that over time, people take more and more of the medication,” Dr. Roth said.

The drug is currently under review by the Food and Drug Administration for MOTN awakening.

In a study designed to address possible abuse liability associated with p.r.n. use of the drug, 75 outpatients received zolpidem and 71 patients received placebo; all were assessed for latency to sleep onset after MOTN dosing across a 4-week treatment period. For a check of rebound potential, outcomes also were observed on the first night of nondosing after 1 or more nights of medication use.

The study found no evidence of residual sleepiness after MOTN dosing with zolpidem. Patients who received the drug actually reported greater alertness compared with baseline. On a scale of 1-9 (with 9 being most alert), the mean score was 4.9 at baseline, increasing to 5.7 after zolpidem dosing. Scores in the placebo arm were 4.7 and 5.2, respectively.

Sleep quality also improved significantly. Mean scores were 4.7 at baseline and 5.8 with zolpidem, vs. 4.5 and 5.2, respectively, with placebo.

The study found no evidence for the development of tolerance to zolpidem's efficacy. Latency to sleep onset improved over the first 2 weeks, and apparently stabilized by week 3, for both the active-treatment and placebo groups, suggesting a nonspecific trend toward improvement in outcome over time.

The response to the medication did not change across the entire treatment period, and drug use was not different between treatment and placebo groups. In fact, drug use during week 4bwas significantly lower than during week 1 in both the active and placebo arms.

There was no evidence of rebound effects on sleep initiation or total sleep time on nondosing nights, regardless of the number of nights of continuous use. On average, for nights during which zolpidem was not dosed, total sleep time was similar for the active and placebo groups.

Dr. Roth noted that the improvement over placebo of about 20 minutes is clinically meaningful. “It doesn't sound impressive, but try sleeping 20 minutes less every night for 3 months – you'll be in a coma. The effect is cumulative. It's about 2 hours a week.”

Sublingual zolpidem helped patients get back to sleep, with no evidence of residual sleepiness.

Source ©iStockphoto/redmonkey8

Major Finding: Persons who received a new formulation of low-dose sublingual zolpidem for middle-of-the-night insomnia showed no potential for abuse of the drug in the form of dependency, tolerance, or rebound potential, compared with placebo recipients.

Data Source: A 4-week outpatient study of 146 subjects.

Disclosures: Dr. Roth has served as a consultant to Transept Pharmaceuticals Inc., the manufacturer of the sublingual formulation of zolpidem tartrate. He has also received research support from and had other relationships with numerous pharmaceutical companies.

AMSTERDAM – A sublingual 3.5-mg formulation of zolpidem tartrate is effective for middle-of-the-night insomnia, producing no tolerance, rebound, or increase in use over 4 weeks, investigators reported at the congress.

“Awakening during the night with difficulty falling back to sleep is a prevalent condition, and a p.r.n. treatment for this is needed as it may decrease overall drug exposure,” said the study's coinvestigator, Thomas Roth, Ph.D., of Henry Ford Hospital, Detroit.

Zolpidem sublingual tablets 3.5 mg and 1.75 mg were developed for the treatment of insomnia that is characterized by difficulty returning to sleep after middle-of-the-night (MOTN) awakening. The compound is formulated with binary buffers to promote buccal absorption of a portion of the drug. This facilitates bioavailability, resulting in a rapid return to sleep. Previous studies have found that sublingual zolpidem significantly reduces sleep latency after MOTN dosing. In a sleep laboratory study, sleep latency time was approximately 28 minutes with placebo but just 10 minutes with zolpidem 3.5 mg (Sleep 2008;31:1277-84).

“This is a reduced dose of zolpidem, and importantly it is a sublingual formulation so you achieve much faster blood levels to help you fall back asleep but you reduce the total blood level as compared to taking it prophylactically. The concern is that over time, people take more and more of the medication,” Dr. Roth said.

The drug is currently under review by the Food and Drug Administration for MOTN awakening.

In a study designed to address possible abuse liability associated with p.r.n. use of the drug, 75 outpatients received zolpidem and 71 patients received placebo; all were assessed for latency to sleep onset after MOTN dosing across a 4-week treatment period. For a check of rebound potential, outcomes also were observed on the first night of nondosing after 1 or more nights of medication use.

The study found no evidence of residual sleepiness after MOTN dosing with zolpidem. Patients who received the drug actually reported greater alertness compared with baseline. On a scale of 1-9 (with 9 being most alert), the mean score was 4.9 at baseline, increasing to 5.7 after zolpidem dosing. Scores in the placebo arm were 4.7 and 5.2, respectively.

Sleep quality also improved significantly. Mean scores were 4.7 at baseline and 5.8 with zolpidem, vs. 4.5 and 5.2, respectively, with placebo.

The study found no evidence for the development of tolerance to zolpidem's efficacy. Latency to sleep onset improved over the first 2 weeks, and apparently stabilized by week 3, for both the active-treatment and placebo groups, suggesting a nonspecific trend toward improvement in outcome over time.

