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Who fares best after successful ECT?
PARIS – , Pascal Sienaert, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This conclusion is based on the results of two prospective studies by ResPECT – the Research in Psychiatry and ECT by the Flemish-Dutch Research Consortium – which, in turn, confirm the findings of an earlier metaanalysis of 32 studies including 702 patients conducted by investigators at Trinity College Dublin, noted Dr. Sienaert, a psychiatrist at the Catholic University of Leuven (Belgium) Academic Center for ECT and Neuromodulation.
Dr. Sienaert noted that the relapse rate in the ECT metaanalysis is nearly identical to that reported in the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial in real-world patients with major depression who achieved remission in response to second-step or later antidepressant medication.
“It’s a common misconception that relapse is higher after ECT than medication,” the psychiatrist said.
In the ECT metaanalysis, continuation ECT after induction of remission did not substantially affect the relapse risk. But that’s because the prevailing maintenance ECT strategy in the studies included in the 2013 metaanalysis relied upon a fixed-dose treatment schedule, according to Dr. Sienaert.
“In most studies, fixed-schedule maintenance ECT is used and with rather high relapse rates. Most clinicians have the experience that flexible, clinically driven on an as-needed-basis maintenance ECT has lower relapse rates,” he said. “Still, relapse remains the most pressing issue in the field, and it is very difficult for us as clinicians to predict which patients will relapse and which will not.”
That’s where the two ResPECT studies come into play.
In one of the studies, 116 patients with major depression at three tertiary psychiatric hospitals were randomized double blind to twice-weekly high-dose ultrabrief pulse (0.3-0.4 milliseconds) right unilateral or high-dose brief pulse (1.0 millisecond) right unilateral ECT. The dosing was at eight times the seizure threshold until remission as defined by a Montgomery-Åsberg Depression Rating Scale (MADRS) score below 10 or for a maximum of 6 weeks. Among the 87 completers, the remission rate was 68% in the brief pulse group, significantly higher than the 49% rate with ultrabrief ECT. Cognitive effects on semantic and lexical memory, and retrograde amnesia were the same in the two groups (J Clin Psychiatry. 2013 Nov;74[11]:e1029-36).
Dr. Sienaert and his coinvestigators then prospectively followed the 50 remitters for 6 months, during which all but one patient remained on antidepressant medication. The relapse rate, defined as rehospitalization for depression, restart of ECT, suicide, or a MADRS score above 15, was 25% at 3 months and about 40% at 6 months. The investigators found several predictors of a lower relapse rate. The strongest was early complete remission as defined by a Clinical Global Impressions Scale score of 1 out of a maximum of a possible 7 points within the first four ECT sessions: The 6-month relapse rate was 10% among those early complete remitters versus 63% in the other remitters (J Affect Disord. 2015 Sep 15;184:137-44).
“These are very small numbers in these groups, but the signal that emerges is the same as we have seen in the Irish metaanalysis: Early complete remitters were older, had shorter current episodes of depression, and showed more baseline psychotic features,” Dr. Sienaert said.
In a more recent ResPECT consortium study, the Mood Disorders in Elderly Treated With ECT (MODECT) study, 110 patients aged 55 and older with unipolar depression treated by ECT were followed with serial brain imaging studies prior to and for 6 months post treatment in an effort to gain insight into the mechanism of the particularly strong benefit of ECT in late-life depression. The response rate to ECT was significantly higher in those with onset of depression at age 55 or older than in those with disease onset before age 55, by a margin of 87% vs. 67%. The presence of baseline psychotic symptoms also was associated with a higher response rate.
In contrast, treatment response proved unrelated to changes in hippocampal volume, white matter hypersensitivities, amyloid load, or serum brain-derived neurotrophic factor, which is believed to be an important mediator of neuroplasticity. Thus, ECT’s mechanism of action in late-life depression remains elusive, the authors reported (Am J Geriatr Psychiatry. 2017 Feb;25[2]:178-89).
In a separate study, Dr. Sienaert and his colleagues found that ECT’s superior efficacy, compared with antidepressant medication in patients with late-life depression, was independent of their vascular disease burden. The study population was comprised of 81 patients in an antidepressant drug trial and 43 in an ECT trial, all of whom were inpatients with unipolar major depression. Their mean age was in the mid-70s.
The investigators gauged vascular burden by adding up each patient’s number of vascular risk factors, namely, diabetes, hypertension, smoking, hypercholesterolemia, known cardiovascular disease, and cerebrovascular disease. The depression remission rate was 80% in the ECT patients with no vascular risk factors, dropping to 58% in those with one or more. In the antidepressant drug trial participants, the remission rate was 38% in those with no vascular risk factors, compared with 32% in patients with one or more. Using different cutoffs for the number of vascular risk factors did not significantly alter the results (Int J Geriatr Psychiatry. 2017 Jun 28. doi: 10.1002/gps.4754).
At present, once a patient has achieved remission in response to ECT, most psychiatrists stop the therapy altogether. That’s often a mistake, according to session cochair Eduard Vieta, MD, PhD.
“. In many cases you need to continue ECT. Especially in patients who are refractory or treatment resistant, I don’t see a reason why maintenance ECT shouldn’t be the first choice. Yet in the guidelines, ECT is always the third- or fourth-line therapy,” said Dr. Vieta, professor of psychiatry at the University of Barcelona and scientific director of the Spanish Research Network on Mental Diseases.
Dr. Sienaert concurred, adding that he has patients who are on weekly maintenance ECT for as long as 16 years, with continued good results.
He reported having received honoraria from Mecta, a manufacturer of ECT equipment.
