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PRIDE study supports novel approach to ECT for geriatric depression
PARIS – Results of the randomized phase 2 portion of the landmark PRIDE study of electroconvulsive therapy for severe unipolar depression in geriatric patients hold a key message for clinicians, according to Charles H. Kellner, MD.
“The clinical take-home message is that practitioners should be liberal in prescribing additional ECT past the acute course. So our recommendation is that tapering ECT courses and being liberal with continuation and maintenance ECT should be adopted in clinical practice more widely with the aim of preventing full syndromic relapse and its catastrophic consequences,” Dr. Kellner said at the annual congress of the European College of Neuropsychopharmacology. 
PRIDE (Prolonging Remission in Depressed Elderly) was a National Institute of Mental Health–sponsored nine-center study of right unilateral ultrabrief pulse ECT at 0.25 msec plus supportive pharmacotherapy for treatment of geriatric depression.
Phase 1 of the study involved 240 affected patients, 62% of whom achieved remission after receiving this form of ECT at six times the seizure threshold thrice weekly for up to 1 month coupled with low- or medium-dose venlafaxine. A mean of 7.3 ECT sessions were needed to attain remission as defined by a score of 10 or less on the Hamilton Rating Scale for Depression (HAM-D24) on two consecutive occasions, down from a mean baseline score of 31.2. The scale was administered three times per week. Safety and tolerability of the ECT regimen were excellent, according to Dr. Kellner, chief of electroconvulsive therapy at New York Community Hospital and a psychiatrist at Mount Sinai School of Medicine in New York.
The PRIDE phase 1 data confirmed several points previously made in earlier studies. One is that the older patients are, the more ECT-responsive they are, even within an all-geriatric cohort such as PRIDE. Indeed, the remission rate was 55% in the 60- to 69-year-olds, compared with 72% in the 70- to 79-year-olds.
Another finding consistent with other studies: Patients with psychotic depression do particularly well with ECT. All PRIDE participants with psychotic depression achieved remission.
Also, ECT had a very rapid antisuicidal effect. At baseline, 24% of patients had a score of 1 on HAM-D24 item 3, which rates suicidality. An additional 34% had a baseline score of 2, 14% scored 3, and only 23% had a score of 0. After only a few weeks of ECT, however, 84% of patients had a score of 0 and 9% scored a 1.
“That’s one of the compelling clinical reasons to refer patients for ECT: This type of ECT is really good for treating suicidality,” Dr. Kellner noted.
Phase 2 was the more interesting part of the PRIDE study, he continued, because it evaluated in randomized fashion the efficacy and tolerability of a novel flexible, individualized strategy for as-needed maintenance ECT to sustain the mood improvement once remission was achieved. Dr. Kellner stressed that some form of maintenance therapy is essential post ECT-induced remission.
“It’s unreasonable to expect that ECT could cure the patients’ underlying illness and protect them from getting sick again for the rest of their lives. One has to understand this is a recurrent episodic illness that we’re treating. What ECT does is treat the current episode, and it does it better and more thoroughly than any other treatment in psychiatry,” Dr. Kellner said.
Post-ECT relapse rates are clearly higher in the modern era, which makes a compelling case for developing safe and effective maintenance strategies.
“We don’t quite understand why relapse rates are higher today. My belief is that for patients who come to ECT, their illness has been destabilized by having been on multiple trials of antidepressant medications beforehand. It may also be that the forms of ECT that we’re using today are somewhat less potent than the ones used in previous decades,” Dr. Kellner conceded.
He and his coinvestigators named their investigational maintenance ECT strategy STABLE, for Symptom-Titrated, Algorithm-Based Longitudinal ECT. It’s a complex algorithm described in detail in a published report (Am J Psychiatry. 2016 Nov 1; 173[11]:1110-18). Basically, it consisted of four mandatory additional ECT sessions administered once weekly for the first month post remission, followed by either one, two, or no ECT sessions per week based upon evidence of deterioration as expressed in HAM-D24 scores.
In phase 2 of PRIDE, 128 remitters from phase 1 were continued on venlafaxine at a mean dose of 192 mg/day. In addition, they were placed on lithium, achieving a mean lithium level of 0.53 mEq/L, which Dr. Kellner deemed “low but reasonable.” These 128 patients were then randomized to the STABLE arm of flexibly administered ECT or to medication only and were followed prospectively for 6 months.
The primary endpoint was change in HAM-D24 score over the course of 6 months. From a baseline mean total score of 6, the mean score climbed to 8.4 in the medication-only group while dropping to 4.2 in the STABLE arm.
“At every time point along the way in the 6-month course of phase 2 of the illness, patients who were in the STABLE arm were less symptomatic and doing better than patients in the medication-only arm,” Dr. Kellner observed.
The key secondary efficacy outcome was change in the Clinical Global Impressions Severity scale. At follow-up, the patients in the flexible ECT plus medication arm were 5.2 times more likely to be rated “not ill at all” than were those on pharmacotherapy only.
In addition, relapse occurred in 20% of the medication-only group versus 13% in the STABLE group.
Global cognitive functioning as assessed by the Mini-Mental State Examination – crudely, in Dr. Kellner’s view – did not differ between the two groups at follow-up. Results of more sophisticated tests of multiple specific domains of cognition will be forthcoming.
Of note, two-thirds of patients in the STABLE arm required no additional ECT after their four continuation ECTs during the first month.
A swipe at ECT’s critics
Dr. Kellner called ECT “a fabulous therapy,” albeit one with a serious image problem.
“I think the problem with ECT is not that we don’t know all the details of how it works or what it does clinically, it’s really a sociopolitical issue about ECT not being adequately accepted. I break down this lack of acceptance into two forms: The first is passive lack of acceptance based on our profession not having embraced ECT and continuing to fail to embrace it. The other is the active propaganda against ECT that is promulgated by the Church of Scientology, which has taken on a life of its own now because of the Internet. ECT is still fought by the Church of Scientology. They fund lots of people to say incorrect nasty things about ECT to inappropriately frighten our patients,” Dr. Kellner charged.
He cautioned that proposed new Food and Drug Administration regulations governing ECT devices would greatly limit the use of ECT, restricting it to adults with treatment-resistant major depressive disorder or bipolar disorder or who require a rapid response. Other currently cleared indications would become off-label uses.
“With off-label ECT, the potential problem is practitioners may not be covered by their malpractice insurance. And the bigger issue is health insurers may not pay for it unless the ECT is for an on-label indication,” Dr. Kellner said.
He shared that he has found extremely helpful a colleague’s advice to demystify ECT by inviting a family member to witness a patient’s treatment session. That witness can then testify to others that what goes on bears no resemblance to what happens to Jack Nicholson in the classic film “One Flew Over the Cuckoo’s Nest.”
The PRIDE study was funded by the National Institute of Mental Health. Dr. Kellner reported having no financial conflicts of interest.
PARIS – Results of the randomized phase 2 portion of the landmark PRIDE study of electroconvulsive therapy for severe unipolar depression in geriatric patients hold a key message for clinicians, according to Charles H. Kellner, MD.
“The clinical take-home message is that practitioners should be liberal in prescribing additional ECT past the acute course. So our recommendation is that tapering ECT courses and being liberal with continuation and maintenance ECT should be adopted in clinical practice more widely with the aim of preventing full syndromic relapse and its catastrophic consequences,” Dr. Kellner said at the annual congress of the European College of Neuropsychopharmacology.
