AAN Annual Meeting

Parkinson’s disease symptoms that affect the quality of life of patients with the condition improved in studies of drugs that are under investigational status or have already been approved, according to new research coming from the annual meeting of the American Academy of Neurology.*

The reports include phase II studies evaluating a novel, nondopaminergic adjunctive treatment with levodopa and an oral precursor to norepinephrine to treat neurogenic orthostatic hypotension, as well as a phase IV study testing an already approved therapy as an add-on treatment to patients not well controlled on a dopamine agonist.

"All of these treatments are promising news for people with Parkinson’s disease," said Dr. Robert Hauser, in a statement issued by the AAN. He is an author in all three studies and is a neurologist at the University of South Florida, Tampa.

In the first of the phase II studies, patients with PD treated with tozadenant as an adjunct to levodopa experienced significant reductions in off-time without worsening dyskinesia, compared with those on placebo. Tozadenant is an oral, selective adenosine 2-alpha receptor antagonist.

The international, 12-week, double-blind study enrolled patients who had had PD for about 9 years, were on stable doses of levodopa, and had at least 2.5 hours of off-time per day. A total of 337 patients (mean age, 63 years) completed treatment. Comparisons against placebo for four different doses of the drug taken twice daily showed that those on the 120-mg and 180-mg twice-daily doses had a mean 1.1-1.2 hours’ reduction in off-time over placebo.

Scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscale also improved significantly among those on these two doses, with a mean reduction of 2.2 and 2.5 among people on the 120-mg and 180-mg twice-daily doses, respectively, compared with placebo. The Patient Global Impression of Improvement (PGI-I) scores also significantly improved among those on 120 mg twice daily.

Dyskinesia, nausea, dizziness, constipation, and worsening of PD were the most common adverse events among all the patients on tozadenant.

"With our most effective doses, we were able to show significant reductions in off-time in comparison with placebo, but importantly, we were able to do that without seeing a worsening of dyskinesia," said the lead author, Dr. C. Warren Olanow. There were also some improvements in motor skills, he added in an interview.

While it is too early to make a statement on how tozadenant compares with other drugs, "the fact that it is nondopaminergic and well tolerated is very promising," said Dr. Olanow, the Henry P. and Georgette Goldschmidt professor of neurology and professor of neuroscience at Mount Sinai School of Medicine, New York.

"Now that we have shown benefit and identified what we think are the good doses," the next step is to conduct phase III confirmatory studies, which will evaluate the two doses that were effective in the phase II study, he said.

In another phase II randomized, double-blind study, 225 people with PD received droxidopa, an oral precursor of norepinephrine, or placebo to treat symptomatic neurogenic orthostatic hypotension. The 10-week study evaluated changes in the OHQ (Orthostatic Hypotension Questionnaire), dizziness/light-headedness (based on the Orthostatic Hypotension Symptom Assessment Item 1), standing systolic blood pressure, and frequency of falls.

The dosing regimen for droxidopa was titrated to 100-600 mg three times a day over a 2-week period. After 1 week on the drug, those on droxidopa had significant improvements in dizziness and light-headedness, compared with those on placebo. At 8 weeks, there was a trend toward improvement over placebo, but the difference was no longer significant, according to the investigators. Significant improvement in standing systolic blood pressure at 1 week (a 6.8 mm Hg difference over placebo) also did not hold up at 8 weeks (a 2.2 mm Hg improvement over placebo).

In the treated patients, there was also a drop in the number of falls per patient per week (0.38 fewer among those on placebo vs. 1.73 fewer among those on droxidopa), which was not statistically significant. Headache, dizziness, hypertension, nausea, and fatigue were each reported in more than 5% of patients taking droxidopa and in more than 5% of untreated patients.

A third study, called ANDANTE, evaluated rasagiline as add-on therapy to a dopamine agonist in 321 patients with early PD whose symptoms were not well controlled on the dopamine agonist. The patients were on stable doses of a dopamine agonist and were randomized to receive 1 mg of rasagiline per day or placebo, while remaining on stable doses of the dopamine agonist (ropinirole or pramipexole).

Approved in 2006, rasagiline (Azilect), a selective irreversible MAO-B inhibitor, is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease as initial monotherapy and as adjunct therapy to levodopa.

Over the first 18 weeks of the postmarketing, randomized, double-blind study, those treated with rasagiline had a significantly greater change from the baseline in the total UPDRS score (a mean reduction of 2.4 vs. placebo), the primary endpoint. There were also significant improvements in UPDRS motor scores among those on rasagiline, but no significant differences between the two groups in UPDRS activities of daily living scores. The rates of adverse events and serious adverse events were similar between the two groups: Among those on rasagiline, the overall rate of adverse events was 64% (5% were serious), compared with 61% (3% serious) for the placebo group.

Dr. Olanow disclosed that he is a consultant for almost all manufacturers of drugs for PD, including Biotie Therapies, the manufacturer of tozadenant, which also supported the study. The droxidopa study was supported by Chelsea Therapeutics, the drug’s manufacturer. The ANDANTE study was supported by Teva Pharmaceuticals, the manufacturer of rasagiline.

* This article was revised on 3/15/13.