The response to the medication did not change across the entire treatment period, and drug use was not different between treatment and placebo groups. In fact, drug use during week 4bwas significantly lower than during week 1 in both the active and placebo arms.

There was no evidence of rebound effects on sleep initiation or total sleep time on nondosing nights, regardless of the number of nights of continuous use. On average, for nights during which zolpidem was not dosed, total sleep time was similar for the active and placebo groups.

Dr. Roth noted that the improvement over placebo of about 20 minutes is clinically meaningful. “It doesn't sound impressive, but try sleeping 20 minutes less every night for 3 months – you'll be in a coma. The effect is cumulative. It's about 2 hours a week.”

Sublingual zolpidem helped patients get back to sleep, with no evidence of residual sleepiness.

Source ©iStockphoto/redmonkey8

Major Finding: Persons who received a new formulation of low-dose sublingual zolpidem for middle-of-the-night insomnia showed no potential for abuse of the drug in the form of dependency, tolerance, or rebound potential, compared with placebo recipients.

Data Source: A 4-week outpatient study of 146 subjects.

Disclosures: Dr. Roth has served as a consultant to Transept Pharmaceuticals Inc., the manufacturer of the sublingual formulation of zolpidem tartrate. He has also received research support from and had other relationships with numerous pharmaceutical companies.

AMSTERDAM – A sublingual 3.5-mg formulation of zolpidem tartrate is effective for middle-of-the-night insomnia, producing no tolerance, rebound, or increase in use over 4 weeks, investigators reported at the congress.

“Awakening during the night with difficulty falling back to sleep is a prevalent condition, and a p.r.n. treatment for this is needed as it may decrease overall drug exposure,” said the study's coinvestigator, Thomas Roth, Ph.D., of Henry Ford Hospital, Detroit.

Zolpidem sublingual tablets 3.5 mg and 1.75 mg were developed for the treatment of insomnia that is characterized by difficulty returning to sleep after middle-of-the-night (MOTN) awakening. The compound is formulated with binary buffers to promote buccal absorption of a portion of the drug. This facilitates bioavailability, resulting in a rapid return to sleep. Previous studies have found that sublingual zolpidem significantly reduces sleep latency after MOTN dosing. In a sleep laboratory study, sleep latency time was approximately 28 minutes with placebo but just 10 minutes with zolpidem 3.5 mg (Sleep 2008;31:1277-84).

“This is a reduced dose of zolpidem, and importantly it is a sublingual formulation so you achieve much faster blood levels to help you fall back asleep but you reduce the total blood level as compared to taking it prophylactically. The concern is that over time, people take more and more of the medication,” Dr. Roth said.

The drug is currently under review by the Food and Drug Administration for MOTN awakening.

In a study designed to address possible abuse liability associated with p.r.n. use of the drug, 75 outpatients received zolpidem and 71 patients received placebo; all were assessed for latency to sleep onset after MOTN dosing across a 4-week treatment period. For a check of rebound potential, outcomes also were observed on the first night of nondosing after 1 or more nights of medication use.

The study found no evidence of residual sleepiness after MOTN dosing with zolpidem. Patients who received the drug actually reported greater alertness compared with baseline. On a scale of 1-9 (with 9 being most alert), the mean score was 4.9 at baseline, increasing to 5.7 after zolpidem dosing. Scores in the placebo arm were 4.7 and 5.2, respectively.

Sleep quality also improved significantly. Mean scores were 4.7 at baseline and 5.8 with zolpidem, vs. 4.5 and 5.2, respectively, with placebo.

The study found no evidence for the development of tolerance to zolpidem's efficacy. Latency to sleep onset improved over the first 2 weeks, and apparently stabilized by week 3, for both the active-treatment and placebo groups, suggesting a nonspecific trend toward improvement in outcome over time.

The response to the medication did not change across the entire treatment period, and drug use was not different between treatment and placebo groups. In fact, drug use during week 4bwas significantly lower than during week 1 in both the active and placebo arms.

There was no evidence of rebound effects on sleep initiation or total sleep time on nondosing nights, regardless of the number of nights of continuous use. On average, for nights during which zolpidem was not dosed, total sleep time was similar for the active and placebo groups.

Dr. Roth noted that the improvement over placebo of about 20 minutes is clinically meaningful. “It doesn't sound impressive, but try sleeping 20 minutes less every night for 3 months – you'll be in a coma. The effect is cumulative. It's about 2 hours a week.”

Sublingual zolpidem helped patients get back to sleep, with no evidence of residual sleepiness.

Source ©iStockphoto/redmonkey8

Major Finding: One in five adult patients with schizophrenia switched antipsychotic medications in the previous 12 weeks, mostly because of lack of efficacy and secondarily because of side effects.

Data Source: Observational study of more than 23,000 patients from 11 countries.

Disclosures: The study was funded by Sanofi-Aventis. Dr. Galinska-Skok had no relevant disclosures.

AMSTERDAM – A large multinational study found that one in five adult patients with schizophrenia switched medications within the previous 12 weeks, mostly because of inadequate symptom control as one-third reported a relapse on the initial drug.