PRIDE (Prolonging Remission in Depressed Elderly) was a National Institute of Mental Health–sponsored nine-center study of right unilateral ultrabrief pulse ECT at 0.25 msec plus supportive pharmacotherapy for treatment of geriatric depression.
Phase 1 of the study involved 240 affected patients, 62% of whom achieved remission after receiving this form of ECT at six times the seizure threshold thrice weekly for up to 1 month coupled with low- or medium-dose venlafaxine. A mean of 7.3 ECT sessions were needed to attain remission as defined by a score of 10 or less on the Hamilton Rating Scale for Depression (HAM-D24) on two consecutive occasions, down from a mean baseline score of 31.2. The scale was administered three times per week. Safety and tolerability of the ECT regimen were excellent, according to Dr. Kellner, chief of electroconvulsive therapy at New York Community Hospital and a psychiatrist at Mount Sinai School of Medicine in New York.
The PRIDE phase 1 data confirmed several points previously made in earlier studies. One is that the older patients are, the more ECT-responsive they are, even within an all-geriatric cohort such as PRIDE. Indeed, the remission rate was 55% in the 60- to 69-year-olds, compared with 72% in the 70- to 79-year-olds.
Another finding consistent with other studies: Patients with psychotic depression do particularly well with ECT. All PRIDE participants with psychotic depression achieved remission.
Also, ECT had a very rapid antisuicidal effect. At baseline, 24% of patients had a score of 1 on HAM-D24 item 3, which rates suicidality. An additional 34% had a baseline score of 2, 14% scored 3, and only 23% had a score of 0. After only a few weeks of ECT, however, 84% of patients had a score of 0 and 9% scored a 1.
“That’s one of the compelling clinical reasons to refer patients for ECT: This type of ECT is really good for treating suicidality,” Dr. Kellner noted.
Phase 2 was the more interesting part of the PRIDE study, he continued, because it evaluated in randomized fashion the efficacy and tolerability of a novel flexible, individualized strategy for as-needed maintenance ECT to sustain the mood improvement once remission was achieved. Dr. Kellner stressed that some form of maintenance therapy is essential post ECT-induced remission.
“It’s unreasonable to expect that ECT could cure the patients’ underlying illness and protect them from getting sick again for the rest of their lives. One has to understand this is a recurrent episodic illness that we’re treating. What ECT does is treat the current episode, and it does it better and more thoroughly than any other treatment in psychiatry,” Dr. Kellner said.
Post-ECT relapse rates are clearly higher in the modern era, which makes a compelling case for developing safe and effective maintenance strategies.
“We don’t quite understand why relapse rates are higher today. My belief is that for patients who come to ECT, their illness has been destabilized by having been on multiple trials of antidepressant medications beforehand. It may also be that the forms of ECT that we’re using today are somewhat less potent than the ones used in previous decades,” Dr. Kellner conceded.
He and his coinvestigators named their investigational maintenance ECT strategy STABLE, for Symptom-Titrated, Algorithm-Based Longitudinal ECT. It’s a complex algorithm described in detail in a published report (Am J Psychiatry. 2016 Nov 1; 173[11]:1110-18). Basically, it consisted of four mandatory additional ECT sessions administered once weekly for the first month post remission, followed by either one, two, or no ECT sessions per week based upon evidence of deterioration as expressed in HAM-D24 scores.
In phase 2 of PRIDE, 128 remitters from phase 1 were continued on venlafaxine at a mean dose of 192 mg/day. In addition, they were placed on lithium, achieving a mean lithium level of 0.53 mEq/L, which Dr. Kellner deemed “low but reasonable.” These 128 patients were then randomized to the STABLE arm of flexibly administered ECT or to medication only and were followed prospectively for 6 months.
The primary endpoint was change in HAM-D24 score over the course of 6 months. From a baseline mean total score of 6, the mean score climbed to 8.4 in the medication-only group while dropping to 4.2 in the STABLE arm.
“At every time point along the way in the 6-month course of phase 2 of the illness, patients who were in the STABLE arm were less symptomatic and doing better than patients in the medication-only arm,” Dr. Kellner observed.
The key secondary efficacy outcome was change in the Clinical Global Impressions Severity scale. At follow-up, the patients in the flexible ECT plus medication arm were 5.2 times more likely to be rated “not ill at all” than were those on pharmacotherapy only.
In addition, relapse occurred in 20% of the medication-only group versus 13% in the STABLE group.
Global cognitive functioning as assessed by the Mini-Mental State Examination – crudely, in Dr. Kellner’s view – did not differ between the two groups at follow-up. Results of more sophisticated tests of multiple specific domains of cognition will be forthcoming.
Of note, two-thirds of patients in the STABLE arm required no additional ECT after their four continuation ECTs during the first month.
A swipe at ECT’s critics
Dr. Kellner called ECT “a fabulous therapy,” albeit one with a serious image problem.
“I think the problem with ECT is not that we don’t know all the details of how it works or what it does clinically, it’s really a sociopolitical issue about ECT not being adequately accepted. I break down this lack of acceptance into two forms: The first is passive lack of acceptance based on our profession not having embraced ECT and continuing to fail to embrace it. The other is the active propaganda against ECT that is promulgated by the Church of Scientology, which has taken on a life of its own now because of the Internet. ECT is still fought by the Church of Scientology. They fund lots of people to say incorrect nasty things about ECT to inappropriately frighten our patients,” Dr. Kellner charged.
He cautioned that proposed new Food and Drug Administration regulations governing ECT devices would greatly limit the use of ECT, restricting it to adults with treatment-resistant major depressive disorder or bipolar disorder or who require a rapid response. Other currently cleared indications would become off-label uses.
“With off-label ECT, the potential problem is practitioners may not be covered by their malpractice insurance. And the bigger issue is health insurers may not pay for it unless the ECT is for an on-label indication,” Dr. Kellner said.
He shared that he has found extremely helpful a colleague’s advice to demystify ECT by inviting a family member to witness a patient’s treatment session. That witness can then testify to others that what goes on bears no resemblance to what happens to Jack Nicholson in the classic film “One Flew Over the Cuckoo’s Nest.”
The PRIDE study was funded by the National Institute of Mental Health. Dr. Kellner reported having no financial conflicts of interest.
PARIS – Results of the randomized phase 2 portion of the landmark PRIDE study of electroconvulsive therapy for severe unipolar depression in geriatric patients hold a key message for clinicians, according to Charles H. Kellner, MD.
“The clinical take-home message is that practitioners should be liberal in prescribing additional ECT past the acute course. So our recommendation is that tapering ECT courses and being liberal with continuation and maintenance ECT should be adopted in clinical practice more widely with the aim of preventing full syndromic relapse and its catastrophic consequences,” Dr. Kellner said at the annual congress of the European College of Neuropsychopharmacology.
PRIDE (Prolonging Remission in Depressed Elderly) was a National Institute of Mental Health–sponsored nine-center study of right unilateral ultrabrief pulse ECT at 0.25 msec plus supportive pharmacotherapy for treatment of geriatric depression.
Phase 1 of the study involved 240 affected patients, 62% of whom achieved remission after receiving this form of ECT at six times the seizure threshold thrice weekly for up to 1 month coupled with low- or medium-dose venlafaxine. A mean of 7.3 ECT sessions were needed to attain remission as defined by a score of 10 or less on the Hamilton Rating Scale for Depression (HAM-D24) on two consecutive occasions, down from a mean baseline score of 31.2. The scale was administered three times per week. Safety and tolerability of the ECT regimen were excellent, according to Dr. Kellner, chief of electroconvulsive therapy at New York Community Hospital and a psychiatrist at Mount Sinai School of Medicine in New York.