[email protected]

Parkinson’s disease symptoms that affect the quality of life of patients with the condition improved in studies of drugs that are under investigational status or have already been approved, according to new research coming from the annual meeting of the American Academy of Neurology.*

The reports include phase II studies evaluating a novel, nondopaminergic adjunctive treatment with levodopa and an oral precursor to norepinephrine to treat neurogenic orthostatic hypotension, as well as a phase IV study testing an already approved therapy as an add-on treatment to patients not well controlled on a dopamine agonist.

"All of these treatments are promising news for people with Parkinson’s disease," said Dr. Robert Hauser, in a statement issued by the AAN. He is an author in all three studies and is a neurologist at the University of South Florida, Tampa.

In the first of the phase II studies, patients with PD treated with tozadenant as an adjunct to levodopa experienced significant reductions in off-time without worsening dyskinesia, compared with those on placebo. Tozadenant is an oral, selective adenosine 2-alpha receptor antagonist.

The international, 12-week, double-blind study enrolled patients who had had PD for about 9 years, were on stable doses of levodopa, and had at least 2.5 hours of off-time per day. A total of 337 patients (mean age, 63 years) completed treatment. Comparisons against placebo for four different doses of the drug taken twice daily showed that those on the 120-mg and 180-mg twice-daily doses had a mean 1.1-1.2 hours’ reduction in off-time over placebo.

Scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscale also improved significantly among those on these two doses, with a mean reduction of 2.2 and 2.5 among people on the 120-mg and 180-mg twice-daily doses, respectively, compared with placebo. The Patient Global Impression of Improvement (PGI-I) scores also significantly improved among those on 120 mg twice daily.

Dyskinesia, nausea, dizziness, constipation, and worsening of PD were the most common adverse events among all the patients on tozadenant.

"With our most effective doses, we were able to show significant reductions in off-time in comparison with placebo, but importantly, we were able to do that without seeing a worsening of dyskinesia," said the lead author, Dr. C. Warren Olanow. There were also some improvements in motor skills, he added in an interview.

While it is too early to make a statement on how tozadenant compares with other drugs, "the fact that it is nondopaminergic and well tolerated is very promising," said Dr. Olanow, the Henry P. and Georgette Goldschmidt professor of neurology and professor of neuroscience at Mount Sinai School of Medicine, New York.

"Now that we have shown benefit and identified what we think are the good doses," the next step is to conduct phase III confirmatory studies, which will evaluate the two doses that were effective in the phase II study, he said.

In another phase II randomized, double-blind study, 225 people with PD received droxidopa, an oral precursor of norepinephrine, or placebo to treat symptomatic neurogenic orthostatic hypotension. The 10-week study evaluated changes in the OHQ (Orthostatic Hypotension Questionnaire), dizziness/light-headedness (based on the Orthostatic Hypotension Symptom Assessment Item 1), standing systolic blood pressure, and frequency of falls.

The dosing regimen for droxidopa was titrated to 100-600 mg three times a day over a 2-week period. After 1 week on the drug, those on droxidopa had significant improvements in dizziness and light-headedness, compared with those on placebo. At 8 weeks, there was a trend toward improvement over placebo, but the difference was no longer significant, according to the investigators. Significant improvement in standing systolic blood pressure at 1 week (a 6.8 mm Hg difference over placebo) also did not hold up at 8 weeks (a 2.2 mm Hg improvement over placebo).

In the treated patients, there was also a drop in the number of falls per patient per week (0.38 fewer among those on placebo vs. 1.73 fewer among those on droxidopa), which was not statistically significant. Headache, dizziness, hypertension, nausea, and fatigue were each reported in more than 5% of patients taking droxidopa and in more than 5% of untreated patients.

A third study, called ANDANTE, evaluated rasagiline as add-on therapy to a dopamine agonist in 321 patients with early PD whose symptoms were not well controlled on the dopamine agonist. The patients were on stable doses of a dopamine agonist and were randomized to receive 1 mg of rasagiline per day or placebo, while remaining on stable doses of the dopamine agonist (ropinirole or pramipexole).

Approved in 2006, rasagiline (Azilect), a selective irreversible MAO-B inhibitor, is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease as initial monotherapy and as adjunct therapy to levodopa.

Over the first 18 weeks of the postmarketing, randomized, double-blind study, those treated with rasagiline had a significantly greater change from the baseline in the total UPDRS score (a mean reduction of 2.4 vs. placebo), the primary endpoint. There were also significant improvements in UPDRS motor scores among those on rasagiline, but no significant differences between the two groups in UPDRS activities of daily living scores. The rates of adverse events and serious adverse events were similar between the two groups: Among those on rasagiline, the overall rate of adverse events was 64% (5% were serious), compared with 61% (3% serious) for the placebo group.

Dr. Olanow disclosed that he is a consultant for almost all manufacturers of drugs for PD, including Biotie Therapies, the manufacturer of tozadenant, which also supported the study. The droxidopa study was supported by Chelsea Therapeutics, the drug’s manufacturer. The ANDANTE study was supported by Teva Pharmaceuticals, the manufacturer of rasagiline.

* This article was revised on 3/15/13.

[email protected]

Parkinson’s disease symptoms that affect the quality of life of patients with the condition improved in studies of drugs that are under investigational status or have already been approved, according to new research coming from the annual meeting of the American Academy of Neurology.*

The reports include phase II studies evaluating a novel, nondopaminergic adjunctive treatment with levodopa and an oral precursor to norepinephrine to treat neurogenic orthostatic hypotension, as well as a phase IV study testing an already approved therapy as an add-on treatment to patients not well controlled on a dopamine agonist.