Tolerability issues also were important and differed between first- and second-generation antipsychotics, reported Dr. Beata Galinska-Skok of the Medical University of Bialystok in Choroszcz, Poland.

“In the long-term management of schizophrenia, around one-third of patients treated with antipsychotic drugs change their medication every year. There is a need to better understand the dynamics of switching in real-world conditions. We performed a naturalistic multinational observational survey to evaluate the parameters of treatment discontinuation and substitutions in the management of schizophrenia in every day clinical practice,” Dr. Galinska-Skok said.

The primary objective of the cross-sectional observational study conducted in 11 countries was to identify the frequency of and reasons for switching antipsychotic treatments in patients with schizophrenia. Participating physicians were community- or hospital-based psychiatrists who reflected local psychiatric practices and patient management.

The countries represented were Algeria, Greece, India, Jordan, Lithuania, Mexico, Philippines, Poland, Slovakia, Ukraine, and Vietnam.

The registry population included 23,441 adult patients (mean age 41), of whom 22,126 were analyzable. Of those, 5,128 patients (23.2%) reported a treatment switch in the previous 12 weeks and thus constituted the switch population; 3,130 consented to the study and constitute the analysis population.

The medication that was discontinued in the previous 12 weeks was a second-generation antipsychotic for 55.6% of patients and a first-generation agent for 41.8%, while 2.6% discontinued both types. After the switch, most patients received a second-generation agent (90%) either alone (72.4%) or in combination with a first-generation agent (18.3%). The remainder received a first-generation agent as monotherapy, she reported.

Main Reason for Switching: Lack of Efficacy

Physicians could report more than one reason for switching. The survey found the main reason to be inadequate symptom control (79.4%), while the occurrence of adverse events was also common (55.3%). Other reasons frequently cited included poor quality of life (31.7%), relapse on medication (30.1%), poor compliance (25.3%), and patient request (18.3%). Two to six percent reported problems with drug availability, financial or life events, and comorbid medical conditions.

“Over half the changes were motivated by an adverse event,” Dr. Galinska-Skok noted. “The nature of the adverse events differed depending on the class of antipsychotic the patient was taking before the switch. Extrapyramidal symptoms and sedation were the two adverse events that most frequently motivated switching from a first-generation agent. Sedation and weight gain were the two most frequent adverse events motivating switching from a second-generation agent.”

Extrapyramidal symptoms were observed in 36% on a first-generation agent, 12% on a second-generation agent, and 28% on the combination. Sedation was observed in 20%, 25%, and 23%, respectively. Weight gain was problematic for 10%, 26%, and 23%, respectively.

Major Finding: One in five adult patients with schizophrenia switched antipsychotic medications in the previous 12 weeks, mostly because of lack of efficacy and secondarily because of side effects.

Data Source: Observational study of more than 23,000 patients from 11 countries.

Disclosures: The study was funded by Sanofi-Aventis. Dr. Galinska-Skok had no relevant disclosures.

AMSTERDAM – A large multinational study found that one in five adult patients with schizophrenia switched medications within the previous 12 weeks, mostly because of inadequate symptom control as one-third reported a relapse on the initial drug.

Tolerability issues also were important and differed between first- and second-generation antipsychotics, reported Dr. Beata Galinska-Skok of the Medical University of Bialystok in Choroszcz, Poland.

“In the long-term management of schizophrenia, around one-third of patients treated with antipsychotic drugs change their medication every year. There is a need to better understand the dynamics of switching in real-world conditions. We performed a naturalistic multinational observational survey to evaluate the parameters of treatment discontinuation and substitutions in the management of schizophrenia in every day clinical practice,” Dr. Galinska-Skok said.

The primary objective of the cross-sectional observational study conducted in 11 countries was to identify the frequency of and reasons for switching antipsychotic treatments in patients with schizophrenia. Participating physicians were community- or hospital-based psychiatrists who reflected local psychiatric practices and patient management.

The countries represented were Algeria, Greece, India, Jordan, Lithuania, Mexico, Philippines, Poland, Slovakia, Ukraine, and Vietnam.

The registry population included 23,441 adult patients (mean age 41), of whom 22,126 were analyzable. Of those, 5,128 patients (23.2%) reported a treatment switch in the previous 12 weeks and thus constituted the switch population; 3,130 consented to the study and constitute the analysis population.

The medication that was discontinued in the previous 12 weeks was a second-generation antipsychotic for 55.6% of patients and a first-generation agent for 41.8%, while 2.6% discontinued both types. After the switch, most patients received a second-generation agent (90%) either alone (72.4%) or in combination with a first-generation agent (18.3%). The remainder received a first-generation agent as monotherapy, she reported.

Main Reason for Switching: Lack of Efficacy

Physicians could report more than one reason for switching. The survey found the main reason to be inadequate symptom control (79.4%), while the occurrence of adverse events was also common (55.3%). Other reasons frequently cited included poor quality of life (31.7%), relapse on medication (30.1%), poor compliance (25.3%), and patient request (18.3%). Two to six percent reported problems with drug availability, financial or life events, and comorbid medical conditions.