The PRIDE phase 1 data confirmed several points previously made in earlier studies. One is that the older patients are, the more ECT-responsive they are, even within an all-geriatric cohort such as PRIDE. Indeed, the remission rate was 55% in the 60- to 69-year-olds, compared with 72% in the 70- to 79-year-olds.
Another finding consistent with other studies: Patients with psychotic depression do particularly well with ECT. All PRIDE participants with psychotic depression achieved remission.
Also, ECT had a very rapid antisuicidal effect. At baseline, 24% of patients had a score of 1 on HAM-D24 item 3, which rates suicidality. An additional 34% had a baseline score of 2, 14% scored 3, and only 23% had a score of 0. After only a few weeks of ECT, however, 84% of patients had a score of 0 and 9% scored a 1.
“That’s one of the compelling clinical reasons to refer patients for ECT: This type of ECT is really good for treating suicidality,” Dr. Kellner noted.
Phase 2 was the more interesting part of the PRIDE study, he continued, because it evaluated in randomized fashion the efficacy and tolerability of a novel flexible, individualized strategy for as-needed maintenance ECT to sustain the mood improvement once remission was achieved. Dr. Kellner stressed that some form of maintenance therapy is essential post ECT-induced remission.
“It’s unreasonable to expect that ECT could cure the patients’ underlying illness and protect them from getting sick again for the rest of their lives. One has to understand this is a recurrent episodic illness that we’re treating. What ECT does is treat the current episode, and it does it better and more thoroughly than any other treatment in psychiatry,” Dr. Kellner said.
Post-ECT relapse rates are clearly higher in the modern era, which makes a compelling case for developing safe and effective maintenance strategies.
“We don’t quite understand why relapse rates are higher today. My belief is that for patients who come to ECT, their illness has been destabilized by having been on multiple trials of antidepressant medications beforehand. It may also be that the forms of ECT that we’re using today are somewhat less potent than the ones used in previous decades,” Dr. Kellner conceded.
He and his coinvestigators named their investigational maintenance ECT strategy STABLE, for Symptom-Titrated, Algorithm-Based Longitudinal ECT. It’s a complex algorithm described in detail in a published report (Am J Psychiatry. 2016 Nov 1; 173[11]:1110-18). Basically, it consisted of four mandatory additional ECT sessions administered once weekly for the first month post remission, followed by either one, two, or no ECT sessions per week based upon evidence of deterioration as expressed in HAM-D24 scores.
In phase 2 of PRIDE, 128 remitters from phase 1 were continued on venlafaxine at a mean dose of 192 mg/day. In addition, they were placed on lithium, achieving a mean lithium level of 0.53 mEq/L, which Dr. Kellner deemed “low but reasonable.” These 128 patients were then randomized to the STABLE arm of flexibly administered ECT or to medication only and were followed prospectively for 6 months.
The primary endpoint was change in HAM-D24 score over the course of 6 months. From a baseline mean total score of 6, the mean score climbed to 8.4 in the medication-only group while dropping to 4.2 in the STABLE arm.
“At every time point along the way in the 6-month course of phase 2 of the illness, patients who were in the STABLE arm were less symptomatic and doing better than patients in the medication-only arm,” Dr. Kellner observed.
The key secondary efficacy outcome was change in the Clinical Global Impressions Severity scale. At follow-up, the patients in the flexible ECT plus medication arm were 5.2 times more likely to be rated “not ill at all” than were those on pharmacotherapy only.
In addition, relapse occurred in 20% of the medication-only group versus 13% in the STABLE group.
Global cognitive functioning as assessed by the Mini-Mental State Examination – crudely, in Dr. Kellner’s view – did not differ between the two groups at follow-up. Results of more sophisticated tests of multiple specific domains of cognition will be forthcoming.
Of note, two-thirds of patients in the STABLE arm required no additional ECT after their four continuation ECTs during the first month.
A swipe at ECT’s critics
Dr. Kellner called ECT “a fabulous therapy,” albeit one with a serious image problem.
“I think the problem with ECT is not that we don’t know all the details of how it works or what it does clinically, it’s really a sociopolitical issue about ECT not being adequately accepted. I break down this lack of acceptance into two forms: The first is passive lack of acceptance based on our profession not having embraced ECT and continuing to fail to embrace it. The other is the active propaganda against ECT that is promulgated by the Church of Scientology, which has taken on a life of its own now because of the Internet. ECT is still fought by the Church of Scientology. They fund lots of people to say incorrect nasty things about ECT to inappropriately frighten our patients,” Dr. Kellner charged.
He cautioned that proposed new Food and Drug Administration regulations governing ECT devices would greatly limit the use of ECT, restricting it to adults with treatment-resistant major depressive disorder or bipolar disorder or who require a rapid response. Other currently cleared indications would become off-label uses.
“With off-label ECT, the potential problem is practitioners may not be covered by their malpractice insurance. And the bigger issue is health insurers may not pay for it unless the ECT is for an on-label indication,” Dr. Kellner said.
He shared that he has found extremely helpful a colleague’s advice to demystify ECT by inviting a family member to witness a patient’s treatment session. That witness can then testify to others that what goes on bears no resemblance to what happens to Jack Nicholson in the classic film “One Flew Over the Cuckoo’s Nest.”
The PRIDE study was funded by the National Institute of Mental Health. Dr. Kellner reported having no financial conflicts of interest.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: At 6 months follow-up, the mean score on the Hamilton Rating Scale for Depression was 4.2 points lower in the flexible maintenance ECT group than in the medication-only group, from a baseline score of 6.
Data source: Phase 2 of the PRIDE study randomized 128 elderly patients whose severe depression remitted in response to ECT to one of two maintenance treatment strategies.
Disclosures: The PRIDE study was funded by the National Institute of Mental Health. The presenter reported having no financial conflicts of interest.
Benzodiazepines and antidepressants do not impair cognition in midlife schizophrenia
PARIS – Cumulative lifetime exposure to benzodiazepines and antidepressants in the relatively modest amounts typically prescribed in schizophrenia did not appear to adversely affect patients’ cognition in midlife, according to a first-of-its-kind study from Finland.
“These findings are reassuring,” said Anja P. Hulkko, MD, a psychiatric resident at the University of Oulu (Finland).
“Similarly, you don’t need to worry about using benzodiazepines in schizophrenia if you are using small doses or for short periods to treat a specific condition like anxiety or sleeplessness,” Dr. Hulkko said at the annual congress of the European College of Neuropsychopharmacology.
These observations were among the key findings of her analysis from the Northern Finnish Birth Cohort 1966. This ongoing unique and naturalistic observational study – or actually, more than 20 different studies conducted in the same population – was designed to study risk factors involved in preterm birth and intrauterine growth retardation, as well as the consequences of these early adverse events on later morbidity and mortality. Data including maternal health during pregnancy have been prospectively collected from first prenatal contact at weeks 10-16 well into adulthood.
The 1966 cohort included 12,058 live births in the two northernmost provinces of Finland, which was 96% of all births there in that year. DNA samples were obtained from nearly 6,000 subjects in the cohort. After birth and again every 7-15 years, the offspring were examined and underwent clinical evaluation in which a wide range of phenotypic, behavioral, and demographic data were collected. Linkage to Finland’s comprehensive national registries provides investigators with up-to-date information about participants’ education, medication, hospitalizations, significant medical diagnoses, pensions, and death. These prospective data allow investigations of the importance of genetic, biologic, social, and behavioral risk factors in the emergence of various target diseases, one of which is schizophrenia.