"All of these treatments are promising news for people with Parkinson’s disease," said Dr. Robert Hauser, in a statement issued by the AAN. He is an author in all three studies and is a neurologist at the University of South Florida, Tampa.

In the first of the phase II studies, patients with PD treated with tozadenant as an adjunct to levodopa experienced significant reductions in off-time without worsening dyskinesia, compared with those on placebo. Tozadenant is an oral, selective adenosine 2-alpha receptor antagonist.

The international, 12-week, double-blind study enrolled patients who had had PD for about 9 years, were on stable doses of levodopa, and had at least 2.5 hours of off-time per day. A total of 337 patients (mean age, 63 years) completed treatment. Comparisons against placebo for four different doses of the drug taken twice daily showed that those on the 120-mg and 180-mg twice-daily doses had a mean 1.1-1.2 hours’ reduction in off-time over placebo.

Scores on the Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscale also improved significantly among those on these two doses, with a mean reduction of 2.2 and 2.5 among people on the 120-mg and 180-mg twice-daily doses, respectively, compared with placebo. The Patient Global Impression of Improvement (PGI-I) scores also significantly improved among those on 120 mg twice daily.

Dyskinesia, nausea, dizziness, constipation, and worsening of PD were the most common adverse events among all the patients on tozadenant.

"With our most effective doses, we were able to show significant reductions in off-time in comparison with placebo, but importantly, we were able to do that without seeing a worsening of dyskinesia," said the lead author, Dr. C. Warren Olanow. There were also some improvements in motor skills, he added in an interview.

While it is too early to make a statement on how tozadenant compares with other drugs, "the fact that it is nondopaminergic and well tolerated is very promising," said Dr. Olanow, the Henry P. and Georgette Goldschmidt professor of neurology and professor of neuroscience at Mount Sinai School of Medicine, New York.

"Now that we have shown benefit and identified what we think are the good doses," the next step is to conduct phase III confirmatory studies, which will evaluate the two doses that were effective in the phase II study, he said.

In another phase II randomized, double-blind study, 225 people with PD received droxidopa, an oral precursor of norepinephrine, or placebo to treat symptomatic neurogenic orthostatic hypotension. The 10-week study evaluated changes in the OHQ (Orthostatic Hypotension Questionnaire), dizziness/light-headedness (based on the Orthostatic Hypotension Symptom Assessment Item 1), standing systolic blood pressure, and frequency of falls.

The dosing regimen for droxidopa was titrated to 100-600 mg three times a day over a 2-week period. After 1 week on the drug, those on droxidopa had significant improvements in dizziness and light-headedness, compared with those on placebo. At 8 weeks, there was a trend toward improvement over placebo, but the difference was no longer significant, according to the investigators. Significant improvement in standing systolic blood pressure at 1 week (a 6.8 mm Hg difference over placebo) also did not hold up at 8 weeks (a 2.2 mm Hg improvement over placebo).

In the treated patients, there was also a drop in the number of falls per patient per week (0.38 fewer among those on placebo vs. 1.73 fewer among those on droxidopa), which was not statistically significant. Headache, dizziness, hypertension, nausea, and fatigue were each reported in more than 5% of patients taking droxidopa and in more than 5% of untreated patients.

A third study, called ANDANTE, evaluated rasagiline as add-on therapy to a dopamine agonist in 321 patients with early PD whose symptoms were not well controlled on the dopamine agonist. The patients were on stable doses of a dopamine agonist and were randomized to receive 1 mg of rasagiline per day or placebo, while remaining on stable doses of the dopamine agonist (ropinirole or pramipexole).

Approved in 2006, rasagiline (Azilect), a selective irreversible MAO-B inhibitor, is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease as initial monotherapy and as adjunct therapy to levodopa.

Over the first 18 weeks of the postmarketing, randomized, double-blind study, those treated with rasagiline had a significantly greater change from the baseline in the total UPDRS score (a mean reduction of 2.4 vs. placebo), the primary endpoint. There were also significant improvements in UPDRS motor scores among those on rasagiline, but no significant differences between the two groups in UPDRS activities of daily living scores. The rates of adverse events and serious adverse events were similar between the two groups: Among those on rasagiline, the overall rate of adverse events was 64% (5% were serious), compared with 61% (3% serious) for the placebo group.

Dr. Olanow disclosed that he is a consultant for almost all manufacturers of drugs for PD, including Biotie Therapies, the manufacturer of tozadenant, which also supported the study. The droxidopa study was supported by Chelsea Therapeutics, the drug’s manufacturer. The ANDANTE study was supported by Teva Pharmaceuticals, the manufacturer of rasagiline.

* This article was revised on 3/15/13.

[email protected]

SAN DIEGO – A new drug under investigation for Alzheimer’s disease showed modest improvements in patients’ episodic memory in a 12-week, phase IIa trial.*

The patients taking the drug, called ORM-12741, saw a 4% increase in their episodic memory performance while the placebo patients’ episodic memory performance declined 33%, Dr. Juha Rouru of Orion Pharmaceuticals, Turku, Finland, and his associates reported at the annual meeting of the American Academy of Neurology.