“Over half the changes were motivated by an adverse event,” Dr. Galinska-Skok noted. “The nature of the adverse events differed depending on the class of antipsychotic the patient was taking before the switch. Extrapyramidal symptoms and sedation were the two adverse events that most frequently motivated switching from a first-generation agent. Sedation and weight gain were the two most frequent adverse events motivating switching from a second-generation agent.”

Extrapyramidal symptoms were observed in 36% on a first-generation agent, 12% on a second-generation agent, and 28% on the combination. Sedation was observed in 20%, 25%, and 23%, respectively. Weight gain was problematic for 10%, 26%, and 23%, respectively.

Major Finding: One in five adult patients with schizophrenia switched antipsychotic medications in the previous 12 weeks, mostly because of lack of efficacy and secondarily because of side effects.

Data Source: Observational study of more than 23,000 patients from 11 countries.

Disclosures: The study was funded by Sanofi-Aventis. Dr. Galinska-Skok had no relevant disclosures.

AMSTERDAM – A large multinational study found that one in five adult patients with schizophrenia switched medications within the previous 12 weeks, mostly because of inadequate symptom control as one-third reported a relapse on the initial drug.

Tolerability issues also were important and differed between first- and second-generation antipsychotics, reported Dr. Beata Galinska-Skok of the Medical University of Bialystok in Choroszcz, Poland.

“In the long-term management of schizophrenia, around one-third of patients treated with antipsychotic drugs change their medication every year. There is a need to better understand the dynamics of switching in real-world conditions. We performed a naturalistic multinational observational survey to evaluate the parameters of treatment discontinuation and substitutions in the management of schizophrenia in every day clinical practice,” Dr. Galinska-Skok said.

The primary objective of the cross-sectional observational study conducted in 11 countries was to identify the frequency of and reasons for switching antipsychotic treatments in patients with schizophrenia. Participating physicians were community- or hospital-based psychiatrists who reflected local psychiatric practices and patient management.

The countries represented were Algeria, Greece, India, Jordan, Lithuania, Mexico, Philippines, Poland, Slovakia, Ukraine, and Vietnam.

The registry population included 23,441 adult patients (mean age 41), of whom 22,126 were analyzable. Of those, 5,128 patients (23.2%) reported a treatment switch in the previous 12 weeks and thus constituted the switch population; 3,130 consented to the study and constitute the analysis population.

The medication that was discontinued in the previous 12 weeks was a second-generation antipsychotic for 55.6% of patients and a first-generation agent for 41.8%, while 2.6% discontinued both types. After the switch, most patients received a second-generation agent (90%) either alone (72.4%) or in combination with a first-generation agent (18.3%). The remainder received a first-generation agent as monotherapy, she reported.

Main Reason for Switching: Lack of Efficacy

Physicians could report more than one reason for switching. The survey found the main reason to be inadequate symptom control (79.4%), while the occurrence of adverse events was also common (55.3%). Other reasons frequently cited included poor quality of life (31.7%), relapse on medication (30.1%), poor compliance (25.3%), and patient request (18.3%). Two to six percent reported problems with drug availability, financial or life events, and comorbid medical conditions.

“Over half the changes were motivated by an adverse event,” Dr. Galinska-Skok noted. “The nature of the adverse events differed depending on the class of antipsychotic the patient was taking before the switch. Extrapyramidal symptoms and sedation were the two adverse events that most frequently motivated switching from a first-generation agent. Sedation and weight gain were the two most frequent adverse events motivating switching from a second-generation agent.”

Extrapyramidal symptoms were observed in 36% on a first-generation agent, 12% on a second-generation agent, and 28% on the combination. Sedation was observed in 20%, 25%, and 23%, respectively. Weight gain was problematic for 10%, 26%, and 23%, respectively.

AMSTERDAM – Magnetic seizure therapy yields outcomes similar to electroconvulsive therapy for the treatment of resistant depression but has the advantage of faster recovery.

“For treatment-resistant depression, electroconvulsive therapy (ECT) is often the treatment of last resort. It has been applied for 75 years and is effective, but has cognitive side effects, relapse rates as high as 50%, and it carries a stigma,” said Dr. Sarah Kayser of the University Hospital of Bonn (Germany), who presented the findings at the meeting.

Magnetic seizure therapy (MST), performed under general anesthesia, is a more focal form of convulsive therapy that uses a strong magnetic field to induce a seizure. It provides greater control over sites of seizure onset and patterns of seizure spread, she said. MST treatment is performed much like ECT. The main difference is that magnetic rather than electrical stimulation is applied to induce seisures.

Previous studies on small groups of patients have suggested that MST is a successful antidepressant approach, with less potential for cognitive side effects, compared with ECT. Although the initial prototype machine was large and unwieldy with multiple components, the newer MagPro MST, which is made in Denmark, is much smaller and easier to work with, Dr. Kayser noted.