Dr. Hulkko’s presentation focused on 60 patients with various schizophrenia spectrum disorders who underwent an extensive battery of neuropsychological tests at age 43, when they averaged 16.5 years of illness.
Lifetime cumulative exposure to benzodiazepines or antidepressants was not significantly associated with a global composite cognition score in a multivariate analysis adjusted for potential confounders including sex, age at schizophrenia onset, and lifetime psychiatric hospital treatment days.
The comprehensive test battery included the California Verbal Learning Test, the Abstraction Inhibition and Working Memory Task, Digit Span and Matrix Reasoning, verbal fluency and vocabulary testing, and the Visual Object Learning Test.
This, she said, is the first report to look at the cognitive impact of these drug classes in midlife schizophrenia. Long-term, high-dose use of benzodiazepines has in recent years been linked to increased risk for cognitive impairment in other populations, but that’s not ordinarily how those drugs are employed in schizophrenia.
In contrast to the new Finnish antidepressant and benzodiazepine findings, higher lifetime antipsychotic dose-years in the study population were recently reported by Dr. Hulkko’s senior coinvestigators to be significantly associated with a worse adjusted cognition score, with no difference between typical and atypical antipsychotics. “It is possible that large antipsychotic doses harm cognition in schizophrenia in the long term,” the researchers concluded (Psychiatry Res. 2017 Jan;247:130-8).
At the meeting, Dr. Hulkko presented new data on the cognitive impact of cumulative exposure to antipsychotics in the midlife schizophrenia cohort. The new finding is that having an antipsychotic-free period of at least 1 year at any point since treatment started an average of more than 16 years earlier was associated with a better adjusted cognitive performance.
The same was true for having an antipsychotic-free interval of at least 11 months directly before administration of the neuropsychological test battery. This is an encouraging finding because it suggests that an antipsychotic drug holiday might promote a measurable degree of cognitive recovery. But this observation must be viewed as hypothesis generating rather than conclusive, given the relatively small size of the study population, the observational nature of the study, and the possibility that the patients on a pretest antipsychotic break had less severe illness.
“Although we have tried to control for many factors, still, it’s possible that we cannot control for everything,” she noted. “It seems likely that both the illness itself and treatment are associated with the course of cognition.”
Kamilla W. Miskowiak, PhD, a neuropsychologist at the University of Copenhagen deemed the Finnish results “highly interesting.”
“This is reassuring, since many patients are worried about taking these medications [antidepressants and benzodiazepines] because of their potential negative effects on cognition. In contrast, long-term high-dose antipsychotic medication was associated with poorer cognitive outcome. This underscores the importance of close dose monitoring of antipsychotic medication for these patients to improve their cognitive outcome,” said Dr. Miskowiak, who was not involved in the study.
The study was supported by the Academy of Finland, the Finnish Cultural Foundation Lapland Regional Fund, and grants from various nonprofit foundations. Dr. Hulkko reported having no financial conflicts of interest.
PARIS – Cumulative lifetime exposure to benzodiazepines and antidepressants in the relatively modest amounts typically prescribed in schizophrenia did not appear to adversely affect patients’ cognition in midlife, according to a first-of-its-kind study from Finland.
“These findings are reassuring,” said Anja P. Hulkko, MD, a psychiatric resident at the University of Oulu (Finland).
“Similarly, you don’t need to worry about using benzodiazepines in schizophrenia if you are using small doses or for short periods to treat a specific condition like anxiety or sleeplessness,” Dr. Hulkko said at the annual congress of the European College of Neuropsychopharmacology.
These observations were among the key findings of her analysis from the Northern Finnish Birth Cohort 1966. This ongoing unique and naturalistic observational study – or actually, more than 20 different studies conducted in the same population – was designed to study risk factors involved in preterm birth and intrauterine growth retardation, as well as the consequences of these early adverse events on later morbidity and mortality. Data including maternal health during pregnancy have been prospectively collected from first prenatal contact at weeks 10-16 well into adulthood.
The 1966 cohort included 12,058 live births in the two northernmost provinces of Finland, which was 96% of all births there in that year. DNA samples were obtained from nearly 6,000 subjects in the cohort. After birth and again every 7-15 years, the offspring were examined and underwent clinical evaluation in which a wide range of phenotypic, behavioral, and demographic data were collected. Linkage to Finland’s comprehensive national registries provides investigators with up-to-date information about participants’ education, medication, hospitalizations, significant medical diagnoses, pensions, and death. These prospective data allow investigations of the importance of genetic, biologic, social, and behavioral risk factors in the emergence of various target diseases, one of which is schizophrenia.
Dr. Hulkko’s presentation focused on 60 patients with various schizophrenia spectrum disorders who underwent an extensive battery of neuropsychological tests at age 43, when they averaged 16.5 years of illness.
Lifetime cumulative exposure to benzodiazepines or antidepressants was not significantly associated with a global composite cognition score in a multivariate analysis adjusted for potential confounders including sex, age at schizophrenia onset, and lifetime psychiatric hospital treatment days.
The comprehensive test battery included the California Verbal Learning Test, the Abstraction Inhibition and Working Memory Task, Digit Span and Matrix Reasoning, verbal fluency and vocabulary testing, and the Visual Object Learning Test.
This, she said, is the first report to look at the cognitive impact of these drug classes in midlife schizophrenia. Long-term, high-dose use of benzodiazepines has in recent years been linked to increased risk for cognitive impairment in other populations, but that’s not ordinarily how those drugs are employed in schizophrenia.
In contrast to the new Finnish antidepressant and benzodiazepine findings, higher lifetime antipsychotic dose-years in the study population were recently reported by Dr. Hulkko’s senior coinvestigators to be significantly associated with a worse adjusted cognition score, with no difference between typical and atypical antipsychotics. “It is possible that large antipsychotic doses harm cognition in schizophrenia in the long term,” the researchers concluded (Psychiatry Res. 2017 Jan;247:130-8).
At the meeting, Dr. Hulkko presented new data on the cognitive impact of cumulative exposure to antipsychotics in the midlife schizophrenia cohort. The new finding is that having an antipsychotic-free period of at least 1 year at any point since treatment started an average of more than 16 years earlier was associated with a better adjusted cognitive performance.
The same was true for having an antipsychotic-free interval of at least 11 months directly before administration of the neuropsychological test battery. This is an encouraging finding because it suggests that an antipsychotic drug holiday might promote a measurable degree of cognitive recovery. But this observation must be viewed as hypothesis generating rather than conclusive, given the relatively small size of the study population, the observational nature of the study, and the possibility that the patients on a pretest antipsychotic break had less severe illness.
“Although we have tried to control for many factors, still, it’s possible that we cannot control for everything,” she noted. “It seems likely that both the illness itself and treatment are associated with the course of cognition.”
Kamilla W. Miskowiak, PhD, a neuropsychologist at the University of Copenhagen deemed the Finnish results “highly interesting.”
“This is reassuring, since many patients are worried about taking these medications [antidepressants and benzodiazepines] because of their potential negative effects on cognition. In contrast, long-term high-dose antipsychotic medication was associated with poorer cognitive outcome. This underscores the importance of close dose monitoring of antipsychotic medication for these patients to improve their cognitive outcome,” said Dr. Miskowiak, who was not involved in the study.