The proof-of-concept trial was a randomized, double-blind, placebo-controlled, multicenter trial that compared two different dosage levels of ORM-12741 against placebo in 100 patients. The patients all had moderate Alzheimer’s disease, with a score between 12 and 21 on the Mini Mental State Examination (MMSE). The patents also had behavioral symptoms with a Neuropsychiatric Inventory (NPI) score of 15 or greater.

The patients received either 30-60 mg or 100-300 mg of ORM-12741, or a matching placebo, twice a day for 12 weeks. The patients were already taking a cholinesterase inhibitor and were allowed to take memantine (Namenda) as well. Dr. Rouru said the ORM-12741 dosage flexibility was built into the study because previous human subjects receiving the drug did not have Alzheimer’s, so the flexibility allowed for safety adjustments if necessary.

The battery of tests to assess cognitive function in the study participants included the Quality of Episodic Memory (QEM), Quality of Working Memory (QWM), Quality of Memory (QM), Speed of Memory, and Power of Attention. The NPI was also used to assess other potential behavioral and psychological symptoms during the trial.

At follow-up, the patients receiving ORM-12741 scored a mean 4% higher on the QEM composite score, which combines both episodic and working memory. No significant difference was noted between dosage amounts. Patients in the placebo group scored a mean 33% lower on the QEM composite. In addition, the researchers reported a positive trend for both the QWM score and NPI total score in the low-dose group. No other significant differences were noted from the other assessments.

ORM-12741 differs from other Alzheimer’s drugs on the market, such as memantine or cholinesterase inhibitors, by acting on a completely different target, Dr. Rouru said. The drug targets a specific subtype of adrenergic receptors in the brain called alpha-2C.

"Quite little has been known about those receptors, and a big part of the work that has been done on them has been done in our company," Dr. Rouru said in an interview. "In animal models, we see very clearly they are involved in memory, but they are also fine tuners for many behavioral things. We have been able to demonstrate in animal models not only that drugs that target to these receptors improve memory, but that they have also beneficial effect on depressive and psychotic symptoms."

The different target offers clinical advantages in terms of treatment combinations, Dr. Rouru said. "The bottom line is that because the target is different, we can very easily use this drug in combination with other medications so that we are adding effect," he said.

Dr. Rouru said the drug was well tolerated among the participants and that adverse events were similar in both the intervention and placebo groups. It is too early to say what adverse events may have been attributed in the intervention group to ORM-12741, he said.

The most commonly reported adverse events were headache in 12% of placebo-treated patients and 5% of patients taking ORM-12741; urinary tract infection in 9% taking placebo and 9% taking ORM-12741; nausea in 9% receiving placebo and 5% receiving ORM-12741; vomiting in 3% taking placebo and 8% taking ORM-12741; diarrhea in 6% on placebo and 5% on ORM-12741; and irritability in 9% on placebo and 3% on ORM-12741.

Dr. Rouru said he is very pleased with the results of this trial, and he and his associates at Orion Pharma are now in the planning stages of the next clinical trial.

"It was very nice that the animal effect we saw, we saw in humans as well," Dr. Rouru said. "Also, the effect that we saw in humans was very clear, which was really encouraging for the future of this compound."

The study was funded by Orion Pharma. Two authors are Orion employees, and two authors work for World Wide Clinical Trials, the contract research organization involved in the trial. One author works for the company providing the computerized memory measurement system.

* This article was revised on 3/27/13.

SAN DIEGO – A new drug under investigation for Alzheimer’s disease showed modest improvements in patients’ episodic memory in a 12-week, phase IIa trial.*

The patients taking the drug, called ORM-12741, saw a 4% increase in their episodic memory performance while the placebo patients’ episodic memory performance declined 33%, Dr. Juha Rouru of Orion Pharmaceuticals, Turku, Finland, and his associates reported at the annual meeting of the American Academy of Neurology.

The proof-of-concept trial was a randomized, double-blind, placebo-controlled, multicenter trial that compared two different dosage levels of ORM-12741 against placebo in 100 patients. The patients all had moderate Alzheimer’s disease, with a score between 12 and 21 on the Mini Mental State Examination (MMSE). The patents also had behavioral symptoms with a Neuropsychiatric Inventory (NPI) score of 15 or greater.

The patients received either 30-60 mg or 100-300 mg of ORM-12741, or a matching placebo, twice a day for 12 weeks. The patients were already taking a cholinesterase inhibitor and were allowed to take memantine (Namenda) as well. Dr. Rouru said the ORM-12741 dosage flexibility was built into the study because previous human subjects receiving the drug did not have Alzheimer’s, so the flexibility allowed for safety adjustments if necessary.

The battery of tests to assess cognitive function in the study participants included the Quality of Episodic Memory (QEM), Quality of Working Memory (QWM), Quality of Memory (QM), Speed of Memory, and Power of Attention. The NPI was also used to assess other potential behavioral and psychological symptoms during the trial.

At follow-up, the patients receiving ORM-12741 scored a mean 4% higher on the QEM composite score, which combines both episodic and working memory. No significant difference was noted between dosage amounts. Patients in the placebo group scored a mean 33% lower on the QEM composite. In addition, the researchers reported a positive trend for both the QWM score and NPI total score in the low-dose group. No other significant differences were noted from the other assessments.