The prospective study included 20 patients: 16 with a DSM-IV diagnosis of major depressive disorder and 4 with bipolar disorder. The average patient was a 50-year-old female who had had six lifetime episodes of illness, been treated with 18 medications, and been hospitalized four times, Dr. Kayser reported.

The average duration of the most recent episode of illness was 6 years in the MST group and 3.5 years in the ECT group. One out of five patients had attempted suicide.

Ten patients received ECT, and the other 10 received a full course (up to 12 treatments) of MST.

The outcome measure of effectiveness was remission or a 50% reduction in depressive symptom severity according to the Hamilton Depression Rating Scale (HDRS₂₈) and the Montgomery-Åsberg Depression Rating Scale (MADRS).

The two treatment groups in the study both demonstrated significant improvement over baseline. Response criteria were met by 65% of the patients, whereas 53% met the criteria for remission, Dr. Kayser reported.

The patients' mean scores on the HDRS₂₈ declined by approximately 12 points in each treatment arm (P less than .001), and on the MADRS they dropped approximately 12 points after ECT and 15 points after MST (P less than .001).

Several aspects of recovery from the procedure were significantly better in the MST arm, compared with ECT, she reported. “Patients were quicker to breathe independently after anesthesia, and their reorientation time was faster, based on their answers to biographical questions such as name, date, and so forth,” she said.

Mean recovery time (defined as independent breathing) was nearly 4 minutes after ECT, compared with approximately 1.5 minutes with MST (P less than .01).

Reorientation time was 8 minutes vs. 2 minutes (P less than .01). EEG showed no effects on brain structure with either approach.

Neither arm showed significant changes in cognitive outcomes, including learning and memory (verbal and visual), abstract knowledge, executive functions (verbal fluency), and speed of processing.

This is an emerging treatment for severe depression that is being studied in only four clinical trials that are centered in New York/Dallas; Australia; Bonn, Germany; and Berlin.

AMSTERDAM – Magnetic seizure therapy yields outcomes similar to electroconvulsive therapy for the treatment of resistant depression but has the advantage of faster recovery.

“For treatment-resistant depression, electroconvulsive therapy (ECT) is often the treatment of last resort. It has been applied for 75 years and is effective, but has cognitive side effects, relapse rates as high as 50%, and it carries a stigma,” said Dr. Sarah Kayser of the University Hospital of Bonn (Germany), who presented the findings at the meeting.

Magnetic seizure therapy (MST), performed under general anesthesia, is a more focal form of convulsive therapy that uses a strong magnetic field to induce a seizure. It provides greater control over sites of seizure onset and patterns of seizure spread, she said. MST treatment is performed much like ECT. The main difference is that magnetic rather than electrical stimulation is applied to induce seisures.

Previous studies on small groups of patients have suggested that MST is a successful antidepressant approach, with less potential for cognitive side effects, compared with ECT. Although the initial prototype machine was large and unwieldy with multiple components, the newer MagPro MST, which is made in Denmark, is much smaller and easier to work with, Dr. Kayser noted.

The prospective study included 20 patients: 16 with a DSM-IV diagnosis of major depressive disorder and 4 with bipolar disorder. The average patient was a 50-year-old female who had had six lifetime episodes of illness, been treated with 18 medications, and been hospitalized four times, Dr. Kayser reported.

The average duration of the most recent episode of illness was 6 years in the MST group and 3.5 years in the ECT group. One out of five patients had attempted suicide.

Ten patients received ECT, and the other 10 received a full course (up to 12 treatments) of MST.

The outcome measure of effectiveness was remission or a 50% reduction in depressive symptom severity according to the Hamilton Depression Rating Scale (HDRS₂₈) and the Montgomery-Åsberg Depression Rating Scale (MADRS).

The two treatment groups in the study both demonstrated significant improvement over baseline. Response criteria were met by 65% of the patients, whereas 53% met the criteria for remission, Dr. Kayser reported.

The patients' mean scores on the HDRS₂₈ declined by approximately 12 points in each treatment arm (P less than .001), and on the MADRS they dropped approximately 12 points after ECT and 15 points after MST (P less than .001).

Several aspects of recovery from the procedure were significantly better in the MST arm, compared with ECT, she reported. “Patients were quicker to breathe independently after anesthesia, and their reorientation time was faster, based on their answers to biographical questions such as name, date, and so forth,” she said.

Mean recovery time (defined as independent breathing) was nearly 4 minutes after ECT, compared with approximately 1.5 minutes with MST (P less than .01).

Reorientation time was 8 minutes vs. 2 minutes (P less than .01). EEG showed no effects on brain structure with either approach.

Neither arm showed significant changes in cognitive outcomes, including learning and memory (verbal and visual), abstract knowledge, executive functions (verbal fluency), and speed of processing.

This is an emerging treatment for severe depression that is being studied in only four clinical trials that are centered in New York/Dallas; Australia; Bonn, Germany; and Berlin.