The study was supported by the Academy of Finland, the Finnish Cultural Foundation Lapland Regional Fund, and grants from various nonprofit foundations. Dr. Hulkko reported having no financial conflicts of interest.
PARIS – Cumulative lifetime exposure to benzodiazepines and antidepressants in the relatively modest amounts typically prescribed in schizophrenia did not appear to adversely affect patients’ cognition in midlife, according to a first-of-its-kind study from Finland.
“These findings are reassuring,” said Anja P. Hulkko, MD, a psychiatric resident at the University of Oulu (Finland).
“Similarly, you don’t need to worry about using benzodiazepines in schizophrenia if you are using small doses or for short periods to treat a specific condition like anxiety or sleeplessness,” Dr. Hulkko said at the annual congress of the European College of Neuropsychopharmacology.
These observations were among the key findings of her analysis from the Northern Finnish Birth Cohort 1966. This ongoing unique and naturalistic observational study – or actually, more than 20 different studies conducted in the same population – was designed to study risk factors involved in preterm birth and intrauterine growth retardation, as well as the consequences of these early adverse events on later morbidity and mortality. Data including maternal health during pregnancy have been prospectively collected from first prenatal contact at weeks 10-16 well into adulthood.
The 1966 cohort included 12,058 live births in the two northernmost provinces of Finland, which was 96% of all births there in that year. DNA samples were obtained from nearly 6,000 subjects in the cohort. After birth and again every 7-15 years, the offspring were examined and underwent clinical evaluation in which a wide range of phenotypic, behavioral, and demographic data were collected. Linkage to Finland’s comprehensive national registries provides investigators with up-to-date information about participants’ education, medication, hospitalizations, significant medical diagnoses, pensions, and death. These prospective data allow investigations of the importance of genetic, biologic, social, and behavioral risk factors in the emergence of various target diseases, one of which is schizophrenia.
Dr. Hulkko’s presentation focused on 60 patients with various schizophrenia spectrum disorders who underwent an extensive battery of neuropsychological tests at age 43, when they averaged 16.5 years of illness.
Lifetime cumulative exposure to benzodiazepines or antidepressants was not significantly associated with a global composite cognition score in a multivariate analysis adjusted for potential confounders including sex, age at schizophrenia onset, and lifetime psychiatric hospital treatment days.
The comprehensive test battery included the California Verbal Learning Test, the Abstraction Inhibition and Working Memory Task, Digit Span and Matrix Reasoning, verbal fluency and vocabulary testing, and the Visual Object Learning Test.
This, she said, is the first report to look at the cognitive impact of these drug classes in midlife schizophrenia. Long-term, high-dose use of benzodiazepines has in recent years been linked to increased risk for cognitive impairment in other populations, but that’s not ordinarily how those drugs are employed in schizophrenia.
In contrast to the new Finnish antidepressant and benzodiazepine findings, higher lifetime antipsychotic dose-years in the study population were recently reported by Dr. Hulkko’s senior coinvestigators to be significantly associated with a worse adjusted cognition score, with no difference between typical and atypical antipsychotics. “It is possible that large antipsychotic doses harm cognition in schizophrenia in the long term,” the researchers concluded (Psychiatry Res. 2017 Jan;247:130-8).
At the meeting, Dr. Hulkko presented new data on the cognitive impact of cumulative exposure to antipsychotics in the midlife schizophrenia cohort. The new finding is that having an antipsychotic-free period of at least 1 year at any point since treatment started an average of more than 16 years earlier was associated with a better adjusted cognitive performance.
The same was true for having an antipsychotic-free interval of at least 11 months directly before administration of the neuropsychological test battery. This is an encouraging finding because it suggests that an antipsychotic drug holiday might promote a measurable degree of cognitive recovery. But this observation must be viewed as hypothesis generating rather than conclusive, given the relatively small size of the study population, the observational nature of the study, and the possibility that the patients on a pretest antipsychotic break had less severe illness.
“Although we have tried to control for many factors, still, it’s possible that we cannot control for everything,” she noted. “It seems likely that both the illness itself and treatment are associated with the course of cognition.”
Kamilla W. Miskowiak, PhD, a neuropsychologist at the University of Copenhagen deemed the Finnish results “highly interesting.”
“This is reassuring, since many patients are worried about taking these medications [antidepressants and benzodiazepines] because of their potential negative effects on cognition. In contrast, long-term high-dose antipsychotic medication was associated with poorer cognitive outcome. This underscores the importance of close dose monitoring of antipsychotic medication for these patients to improve their cognitive outcome,” said Dr. Miskowiak, who was not involved in the study.
The study was supported by the Academy of Finland, the Finnish Cultural Foundation Lapland Regional Fund, and grants from various nonprofit foundations. Dr. Hulkko reported having no financial conflicts of interest.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: As-needed prescription of antidepressants and benzodiazepines in the dose typically used in schizophrenia does not impair midlife cognition.
Data source: An ongoing naturalistic, observational, general population-based study of more than 12,000 babies born in Northern Finland in 1966 from fetal life through middle age.
Disclosures: The study was supported by the Academy of Finland, the Finnish Cultural Foundation Lapland Regional Fund, and grants from various nonprofit charitable foundations. The presenter reported having no financial conflicts of interest.
Antipsychotics may reduce mortality in schizophrenia
PARIS – All-cause mortality was 46% lower while schizophrenia patients were on antipsychotic agents than when off therapy in a nationwide observational study of nearly 30,000 Swedes with schizophrenia – and the biggest risk reduction occurred in patients on second-generation long-acting injectables, according to Jari Tiihonen, MD, PhD.
“The guidelines say there are special situations where you should consider using depot antipsychotics. I think the guidelines got it wrong. I think the right way to think of it is there are special situations where you might consider oral agents; otherwise you should use long-acting injectables,” said Dr. Tiihonen, who holds joint appointments as professor of psychiatry at the University of Eastern Finland in Kuopio and the Karolinska Institute in Stockholm.
During a mean follow-up of 5.7 years, 8.4% of the patients died. In a multivariate Cox regression analysis adjusted for 20 potential confounding variables, including age, sex, time since diagnosis, education, and comorbid conditions, the all-cause mortality was 46% lower when patients were on an antipsychotic agent than when off therapy.
The lowest mortality was observed in patients on a second-generation long-acting injectable (LAI) antipsychotic agent. Specifically, all-cause mortality was reduced by 89% while patients were on once-monthly palpiperidone palmitate LAI (Invega Sustenna) than during periods when they were not using an antipsychotic. They were 69% less likely to die while on risperidone LAI (Risperdal Consta), and 77% less likely to die while taking oral aripiprazole (Abilify).
In a pairwise comparison between the LAI and oral versions of antipsychotic agents, the LAIs were associated with a 33% lower mortality than the equivalent oral drugs.
Compared with periods of nonuse of any antipsychotic agent, the adjusted risk of mortality was reduced by 85% while patients were on a second-generation LAI, by 47% when on second-generation oral agents, by 36% with first-generation LAIs, and by 34% for first-generation oral antipsychotics.
Also at the ECNP congress, Dr. Tiihonen presented a separate analysis of the same cohort of 29,823 patients, this time examining the real-world effectiveness of various antipsychotic agents in preventing relapse, treatment failure, and rehospitalization. For this purpose, he and his coinvestigators performed a within-individual analysis in which each patient served as his or her own control. The advantage of this analytic strategy is that it corrects for selection bias and other forms of residual confounding inherent in observational studies.