ORM-12741 differs from other Alzheimer’s drugs on the market, such as memantine or cholinesterase inhibitors, by acting on a completely different target, Dr. Rouru said. The drug targets a specific subtype of adrenergic receptors in the brain called alpha-2C.

"Quite little has been known about those receptors, and a big part of the work that has been done on them has been done in our company," Dr. Rouru said in an interview. "In animal models, we see very clearly they are involved in memory, but they are also fine tuners for many behavioral things. We have been able to demonstrate in animal models not only that drugs that target to these receptors improve memory, but that they have also beneficial effect on depressive and psychotic symptoms."

The different target offers clinical advantages in terms of treatment combinations, Dr. Rouru said. "The bottom line is that because the target is different, we can very easily use this drug in combination with other medications so that we are adding effect," he said.

Dr. Rouru said the drug was well tolerated among the participants and that adverse events were similar in both the intervention and placebo groups. It is too early to say what adverse events may have been attributed in the intervention group to ORM-12741, he said.

The most commonly reported adverse events were headache in 12% of placebo-treated patients and 5% of patients taking ORM-12741; urinary tract infection in 9% taking placebo and 9% taking ORM-12741; nausea in 9% receiving placebo and 5% receiving ORM-12741; vomiting in 3% taking placebo and 8% taking ORM-12741; diarrhea in 6% on placebo and 5% on ORM-12741; and irritability in 9% on placebo and 3% on ORM-12741.

Dr. Rouru said he is very pleased with the results of this trial, and he and his associates at Orion Pharma are now in the planning stages of the next clinical trial.

"It was very nice that the animal effect we saw, we saw in humans as well," Dr. Rouru said. "Also, the effect that we saw in humans was very clear, which was really encouraging for the future of this compound."

The study was funded by Orion Pharma. Two authors are Orion employees, and two authors work for World Wide Clinical Trials, the contract research organization involved in the trial. One author works for the company providing the computerized memory measurement system.

* This article was revised on 3/27/13.

SAN DIEGO – A new drug under investigation for Alzheimer’s disease showed modest improvements in patients’ episodic memory in a 12-week, phase IIa trial.*

The patients taking the drug, called ORM-12741, saw a 4% increase in their episodic memory performance while the placebo patients’ episodic memory performance declined 33%, Dr. Juha Rouru of Orion Pharmaceuticals, Turku, Finland, and his associates reported at the annual meeting of the American Academy of Neurology.

The proof-of-concept trial was a randomized, double-blind, placebo-controlled, multicenter trial that compared two different dosage levels of ORM-12741 against placebo in 100 patients. The patients all had moderate Alzheimer’s disease, with a score between 12 and 21 on the Mini Mental State Examination (MMSE). The patents also had behavioral symptoms with a Neuropsychiatric Inventory (NPI) score of 15 or greater.

The patients received either 30-60 mg or 100-300 mg of ORM-12741, or a matching placebo, twice a day for 12 weeks. The patients were already taking a cholinesterase inhibitor and were allowed to take memantine (Namenda) as well. Dr. Rouru said the ORM-12741 dosage flexibility was built into the study because previous human subjects receiving the drug did not have Alzheimer’s, so the flexibility allowed for safety adjustments if necessary.

The battery of tests to assess cognitive function in the study participants included the Quality of Episodic Memory (QEM), Quality of Working Memory (QWM), Quality of Memory (QM), Speed of Memory, and Power of Attention. The NPI was also used to assess other potential behavioral and psychological symptoms during the trial.

At follow-up, the patients receiving ORM-12741 scored a mean 4% higher on the QEM composite score, which combines both episodic and working memory. No significant difference was noted between dosage amounts. Patients in the placebo group scored a mean 33% lower on the QEM composite. In addition, the researchers reported a positive trend for both the QWM score and NPI total score in the low-dose group. No other significant differences were noted from the other assessments.

ORM-12741 differs from other Alzheimer’s drugs on the market, such as memantine or cholinesterase inhibitors, by acting on a completely different target, Dr. Rouru said. The drug targets a specific subtype of adrenergic receptors in the brain called alpha-2C.

"Quite little has been known about those receptors, and a big part of the work that has been done on them has been done in our company," Dr. Rouru said in an interview. "In animal models, we see very clearly they are involved in memory, but they are also fine tuners for many behavioral things. We have been able to demonstrate in animal models not only that drugs that target to these receptors improve memory, but that they have also beneficial effect on depressive and psychotic symptoms."

The different target offers clinical advantages in terms of treatment combinations, Dr. Rouru said. "The bottom line is that because the target is different, we can very easily use this drug in combination with other medications so that we are adding effect," he said.

Dr. Rouru said the drug was well tolerated among the participants and that adverse events were similar in both the intervention and placebo groups. It is too early to say what adverse events may have been attributed in the intervention group to ORM-12741, he said.

The most commonly reported adverse events were headache in 12% of placebo-treated patients and 5% of patients taking ORM-12741; urinary tract infection in 9% taking placebo and 9% taking ORM-12741; nausea in 9% receiving placebo and 5% receiving ORM-12741; vomiting in 3% taking placebo and 8% taking ORM-12741; diarrhea in 6% on placebo and 5% on ORM-12741; and irritability in 9% on placebo and 3% on ORM-12741.