AMSTERDAM – Magnetic seizure therapy yields outcomes similar to electroconvulsive therapy for the treatment of resistant depression but has the advantage of faster recovery.

“For treatment-resistant depression, electroconvulsive therapy (ECT) is often the treatment of last resort. It has been applied for 75 years and is effective, but has cognitive side effects, relapse rates as high as 50%, and it carries a stigma,” said Dr. Sarah Kayser of the University Hospital of Bonn (Germany), who presented the findings at the meeting.

Magnetic seizure therapy (MST), performed under general anesthesia, is a more focal form of convulsive therapy that uses a strong magnetic field to induce a seizure. It provides greater control over sites of seizure onset and patterns of seizure spread, she said. MST treatment is performed much like ECT. The main difference is that magnetic rather than electrical stimulation is applied to induce seisures.

Previous studies on small groups of patients have suggested that MST is a successful antidepressant approach, with less potential for cognitive side effects, compared with ECT. Although the initial prototype machine was large and unwieldy with multiple components, the newer MagPro MST, which is made in Denmark, is much smaller and easier to work with, Dr. Kayser noted.

The prospective study included 20 patients: 16 with a DSM-IV diagnosis of major depressive disorder and 4 with bipolar disorder. The average patient was a 50-year-old female who had had six lifetime episodes of illness, been treated with 18 medications, and been hospitalized four times, Dr. Kayser reported.

The average duration of the most recent episode of illness was 6 years in the MST group and 3.5 years in the ECT group. One out of five patients had attempted suicide.

Ten patients received ECT, and the other 10 received a full course (up to 12 treatments) of MST.

The outcome measure of effectiveness was remission or a 50% reduction in depressive symptom severity according to the Hamilton Depression Rating Scale (HDRS₂₈) and the Montgomery-Åsberg Depression Rating Scale (MADRS).

The two treatment groups in the study both demonstrated significant improvement over baseline. Response criteria were met by 65% of the patients, whereas 53% met the criteria for remission, Dr. Kayser reported.

The patients' mean scores on the HDRS₂₈ declined by approximately 12 points in each treatment arm (P less than .001), and on the MADRS they dropped approximately 12 points after ECT and 15 points after MST (P less than .001).

Several aspects of recovery from the procedure were significantly better in the MST arm, compared with ECT, she reported. “Patients were quicker to breathe independently after anesthesia, and their reorientation time was faster, based on their answers to biographical questions such as name, date, and so forth,” she said.

Mean recovery time (defined as independent breathing) was nearly 4 minutes after ECT, compared with approximately 1.5 minutes with MST (P less than .01).

Reorientation time was 8 minutes vs. 2 minutes (P less than .01). EEG showed no effects on brain structure with either approach.

Neither arm showed significant changes in cognitive outcomes, including learning and memory (verbal and visual), abstract knowledge, executive functions (verbal fluency), and speed of processing.

This is an emerging treatment for severe depression that is being studied in only four clinical trials that are centered in New York/Dallas; Australia; Bonn, Germany; and Berlin.

AMSTERDAM – Novel trial designs can be used to reduce the high placebo response seen in clinical trials of antidepressants and thus increase the efficiency of those trials, according to a drug development scientist who proposed a “filtering” approach at the annual congress of the European College of Neuropsychopharmacology.

“We have found that the response to placebo is the strongest factor in a failed clinical trial,” said Dr. Emilio Merlo-Pich of the Centre of Excellence for External Drug Discovery, GlaxoSmithKline (GSK) in Verona, Italy, who spoke at a session called “The Placebo in Psychiatry.”

The placebo response trumps other reasons proposed to explain the high clinical trial failure rate for novel antidepressants, he said, including trial design features, heterogeneity of the study population, site-subject interactions, and low assay sensitivity related to clinical rating scale deficiencies.

Randomized clinical trial (RCT) outcomes can be improved by learning from past experience and using clinical databases and trial modeling, Dr. Merlo-Pich said. He and his colleagues have proposed an approach to improving RCTs using data to assess the role of recruitment centers and the problem of signal detection.

“Our study supports the implementation of prior-driven data preprocessing into RCT protocols to attenuate their failure rate, leading to a more efficient antidepressant drug discovery,” he said.

A meta-analysis of 52 RCTs indicated that placebo change from baseline to the end of study strongly affects the detection of active treatment superiority (J. Nerv. Ment. Dis. 2003;191:211-8). A statistically significant positive correlation was seen between placebo response magnitude and the advantage of antidepressants over placebo (P less than .0001). Only 21% of antidepressant treatment arms in trials with high placebo responses (more than a 30% mean change from baseline) showed superiority over placebo, compared with 74% in trials with a lower placebo response.

For the present study, a meta-analysis was conducted on nine GSK clinical trials, including 3,953 subjects with major depressive disorder, 1,197 of whom were exposed to placebo and 2,756 who had received antidepressants. The placebo response (reduction in depression score) varied highly according to the center.