During 7 years of follow-up, 44% of patients were rehospitalized. The risk of psychiatric rehospitalization was lowest when patients were on monotherapy with once-monthly palpiperidone LAI, as evidenced by a 49% reduction, compared with no use of antipsychotic agents. Clozapine (Clozaril) monotherapy and zuclopenthixol LAI (Clopixol) were similarly effective, with each conferring a 47% reduction in rehospitalization risk, compared with periods off therapy. Perphenazine LAI (Trilafon) and olanzapine LAI (Relprevv) each brought a 42% reduction in rehospitalization risk, while the oral version of perphenazine was associated with a 14% risk reduction.
In contrast, the risk of rehospitalization when patients were on oral flupentixol (Depixol) or quetiapine (Seroquel) was not significantly different from when they were off antipsychotic agents altogether.
Collectively, the LAIs were associated with a 22% lower risk of rehospitalization, compared with their equivalent oral versions. And among the 4,603 patients newly diagnosed with schizophrenia in 2006, the LAIs were associated with a more substantial 32% risk reduction, compared with their oral formulations.
Oral clozapine had the lowest treatment failure rate: 42% less than with oral olanzapine (Zyprexa), which served as the reference standard because it was the most commonly used antipsychotic agent. Treatment failure was defined as psychiatric rehospitalization, attempted suicide, treatment discontinuation or a switch to another antipsychotic agent, or death. The various LAIs were associated with 20%-35% lower treatment failure rates than oral olanzapine.
Dr. Tiihonen’s relapse prevention analysis has been published (JAMA Psychiatry. 2017 Jul 1;74[7]:686-93).
The two studies were funded by Janssen-Cilag. Dr. Tiihonen reported serving as a consultant to that pharmaceutical company and a half-dozen others.
PARIS – All-cause mortality was 46% lower while schizophrenia patients were on antipsychotic agents than when off therapy in a nationwide observational study of nearly 30,000 Swedes with schizophrenia – and the biggest risk reduction occurred in patients on second-generation long-acting injectables, according to Jari Tiihonen, MD, PhD.
“The guidelines say there are special situations where you should consider using depot antipsychotics. I think the guidelines got it wrong. I think the right way to think of it is there are special situations where you might consider oral agents; otherwise you should use long-acting injectables,” said Dr. Tiihonen, who holds joint appointments as professor of psychiatry at the University of Eastern Finland in Kuopio and the Karolinska Institute in Stockholm.
During a mean follow-up of 5.7 years, 8.4% of the patients died. In a multivariate Cox regression analysis adjusted for 20 potential confounding variables, including age, sex, time since diagnosis, education, and comorbid conditions, the all-cause mortality was 46% lower when patients were on an antipsychotic agent than when off therapy.
The lowest mortality was observed in patients on a second-generation long-acting injectable (LAI) antipsychotic agent. Specifically, all-cause mortality was reduced by 89% while patients were on once-monthly palpiperidone palmitate LAI (Invega Sustenna) than during periods when they were not using an antipsychotic. They were 69% less likely to die while on risperidone LAI (Risperdal Consta), and 77% less likely to die while taking oral aripiprazole (Abilify).
In a pairwise comparison between the LAI and oral versions of antipsychotic agents, the LAIs were associated with a 33% lower mortality than the equivalent oral drugs.
Compared with periods of nonuse of any antipsychotic agent, the adjusted risk of mortality was reduced by 85% while patients were on a second-generation LAI, by 47% when on second-generation oral agents, by 36% with first-generation LAIs, and by 34% for first-generation oral antipsychotics.
Also at the ECNP congress, Dr. Tiihonen presented a separate analysis of the same cohort of 29,823 patients, this time examining the real-world effectiveness of various antipsychotic agents in preventing relapse, treatment failure, and rehospitalization. For this purpose, he and his coinvestigators performed a within-individual analysis in which each patient served as his or her own control. The advantage of this analytic strategy is that it corrects for selection bias and other forms of residual confounding inherent in observational studies.
During 7 years of follow-up, 44% of patients were rehospitalized. The risk of psychiatric rehospitalization was lowest when patients were on monotherapy with once-monthly palpiperidone LAI, as evidenced by a 49% reduction, compared with no use of antipsychotic agents. Clozapine (Clozaril) monotherapy and zuclopenthixol LAI (Clopixol) were similarly effective, with each conferring a 47% reduction in rehospitalization risk, compared with periods off therapy. Perphenazine LAI (Trilafon) and olanzapine LAI (Relprevv) each brought a 42% reduction in rehospitalization risk, while the oral version of perphenazine was associated with a 14% risk reduction.
In contrast, the risk of rehospitalization when patients were on oral flupentixol (Depixol) or quetiapine (Seroquel) was not significantly different from when they were off antipsychotic agents altogether.
Collectively, the LAIs were associated with a 22% lower risk of rehospitalization, compared with their equivalent oral versions. And among the 4,603 patients newly diagnosed with schizophrenia in 2006, the LAIs were associated with a more substantial 32% risk reduction, compared with their oral formulations.
Oral clozapine had the lowest treatment failure rate: 42% less than with oral olanzapine (Zyprexa), which served as the reference standard because it was the most commonly used antipsychotic agent. Treatment failure was defined as psychiatric rehospitalization, attempted suicide, treatment discontinuation or a switch to another antipsychotic agent, or death. The various LAIs were associated with 20%-35% lower treatment failure rates than oral olanzapine.
Dr. Tiihonen’s relapse prevention analysis has been published (JAMA Psychiatry. 2017 Jul 1;74[7]:686-93).
The two studies were funded by Janssen-Cilag. Dr. Tiihonen reported serving as a consultant to that pharmaceutical company and a half-dozen others.
PARIS – All-cause mortality was 46% lower while schizophrenia patients were on antipsychotic agents than when off therapy in a nationwide observational study of nearly 30,000 Swedes with schizophrenia – and the biggest risk reduction occurred in patients on second-generation long-acting injectables, according to Jari Tiihonen, MD, PhD.
“The guidelines say there are special situations where you should consider using depot antipsychotics. I think the guidelines got it wrong. I think the right way to think of it is there are special situations where you might consider oral agents; otherwise you should use long-acting injectables,” said Dr. Tiihonen, who holds joint appointments as professor of psychiatry at the University of Eastern Finland in Kuopio and the Karolinska Institute in Stockholm.
During a mean follow-up of 5.7 years, 8.4% of the patients died. In a multivariate Cox regression analysis adjusted for 20 potential confounding variables, including age, sex, time since diagnosis, education, and comorbid conditions, the all-cause mortality was 46% lower when patients were on an antipsychotic agent than when off therapy.
The lowest mortality was observed in patients on a second-generation long-acting injectable (LAI) antipsychotic agent. Specifically, all-cause mortality was reduced by 89% while patients were on once-monthly palpiperidone palmitate LAI (Invega Sustenna) than during periods when they were not using an antipsychotic. They were 69% less likely to die while on risperidone LAI (Risperdal Consta), and 77% less likely to die while taking oral aripiprazole (Abilify).
In a pairwise comparison between the LAI and oral versions of antipsychotic agents, the LAIs were associated with a 33% lower mortality than the equivalent oral drugs.
Compared with periods of nonuse of any antipsychotic agent, the adjusted risk of mortality was reduced by 85% while patients were on a second-generation LAI, by 47% when on second-generation oral agents, by 36% with first-generation LAIs, and by 34% for first-generation oral antipsychotics.