Dr. Rouru said he is very pleased with the results of this trial, and he and his associates at Orion Pharma are now in the planning stages of the next clinical trial.

"It was very nice that the animal effect we saw, we saw in humans as well," Dr. Rouru said. "Also, the effect that we saw in humans was very clear, which was really encouraging for the future of this compound."

The study was funded by Orion Pharma. Two authors are Orion employees, and two authors work for World Wide Clinical Trials, the contract research organization involved in the trial. One author works for the company providing the computerized memory measurement system.

* This article was revised on 3/27/13.

Patients who become depressed after having had a stroke are four times more likely to die than those who have not had a stroke and who are not depressed.

Results of a large 21-year follow-up study stress the importance of depression screening in poststroke care, according to Dr. Amytis Towfighi, who will present her data in March at the annual meeting of the American Academy of Neurology in San Diego.

"Our research highlights the importance of screening for and treating depression in people who have experienced a stroke," said Dr. Towfighi, chair of the neurology department at the Rancho Los Amigos National Rehabilitation Center in Downey, Calif. "Given how common depression is after stroke and the potential consequences of having depression, looking for signs and symptoms and addressing them may be key."

Her study cohort comprised 10,550 people aged 25-74 years who participated in the 1971-1975 National Health and Nutrition Examination Survey. They were interviewed again in 1982-1984 and then followed through 1992. Dr. Towfighi and her colleagues examined the risk of death in four groups: Patients who had a stroke but no depression (73); those who had a stroke and depression (48); those who had neither stroke nor depression (8,138); and those who did not have a stroke but did have depression (2,291).

Subjects with both stroke and depression were about four times more likely to die than those with neither condition in the unadjusted (hazard ratio, 4.06) and adjusted (HR 3.69) analyses.

The multivariate analysis adjusted for age, gender, race, education and income levels, and marital status.

The factors linking stroke, depression, and mortality aren’t fully understood, Dr. Towfighi said in an interview. "However, there are both behavioral and physiological explanations. Behaviorally, individuals who are depressed may be less likely to live healthy lifestyles (abstaining from smoking, exercising regularly, and eating healthy). In addition, they may be less likely to take their medications and go to health care practitioners for routine follow-up. Physiologic processes such as changes in platelet function could also play a role."

In this study, depression did not seem to be simply a marker of having had a more severe stroke with lasting disability. "While some studies have revealed a link between severity of stroke and depression, others have not. A recent study also showed that transient ischemic attack is associated with depression. Since individuals with TIA do not exhibit any lasting symptoms, this would make the association between depression and stroke severity less likely," she said.

Checking on a stroke survivor’s psychological well-being can be a fast and easy step to include in stroke follow-up, Dr. Towfighi said. "There are simple tools for quickly screening for depression in a busy ambulatory care setting, including the Patient Health Questionnaires 2 and 9."

Depression is common after stroke and is treatable, she added. "It is important for patients, family members, and health care practitioners to be aware of the signs and symptoms of depression so that it can be identified and treated promptly."

Dr. Towfighi had no financial disclosures.

[email protected]

Patients who become depressed after having had a stroke are four times more likely to die than those who have not had a stroke and who are not depressed.

Results of a large 21-year follow-up study stress the importance of depression screening in poststroke care, according to Dr. Amytis Towfighi, who will present her data in March at the annual meeting of the American Academy of Neurology in San Diego.

"Our research highlights the importance of screening for and treating depression in people who have experienced a stroke," said Dr. Towfighi, chair of the neurology department at the Rancho Los Amigos National Rehabilitation Center in Downey, Calif. "Given how common depression is after stroke and the potential consequences of having depression, looking for signs and symptoms and addressing them may be key."

Her study cohort comprised 10,550 people aged 25-74 years who participated in the 1971-1975 National Health and Nutrition Examination Survey. They were interviewed again in 1982-1984 and then followed through 1992. Dr. Towfighi and her colleagues examined the risk of death in four groups: Patients who had a stroke but no depression (73); those who had a stroke and depression (48); those who had neither stroke nor depression (8,138); and those who did not have a stroke but did have depression (2,291).

Subjects with both stroke and depression were about four times more likely to die than those with neither condition in the unadjusted (hazard ratio, 4.06) and adjusted (HR 3.69) analyses.

The multivariate analysis adjusted for age, gender, race, education and income levels, and marital status.

The factors linking stroke, depression, and mortality aren’t fully understood, Dr. Towfighi said in an interview. "However, there are both behavioral and physiological explanations. Behaviorally, individuals who are depressed may be less likely to live healthy lifestyles (abstaining from smoking, exercising regularly, and eating healthy). In addition, they may be less likely to take their medications and go to health care practitioners for routine follow-up. Physiologic processes such as changes in platelet function could also play a role."

In this study, depression did not seem to be simply a marker of having had a more severe stroke with lasting disability. "While some studies have revealed a link between severity of stroke and depression, others have not. A recent study also showed that transient ischemic attack is associated with depression. Since individuals with TIA do not exhibit any lasting symptoms, this would make the association between depression and stroke severity less likely," she said.

Checking on a stroke survivor’s psychological well-being can be a fast and easy step to include in stroke follow-up, Dr. Towfighi said. "There are simple tools for quickly screening for depression in a busy ambulatory care setting, including the Patient Health Questionnaires 2 and 9."