A sensitivity analysis indicated that the placebo response by center was relevant for the detection of a treatment effect and for the success of the whole trial, Dr. Merlo-Pich reported. Placebo responses that are “too high” or “too low” generate noise within an RCT, he explained.

“We found that the placebo response can be so strong as to prevent any detection of a signal of pharmacologic effects, even if one is present. Therefore, the performance of each recruitment center is critical for the success of the whole trial,” he said. “In spite of training, recruitment centers manage protocols differently and handle patients differently, and this introduces bias. In fact, we have found the majority of the treatment effect depends on the center’s performance.”

Based on the level of the placebo response, the investigators classified individual centers as “informative” or “noninformative.” This classification was associated with the probability of detecting a signal of a clinically relevant treatment effect. The number of “informative” centers per study is relevant for the clinical trial outcome. “If you have enough informative centers, there is a higher probability of a positive trial,” he said.

In the study, only 60% of centers in the GSK database were classified as informative based on their specific level of placebo response, he reported.

Using this information, Dr. Merlo-Pich and his colleagues then ranked the centers’ performance, varying from 0 (high background nose and no chance to detect a treatment effect) to 100 (low noise and optimal condition for detecting a treatment effect). They then applied a “band-pass filter preprocessing approach” prior to statistical analysis as an enrichment strategy to single out the informative study population, reduce the noise, and improve the outcomes.

A clinical trial simulation was conducted to assess the performance of this “filtering” approach. The result was that the proportion of failed RCTs was reduced from 50% to 10%, he reported.

In implementing the model, the researchers define a-priori per-protocol high and low enrichment criteria to be applied at the end of treatment and before the statistical analysis. This identifies the noninformative centers to be eliminated, leaving the informative centers for the per-protocol efficacy analysis. The noninformative centers are still included in the intention-to-treat efficacy analysis and the safety analysis, he said.

“We believe we can apply this approach to any clinical trial. This will maximize our investment and enhance patient exposure to promising new compounds,” he concluded.

Disclosures: Dr. Merlo-Pich is a full-time employee of GlaxoSmithKline.

AMSTERDAM – Novel trial designs can be used to reduce the high placebo response seen in clinical trials of antidepressants and thus increase the efficiency of those trials, according to a drug development scientist who proposed a “filtering” approach at the annual congress of the European College of Neuropsychopharmacology.

“We have found that the response to placebo is the strongest factor in a failed clinical trial,” said Dr. Emilio Merlo-Pich of the Centre of Excellence for External Drug Discovery, GlaxoSmithKline (GSK) in Verona, Italy, who spoke at a session called “The Placebo in Psychiatry.”

The placebo response trumps other reasons proposed to explain the high clinical trial failure rate for novel antidepressants, he said, including trial design features, heterogeneity of the study population, site-subject interactions, and low assay sensitivity related to clinical rating scale deficiencies.

Randomized clinical trial (RCT) outcomes can be improved by learning from past experience and using clinical databases and trial modeling, Dr. Merlo-Pich said. He and his colleagues have proposed an approach to improving RCTs using data to assess the role of recruitment centers and the problem of signal detection.

“Our study supports the implementation of prior-driven data preprocessing into RCT protocols to attenuate their failure rate, leading to a more efficient antidepressant drug discovery,” he said.

A meta-analysis of 52 RCTs indicated that placebo change from baseline to the end of study strongly affects the detection of active treatment superiority (J. Nerv. Ment. Dis. 2003;191:211-8). A statistically significant positive correlation was seen between placebo response magnitude and the advantage of antidepressants over placebo (P less than .0001). Only 21% of antidepressant treatment arms in trials with high placebo responses (more than a 30% mean change from baseline) showed superiority over placebo, compared with 74% in trials with a lower placebo response.

For the present study, a meta-analysis was conducted on nine GSK clinical trials, including 3,953 subjects with major depressive disorder, 1,197 of whom were exposed to placebo and 2,756 who had received antidepressants. The placebo response (reduction in depression score) varied highly according to the center.

A sensitivity analysis indicated that the placebo response by center was relevant for the detection of a treatment effect and for the success of the whole trial, Dr. Merlo-Pich reported. Placebo responses that are “too high” or “too low” generate noise within an RCT, he explained.

“We found that the placebo response can be so strong as to prevent any detection of a signal of pharmacologic effects, even if one is present. Therefore, the performance of each recruitment center is critical for the success of the whole trial,” he said. “In spite of training, recruitment centers manage protocols differently and handle patients differently, and this introduces bias. In fact, we have found the majority of the treatment effect depends on the center’s performance.”

Based on the level of the placebo response, the investigators classified individual centers as “informative” or “noninformative.” This classification was associated with the probability of detecting a signal of a clinically relevant treatment effect. The number of “informative” centers per study is relevant for the clinical trial outcome. “If you have enough informative centers, there is a higher probability of a positive trial,” he said.

In the study, only 60% of centers in the GSK database were classified as informative based on their specific level of placebo response, he reported.