Also at the ECNP congress, Dr. Tiihonen presented a separate analysis of the same cohort of 29,823 patients, this time examining the real-world effectiveness of various antipsychotic agents in preventing relapse, treatment failure, and rehospitalization. For this purpose, he and his coinvestigators performed a within-individual analysis in which each patient served as his or her own control. The advantage of this analytic strategy is that it corrects for selection bias and other forms of residual confounding inherent in observational studies.
During 7 years of follow-up, 44% of patients were rehospitalized. The risk of psychiatric rehospitalization was lowest when patients were on monotherapy with once-monthly palpiperidone LAI, as evidenced by a 49% reduction, compared with no use of antipsychotic agents. Clozapine (Clozaril) monotherapy and zuclopenthixol LAI (Clopixol) were similarly effective, with each conferring a 47% reduction in rehospitalization risk, compared with periods off therapy. Perphenazine LAI (Trilafon) and olanzapine LAI (Relprevv) each brought a 42% reduction in rehospitalization risk, while the oral version of perphenazine was associated with a 14% risk reduction.
In contrast, the risk of rehospitalization when patients were on oral flupentixol (Depixol) or quetiapine (Seroquel) was not significantly different from when they were off antipsychotic agents altogether.
Collectively, the LAIs were associated with a 22% lower risk of rehospitalization, compared with their equivalent oral versions. And among the 4,603 patients newly diagnosed with schizophrenia in 2006, the LAIs were associated with a more substantial 32% risk reduction, compared with their oral formulations.
Oral clozapine had the lowest treatment failure rate: 42% less than with oral olanzapine (Zyprexa), which served as the reference standard because it was the most commonly used antipsychotic agent. Treatment failure was defined as psychiatric rehospitalization, attempted suicide, treatment discontinuation or a switch to another antipsychotic agent, or death. The various LAIs were associated with 20%-35% lower treatment failure rates than oral olanzapine.
Dr. Tiihonen’s relapse prevention analysis has been published (JAMA Psychiatry. 2017 Jul 1;74[7]:686-93).
The two studies were funded by Janssen-Cilag. Dr. Tiihonen reported serving as a consultant to that pharmaceutical company and a half-dozen others.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: The all-cause mortality rate was 85% lower when patients with schizophrenia were on a second-generation long-acting injectable antipsychotic than when not taking an antipsychotic.
Data source: An observational study of the association between antipsychotic medication use and all-cause mortality over the course of more than half a decade in nearly 30,000 Swedish schizophrenia patients.
Disclosures: The study was funded by Janssen-Cilag. The presenter reported serving as a consultant to that pharmaceutical company and a half-dozen others.
Screening tool spots teens headed for substance-dependent adulthood
VIENNA – The creation of a simple risk score that accurately predicts which adolescents in the general population will develop persistent substance dependence as adults has been one of the highlights of the year in addiction medicine, Wim van den Brink, MD, said at the annual congress of the European College of Neuropsychopharmacology.
“These predictors are not very difficult to assess. Clinicians will be interested to know that the positive predictive value of the screen is threefold greater than the persistent prevalence rate,” noted Dr. van den Brink, professor of psychiatry and addiction at the University of Amsterdam and director of the Amsterdam Institute for Addiction Research.
The New Zealand researchers developed what they call “a universal screening tool” by working backward in an analysis of a representative group of 1,037 individuals born in Dunedin, New Zealand, in 1972-1973 and prospectively followed to age 38 years, with a 95% study retention rate. Along the way, participants were assessed for dependence on alcohol, tobacco, cannabis, or hard drugs at ages 21, 26, 32, and 38.
Persistent substance dependence in adulthood, defined as dependence at a minimum of three of the assessments, was present in 19% of subjects.
The investigators found that the presence in childhood or adolescence of any four of nine risk factors had an area under the curve of 80% for persistent substance dependence as an adult. The sensitivity was 43%, with a 93% specificity. The positive predictive value was 60%, and the negative predictive value was 87% (Psychol Med. 2016 Mar;46[4]:877-89).
The nine risk factors are low family socioeconomic status, a family history of substance dependence, childhood depression, childhood conduct disorder, early exposure to substances, adolescent frequent alcohol use, adolescent frequent cannabis use, male gender, and adolescent frequent tobacco use.
The single least potent predictor was low family socioeconomic status, with an associated 1.73-fold increased risk. The strongest predictors were adolescent frequent tobacco use, which conferred a 5.41-fold increased risk; adolescent frequent cannabis use, with a 4.25-fold risk; and childhood conduct disorder, with a 3.2-fold increased risk.
The investigators also analyzed the screening tool’s performance in predicting a modified outcome consisting of adult persistent dependence on any of the target substances except for tobacco. The predictive power of having any four of the risk factors was similar to that found in the main analysis; however, the two strongest predictors now became adolescent frequent cannabis use, with a 9.5-fold increased risk, and childhood conduct disorder, with a relative risk of 5.42.
Regarding childhood conduct disorder as a risk factor, Dr. van den Brink said, “If you are a child with conduct disorder, your chances of becoming substance dependent in coming years is more than fivefold greater than in a child without conduct disorder.”
This raises the question of whether effective treatment of childhood conduct disorder might prevent later development of persistent substance dependence in adulthood. The answer remains unknown. Although there is no approved drug therapy for conduct disorder, methylphenidate is widely prescribed, especially in young patients with comorbid attention-deficit/hyperactivity disorder.
Several years ago a meta-analysis of 15 longitudinal studies with more than 2,500 participants concluded that stimulant therapy of childhood ADHD neither increased nor reduced the risk of subsequent substance use disorders (JAMA Psychiatry. 2013 Jul;70[7]:740-9). Prescribing physicians were happy to hear they weren’t causing iatrogenic injury, but Dr. van den Brink said he was never comfortable with the investigators’ conclusion.
“There was a lot of heterogeneity in the data, so the overall conclusion might not be the best conclusion,” he said.
He said has become more convinced of that than ever as a result of a recent randomized, double-blind, placebo-controlled MRI study of cerebral blood flow in response to methylphenidate in stimulant-naive patients with childhood or adult AHDH. The investigators found that MRIs obtained 1 week after the conclusion of 16 weeks of methylphenidate therapy showed increased blood flow in the strial and thalamic areas in the pediatric ADHD patients but not in the adults with ADHD (JAMA Psychiatry. 2016 Sep 1;73[9]:955-62).
This is evidence of an age-dependent sustained effect of methylphenidate therapy on dopamine striatal-thalamic circuitry in children that’s not related to the drug’s clinical effects, which were gone after a week off therapy. The question is, Does this effect represent neurotoxicity, or is it an expression of enhanced brain maturation? Dr. van den Brink said he suspects it’s the latter but cannot exclude the former possibility.
VIENNA – The creation of a simple risk score that accurately predicts which adolescents in the general population will develop persistent substance dependence as adults has been one of the highlights of the year in addiction medicine, Wim van den Brink, MD, said at the annual congress of the European College of Neuropsychopharmacology.
“These predictors are not very difficult to assess. Clinicians will be interested to know that the positive predictive value of the screen is threefold greater than the persistent prevalence rate,” noted Dr. van den Brink, professor of psychiatry and addiction at the University of Amsterdam and director of the Amsterdam Institute for Addiction Research.
The New Zealand researchers developed what they call “a universal screening tool” by working backward in an analysis of a representative group of 1,037 individuals born in Dunedin, New Zealand, in 1972-1973 and prospectively followed to age 38 years, with a 95% study retention rate. Along the way, participants were assessed for dependence on alcohol, tobacco, cannabis, or hard drugs at ages 21, 26, 32, and 38.