Depression is common after stroke and is treatable, she added. "It is important for patients, family members, and health care practitioners to be aware of the signs and symptoms of depression so that it can be identified and treated promptly."

Dr. Towfighi had no financial disclosures.

[email protected]

Patients who become depressed after having had a stroke are four times more likely to die than those who have not had a stroke and who are not depressed.

Results of a large 21-year follow-up study stress the importance of depression screening in poststroke care, according to Dr. Amytis Towfighi, who will present her data in March at the annual meeting of the American Academy of Neurology in San Diego.

"Our research highlights the importance of screening for and treating depression in people who have experienced a stroke," said Dr. Towfighi, chair of the neurology department at the Rancho Los Amigos National Rehabilitation Center in Downey, Calif. "Given how common depression is after stroke and the potential consequences of having depression, looking for signs and symptoms and addressing them may be key."

Her study cohort comprised 10,550 people aged 25-74 years who participated in the 1971-1975 National Health and Nutrition Examination Survey. They were interviewed again in 1982-1984 and then followed through 1992. Dr. Towfighi and her colleagues examined the risk of death in four groups: Patients who had a stroke but no depression (73); those who had a stroke and depression (48); those who had neither stroke nor depression (8,138); and those who did not have a stroke but did have depression (2,291).

Subjects with both stroke and depression were about four times more likely to die than those with neither condition in the unadjusted (hazard ratio, 4.06) and adjusted (HR 3.69) analyses.

The multivariate analysis adjusted for age, gender, race, education and income levels, and marital status.

The factors linking stroke, depression, and mortality aren’t fully understood, Dr. Towfighi said in an interview. "However, there are both behavioral and physiological explanations. Behaviorally, individuals who are depressed may be less likely to live healthy lifestyles (abstaining from smoking, exercising regularly, and eating healthy). In addition, they may be less likely to take their medications and go to health care practitioners for routine follow-up. Physiologic processes such as changes in platelet function could also play a role."

In this study, depression did not seem to be simply a marker of having had a more severe stroke with lasting disability. "While some studies have revealed a link between severity of stroke and depression, others have not. A recent study also showed that transient ischemic attack is associated with depression. Since individuals with TIA do not exhibit any lasting symptoms, this would make the association between depression and stroke severity less likely," she said.

Checking on a stroke survivor’s psychological well-being can be a fast and easy step to include in stroke follow-up, Dr. Towfighi said. "There are simple tools for quickly screening for depression in a busy ambulatory care setting, including the Patient Health Questionnaires 2 and 9."

Depression is common after stroke and is treatable, she added. "It is important for patients, family members, and health care practitioners to be aware of the signs and symptoms of depression so that it can be identified and treated promptly."

Dr. Towfighi had no financial disclosures.

[email protected]

Migraine with aura was a large risk factor for cardiovascular events among women who participated in the Women’s Health Study.

Although the physiologic connection isn’t yet clear, the finding is, according to Dr. Tobias Kurth, who is the primary investigator in the study that examined the association. He will present the full results of the study in March at the annual meeting of American Academy of Neurology in San Diego.

"Migraine with aura was the second-largest factor contributing to the risk of heart attack and stroke," said Dr. Kurth of the French National Institute of Health and Medical Research in Bordeaux. "It was ahead of diabetes, smoking, body mass index, and a family history of heart disease."

Dr. Kurth, also of Brigham and Women’s Hospital in Boston, used the Women’s Health Study to examine how migraine with aura fits in with other well-known risk factors for cardiovascular disease in women. The 15-year study was originally designed to examine the impact of low-dose aspirin and vitamin E for the primary prevention of cardiovascular disease and cancer. It enrolled nearly 40,000 women who were aged 45 years or older when they were entered in 1993, he said in an interview.

The cohort for Dr. Kurth’s study comprised 27,860 women who provided baseline blood samples and were without major cardiovascular disease at baseline. Overall, 1,435 had migraine with aura.

During the entire study, there were 1,030 cases of heart attack, stroke, or cardiovascular death. A systolic blood pressure of 180 mm Hg or higher was the strongest risk factor, with an incidence of 9.8 per 1,000 women per year. That was an expected association, Dr. Kurth said.

What he did not expect was to see was an incidence of 7.9 per 1,000 women per year in women who had migraine with aura. This exceeded the rates of cardiovascular disease in all other risk groups, including diabetes (7.1), family history of prior myocardial infarction (5.4), current smoking (5.4), and having a body mass index of 35 kg/m² or more (5.3).

The study doesn’t address any underlying physiologic connections. There are some theories, however.

"These involve vascular dysfunction," Dr. Kurth said. "People with migraines may have a different vascular reactivity, which might lead to some kind of a shared mechanism between migraine and cardiovascular disease. Inflammation, which is seen in both migraine and cardiovascular disease, might play a role. And genetic factors could be contributing as well."

Recognition of these patients is important, he said. "Patients who have migraine with aura could also potentially develop cardiovascular disease. This should be carefully assessed, because, unlike some of the other risk factors, migraine is not really modifiable."

Patients who have migraine with aura might especially benefit from lifestyle modification to further reduce their risk of heart disease. "People with migraine with aura can reduce their risk in the same ways others can, such as [by] not smoking, keeping blood pressure low and weight down, and exercising."

The National Institutes of Health funded the study. Dr. Kurth had no financial disclosures.