Using this information, Dr. Merlo-Pich and his colleagues then ranked the centers’ performance, varying from 0 (high background nose and no chance to detect a treatment effect) to 100 (low noise and optimal condition for detecting a treatment effect). They then applied a “band-pass filter preprocessing approach” prior to statistical analysis as an enrichment strategy to single out the informative study population, reduce the noise, and improve the outcomes.

A clinical trial simulation was conducted to assess the performance of this “filtering” approach. The result was that the proportion of failed RCTs was reduced from 50% to 10%, he reported.

In implementing the model, the researchers define a-priori per-protocol high and low enrichment criteria to be applied at the end of treatment and before the statistical analysis. This identifies the noninformative centers to be eliminated, leaving the informative centers for the per-protocol efficacy analysis. The noninformative centers are still included in the intention-to-treat efficacy analysis and the safety analysis, he said.

“We believe we can apply this approach to any clinical trial. This will maximize our investment and enhance patient exposure to promising new compounds,” he concluded.

Disclosures: Dr. Merlo-Pich is a full-time employee of GlaxoSmithKline.

AMSTERDAM – Novel trial designs can be used to reduce the high placebo response seen in clinical trials of antidepressants and thus increase the efficiency of those trials, according to a drug development scientist who proposed a “filtering” approach at the annual congress of the European College of Neuropsychopharmacology.

“We have found that the response to placebo is the strongest factor in a failed clinical trial,” said Dr. Emilio Merlo-Pich of the Centre of Excellence for External Drug Discovery, GlaxoSmithKline (GSK) in Verona, Italy, who spoke at a session called “The Placebo in Psychiatry.”

The placebo response trumps other reasons proposed to explain the high clinical trial failure rate for novel antidepressants, he said, including trial design features, heterogeneity of the study population, site-subject interactions, and low assay sensitivity related to clinical rating scale deficiencies.

Randomized clinical trial (RCT) outcomes can be improved by learning from past experience and using clinical databases and trial modeling, Dr. Merlo-Pich said. He and his colleagues have proposed an approach to improving RCTs using data to assess the role of recruitment centers and the problem of signal detection.

“Our study supports the implementation of prior-driven data preprocessing into RCT protocols to attenuate their failure rate, leading to a more efficient antidepressant drug discovery,” he said.

A meta-analysis of 52 RCTs indicated that placebo change from baseline to the end of study strongly affects the detection of active treatment superiority (J. Nerv. Ment. Dis. 2003;191:211-8). A statistically significant positive correlation was seen between placebo response magnitude and the advantage of antidepressants over placebo (P less than .0001). Only 21% of antidepressant treatment arms in trials with high placebo responses (more than a 30% mean change from baseline) showed superiority over placebo, compared with 74% in trials with a lower placebo response.

For the present study, a meta-analysis was conducted on nine GSK clinical trials, including 3,953 subjects with major depressive disorder, 1,197 of whom were exposed to placebo and 2,756 who had received antidepressants. The placebo response (reduction in depression score) varied highly according to the center.

A sensitivity analysis indicated that the placebo response by center was relevant for the detection of a treatment effect and for the success of the whole trial, Dr. Merlo-Pich reported. Placebo responses that are “too high” or “too low” generate noise within an RCT, he explained.

“We found that the placebo response can be so strong as to prevent any detection of a signal of pharmacologic effects, even if one is present. Therefore, the performance of each recruitment center is critical for the success of the whole trial,” he said. “In spite of training, recruitment centers manage protocols differently and handle patients differently, and this introduces bias. In fact, we have found the majority of the treatment effect depends on the center’s performance.”

Based on the level of the placebo response, the investigators classified individual centers as “informative” or “noninformative.” This classification was associated with the probability of detecting a signal of a clinically relevant treatment effect. The number of “informative” centers per study is relevant for the clinical trial outcome. “If you have enough informative centers, there is a higher probability of a positive trial,” he said.

In the study, only 60% of centers in the GSK database were classified as informative based on their specific level of placebo response, he reported.

Using this information, Dr. Merlo-Pich and his colleagues then ranked the centers’ performance, varying from 0 (high background nose and no chance to detect a treatment effect) to 100 (low noise and optimal condition for detecting a treatment effect). They then applied a “band-pass filter preprocessing approach” prior to statistical analysis as an enrichment strategy to single out the informative study population, reduce the noise, and improve the outcomes.

A clinical trial simulation was conducted to assess the performance of this “filtering” approach. The result was that the proportion of failed RCTs was reduced from 50% to 10%, he reported.

In implementing the model, the researchers define a-priori per-protocol high and low enrichment criteria to be applied at the end of treatment and before the statistical analysis. This identifies the noninformative centers to be eliminated, leaving the informative centers for the per-protocol efficacy analysis. The noninformative centers are still included in the intention-to-treat efficacy analysis and the safety analysis, he said.

“We believe we can apply this approach to any clinical trial. This will maximize our investment and enhance patient exposure to promising new compounds,” he concluded.

Disclosures: Dr. Merlo-Pich is a full-time employee of GlaxoSmithKline.