Persistent substance dependence in adulthood, defined as dependence at a minimum of three of the assessments, was present in 19% of subjects.
The investigators found that the presence in childhood or adolescence of any four of nine risk factors had an area under the curve of 80% for persistent substance dependence as an adult. The sensitivity was 43%, with a 93% specificity. The positive predictive value was 60%, and the negative predictive value was 87% (Psychol Med. 2016 Mar;46[4]:877-89).
The nine risk factors are low family socioeconomic status, a family history of substance dependence, childhood depression, childhood conduct disorder, early exposure to substances, adolescent frequent alcohol use, adolescent frequent cannabis use, male gender, and adolescent frequent tobacco use.
The single least potent predictor was low family socioeconomic status, with an associated 1.73-fold increased risk. The strongest predictors were adolescent frequent tobacco use, which conferred a 5.41-fold increased risk; adolescent frequent cannabis use, with a 4.25-fold risk; and childhood conduct disorder, with a 3.2-fold increased risk.
The investigators also analyzed the screening tool’s performance in predicting a modified outcome consisting of adult persistent dependence on any of the target substances except for tobacco. The predictive power of having any four of the risk factors was similar to that found in the main analysis; however, the two strongest predictors now became adolescent frequent cannabis use, with a 9.5-fold increased risk, and childhood conduct disorder, with a relative risk of 5.42.
Regarding childhood conduct disorder as a risk factor, Dr. van den Brink said, “If you are a child with conduct disorder, your chances of becoming substance dependent in coming years is more than fivefold greater than in a child without conduct disorder.”
This raises the question of whether effective treatment of childhood conduct disorder might prevent later development of persistent substance dependence in adulthood. The answer remains unknown. Although there is no approved drug therapy for conduct disorder, methylphenidate is widely prescribed, especially in young patients with comorbid attention-deficit/hyperactivity disorder.
Several years ago a meta-analysis of 15 longitudinal studies with more than 2,500 participants concluded that stimulant therapy of childhood ADHD neither increased nor reduced the risk of subsequent substance use disorders (JAMA Psychiatry. 2013 Jul;70[7]:740-9). Prescribing physicians were happy to hear they weren’t causing iatrogenic injury, but Dr. van den Brink said he was never comfortable with the investigators’ conclusion.
“There was a lot of heterogeneity in the data, so the overall conclusion might not be the best conclusion,” he said.
He said has become more convinced of that than ever as a result of a recent randomized, double-blind, placebo-controlled MRI study of cerebral blood flow in response to methylphenidate in stimulant-naive patients with childhood or adult AHDH. The investigators found that MRIs obtained 1 week after the conclusion of 16 weeks of methylphenidate therapy showed increased blood flow in the strial and thalamic areas in the pediatric ADHD patients but not in the adults with ADHD (JAMA Psychiatry. 2016 Sep 1;73[9]:955-62).
This is evidence of an age-dependent sustained effect of methylphenidate therapy on dopamine striatal-thalamic circuitry in children that’s not related to the drug’s clinical effects, which were gone after a week off therapy. The question is, Does this effect represent neurotoxicity, or is it an expression of enhanced brain maturation? Dr. van den Brink said he suspects it’s the latter but cannot exclude the former possibility.
VIENNA – The creation of a simple risk score that accurately predicts which adolescents in the general population will develop persistent substance dependence as adults has been one of the highlights of the year in addiction medicine, Wim van den Brink, MD, said at the annual congress of the European College of Neuropsychopharmacology.
“These predictors are not very difficult to assess. Clinicians will be interested to know that the positive predictive value of the screen is threefold greater than the persistent prevalence rate,” noted Dr. van den Brink, professor of psychiatry and addiction at the University of Amsterdam and director of the Amsterdam Institute for Addiction Research.
The New Zealand researchers developed what they call “a universal screening tool” by working backward in an analysis of a representative group of 1,037 individuals born in Dunedin, New Zealand, in 1972-1973 and prospectively followed to age 38 years, with a 95% study retention rate. Along the way, participants were assessed for dependence on alcohol, tobacco, cannabis, or hard drugs at ages 21, 26, 32, and 38.
Persistent substance dependence in adulthood, defined as dependence at a minimum of three of the assessments, was present in 19% of subjects.
The investigators found that the presence in childhood or adolescence of any four of nine risk factors had an area under the curve of 80% for persistent substance dependence as an adult. The sensitivity was 43%, with a 93% specificity. The positive predictive value was 60%, and the negative predictive value was 87% (Psychol Med. 2016 Mar;46[4]:877-89).
The nine risk factors are low family socioeconomic status, a family history of substance dependence, childhood depression, childhood conduct disorder, early exposure to substances, adolescent frequent alcohol use, adolescent frequent cannabis use, male gender, and adolescent frequent tobacco use.
The single least potent predictor was low family socioeconomic status, with an associated 1.73-fold increased risk. The strongest predictors were adolescent frequent tobacco use, which conferred a 5.41-fold increased risk; adolescent frequent cannabis use, with a 4.25-fold risk; and childhood conduct disorder, with a 3.2-fold increased risk.
The investigators also analyzed the screening tool’s performance in predicting a modified outcome consisting of adult persistent dependence on any of the target substances except for tobacco. The predictive power of having any four of the risk factors was similar to that found in the main analysis; however, the two strongest predictors now became adolescent frequent cannabis use, with a 9.5-fold increased risk, and childhood conduct disorder, with a relative risk of 5.42.
Regarding childhood conduct disorder as a risk factor, Dr. van den Brink said, “If you are a child with conduct disorder, your chances of becoming substance dependent in coming years is more than fivefold greater than in a child without conduct disorder.”
This raises the question of whether effective treatment of childhood conduct disorder might prevent later development of persistent substance dependence in adulthood. The answer remains unknown. Although there is no approved drug therapy for conduct disorder, methylphenidate is widely prescribed, especially in young patients with comorbid attention-deficit/hyperactivity disorder.
Several years ago a meta-analysis of 15 longitudinal studies with more than 2,500 participants concluded that stimulant therapy of childhood ADHD neither increased nor reduced the risk of subsequent substance use disorders (JAMA Psychiatry. 2013 Jul;70[7]:740-9). Prescribing physicians were happy to hear they weren’t causing iatrogenic injury, but Dr. van den Brink said he was never comfortable with the investigators’ conclusion.
“There was a lot of heterogeneity in the data, so the overall conclusion might not be the best conclusion,” he said.
He said has become more convinced of that than ever as a result of a recent randomized, double-blind, placebo-controlled MRI study of cerebral blood flow in response to methylphenidate in stimulant-naive patients with childhood or adult AHDH. The investigators found that MRIs obtained 1 week after the conclusion of 16 weeks of methylphenidate therapy showed increased blood flow in the strial and thalamic areas in the pediatric ADHD patients but not in the adults with ADHD (JAMA Psychiatry. 2016 Sep 1;73[9]:955-62).
This is evidence of an age-dependent sustained effect of methylphenidate therapy on dopamine striatal-thalamic circuitry in children that’s not related to the drug’s clinical effects, which were gone after a week off therapy. The question is, Does this effect represent neurotoxicity, or is it an expression of enhanced brain maturation? Dr. van den Brink said he suspects it’s the latter but cannot exclude the former possibility.
EXPERT ANALYSIS FROM THE ECNP CONGRESS