[email protected]

Migraine with aura was a large risk factor for cardiovascular events among women who participated in the Women’s Health Study.

Although the physiologic connection isn’t yet clear, the finding is, according to Dr. Tobias Kurth, who is the primary investigator in the study that examined the association. He will present the full results of the study in March at the annual meeting of American Academy of Neurology in San Diego.

"Migraine with aura was the second-largest factor contributing to the risk of heart attack and stroke," said Dr. Kurth of the French National Institute of Health and Medical Research in Bordeaux. "It was ahead of diabetes, smoking, body mass index, and a family history of heart disease."

Dr. Kurth, also of Brigham and Women’s Hospital in Boston, used the Women’s Health Study to examine how migraine with aura fits in with other well-known risk factors for cardiovascular disease in women. The 15-year study was originally designed to examine the impact of low-dose aspirin and vitamin E for the primary prevention of cardiovascular disease and cancer. It enrolled nearly 40,000 women who were aged 45 years or older when they were entered in 1993, he said in an interview.

The cohort for Dr. Kurth’s study comprised 27,860 women who provided baseline blood samples and were without major cardiovascular disease at baseline. Overall, 1,435 had migraine with aura.

During the entire study, there were 1,030 cases of heart attack, stroke, or cardiovascular death. A systolic blood pressure of 180 mm Hg or higher was the strongest risk factor, with an incidence of 9.8 per 1,000 women per year. That was an expected association, Dr. Kurth said.

What he did not expect was to see was an incidence of 7.9 per 1,000 women per year in women who had migraine with aura. This exceeded the rates of cardiovascular disease in all other risk groups, including diabetes (7.1), family history of prior myocardial infarction (5.4), current smoking (5.4), and having a body mass index of 35 kg/m² or more (5.3).

The study doesn’t address any underlying physiologic connections. There are some theories, however.

"These involve vascular dysfunction," Dr. Kurth said. "People with migraines may have a different vascular reactivity, which might lead to some kind of a shared mechanism between migraine and cardiovascular disease. Inflammation, which is seen in both migraine and cardiovascular disease, might play a role. And genetic factors could be contributing as well."

Recognition of these patients is important, he said. "Patients who have migraine with aura could also potentially develop cardiovascular disease. This should be carefully assessed, because, unlike some of the other risk factors, migraine is not really modifiable."

Patients who have migraine with aura might especially benefit from lifestyle modification to further reduce their risk of heart disease. "People with migraine with aura can reduce their risk in the same ways others can, such as [by] not smoking, keeping blood pressure low and weight down, and exercising."

The National Institutes of Health funded the study. Dr. Kurth had no financial disclosures.

[email protected]

Migraine with aura was a large risk factor for cardiovascular events among women who participated in the Women’s Health Study.

Although the physiologic connection isn’t yet clear, the finding is, according to Dr. Tobias Kurth, who is the primary investigator in the study that examined the association. He will present the full results of the study in March at the annual meeting of American Academy of Neurology in San Diego.

"Migraine with aura was the second-largest factor contributing to the risk of heart attack and stroke," said Dr. Kurth of the French National Institute of Health and Medical Research in Bordeaux. "It was ahead of diabetes, smoking, body mass index, and a family history of heart disease."

Dr. Kurth, also of Brigham and Women’s Hospital in Boston, used the Women’s Health Study to examine how migraine with aura fits in with other well-known risk factors for cardiovascular disease in women. The 15-year study was originally designed to examine the impact of low-dose aspirin and vitamin E for the primary prevention of cardiovascular disease and cancer. It enrolled nearly 40,000 women who were aged 45 years or older when they were entered in 1993, he said in an interview.

The cohort for Dr. Kurth’s study comprised 27,860 women who provided baseline blood samples and were without major cardiovascular disease at baseline. Overall, 1,435 had migraine with aura.

During the entire study, there were 1,030 cases of heart attack, stroke, or cardiovascular death. A systolic blood pressure of 180 mm Hg or higher was the strongest risk factor, with an incidence of 9.8 per 1,000 women per year. That was an expected association, Dr. Kurth said.

What he did not expect was to see was an incidence of 7.9 per 1,000 women per year in women who had migraine with aura. This exceeded the rates of cardiovascular disease in all other risk groups, including diabetes (7.1), family history of prior myocardial infarction (5.4), current smoking (5.4), and having a body mass index of 35 kg/m² or more (5.3).

The study doesn’t address any underlying physiologic connections. There are some theories, however.

"These involve vascular dysfunction," Dr. Kurth said. "People with migraines may have a different vascular reactivity, which might lead to some kind of a shared mechanism between migraine and cardiovascular disease. Inflammation, which is seen in both migraine and cardiovascular disease, might play a role. And genetic factors could be contributing as well."

Recognition of these patients is important, he said. "Patients who have migraine with aura could also potentially develop cardiovascular disease. This should be carefully assessed, because, unlike some of the other risk factors, migraine is not really modifiable."

Patients who have migraine with aura might especially benefit from lifestyle modification to further reduce their risk of heart disease. "People with migraine with aura can reduce their risk in the same ways others can, such as [by] not smoking, keeping blood pressure low and weight down, and exercising."

The National Institutes of Health funded the study. Dr. Kurth had no financial disclosures.

[email protected]