[email protected]
PARIS – , Pascal Sienaert, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This conclusion is based on the results of two prospective studies by ResPECT – the Research in Psychiatry and ECT by the Flemish-Dutch Research Consortium – which, in turn, confirm the findings of an earlier metaanalysis of 32 studies including 702 patients conducted by investigators at Trinity College Dublin, noted Dr. Sienaert, a psychiatrist at the Catholic University of Leuven (Belgium) Academic Center for ECT and Neuromodulation.
Dr. Sienaert noted that the relapse rate in the ECT metaanalysis is nearly identical to that reported in the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial in real-world patients with major depression who achieved remission in response to second-step or later antidepressant medication.
“It’s a common misconception that relapse is higher after ECT than medication,” the psychiatrist said.
In the ECT metaanalysis, continuation ECT after induction of remission did not substantially affect the relapse risk. But that’s because the prevailing maintenance ECT strategy in the studies included in the 2013 metaanalysis relied upon a fixed-dose treatment schedule, according to Dr. Sienaert.
“In most studies, fixed-schedule maintenance ECT is used and with rather high relapse rates. Most clinicians have the experience that flexible, clinically driven on an as-needed-basis maintenance ECT has lower relapse rates,” he said. “Still, relapse remains the most pressing issue in the field, and it is very difficult for us as clinicians to predict which patients will relapse and which will not.”
That’s where the two ResPECT studies come into play.
In one of the studies, 116 patients with major depression at three tertiary psychiatric hospitals were randomized double blind to twice-weekly high-dose ultrabrief pulse (0.3-0.4 milliseconds) right unilateral or high-dose brief pulse (1.0 millisecond) right unilateral ECT. The dosing was at eight times the seizure threshold until remission as defined by a Montgomery-Åsberg Depression Rating Scale (MADRS) score below 10 or for a maximum of 6 weeks. Among the 87 completers, the remission rate was 68% in the brief pulse group, significantly higher than the 49% rate with ultrabrief ECT. Cognitive effects on semantic and lexical memory, and retrograde amnesia were the same in the two groups (J Clin Psychiatry. 2013 Nov;74[11]:e1029-36).
Dr. Sienaert and his coinvestigators then prospectively followed the 50 remitters for 6 months, during which all but one patient remained on antidepressant medication. The relapse rate, defined as rehospitalization for depression, restart of ECT, suicide, or a MADRS score above 15, was 25% at 3 months and about 40% at 6 months. The investigators found several predictors of a lower relapse rate. The strongest was early complete remission as defined by a Clinical Global Impressions Scale score of 1 out of a maximum of a possible 7 points within the first four ECT sessions: The 6-month relapse rate was 10% among those early complete remitters versus 63% in the other remitters (J Affect Disord. 2015 Sep 15;184:137-44).
“These are very small numbers in these groups, but the signal that emerges is the same as we have seen in the Irish metaanalysis: Early complete remitters were older, had shorter current episodes of depression, and showed more baseline psychotic features,” Dr. Sienaert said.
In a more recent ResPECT consortium study, the Mood Disorders in Elderly Treated With ECT (MODECT) study, 110 patients aged 55 and older with unipolar depression treated by ECT were followed with serial brain imaging studies prior to and for 6 months post treatment in an effort to gain insight into the mechanism of the particularly strong benefit of ECT in late-life depression. The response rate to ECT was significantly higher in those with onset of depression at age 55 or older than in those with disease onset before age 55, by a margin of 87% vs. 67%. The presence of baseline psychotic symptoms also was associated with a higher response rate.
In contrast, treatment response proved unrelated to changes in hippocampal volume, white matter hypersensitivities, amyloid load, or serum brain-derived neurotrophic factor, which is believed to be an important mediator of neuroplasticity. Thus, ECT’s mechanism of action in late-life depression remains elusive, the authors reported (Am J Geriatr Psychiatry. 2017 Feb;25[2]:178-89).
In a separate study, Dr. Sienaert and his colleagues found that ECT’s superior efficacy, compared with antidepressant medication in patients with late-life depression, was independent of their vascular disease burden. The study population was comprised of 81 patients in an antidepressant drug trial and 43 in an ECT trial, all of whom were inpatients with unipolar major depression. Their mean age was in the mid-70s.
The investigators gauged vascular burden by adding up each patient’s number of vascular risk factors, namely, diabetes, hypertension, smoking, hypercholesterolemia, known cardiovascular disease, and cerebrovascular disease. The depression remission rate was 80% in the ECT patients with no vascular risk factors, dropping to 58% in those with one or more. In the antidepressant drug trial participants, the remission rate was 38% in those with no vascular risk factors, compared with 32% in patients with one or more. Using different cutoffs for the number of vascular risk factors did not significantly alter the results (Int J Geriatr Psychiatry. 2017 Jun 28. doi: 10.1002/gps.4754).
At present, once a patient has achieved remission in response to ECT, most psychiatrists stop the therapy altogether. That’s often a mistake, according to session cochair Eduard Vieta, MD, PhD.
“. In many cases you need to continue ECT. Especially in patients who are refractory or treatment resistant, I don’t see a reason why maintenance ECT shouldn’t be the first choice. Yet in the guidelines, ECT is always the third- or fourth-line therapy,” said Dr. Vieta, professor of psychiatry at the University of Barcelona and scientific director of the Spanish Research Network on Mental Diseases.
Dr. Sienaert concurred, adding that he has patients who are on weekly maintenance ECT for as long as 16 years, with continued good results.
He reported having received honoraria from Mecta, a manufacturer of ECT equipment.
[email protected]
PARIS – , Pascal Sienaert, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This conclusion is based on the results of two prospective studies by ResPECT – the Research in Psychiatry and ECT by the Flemish-Dutch Research Consortium – which, in turn, confirm the findings of an earlier metaanalysis of 32 studies including 702 patients conducted by investigators at Trinity College Dublin, noted Dr. Sienaert, a psychiatrist at the Catholic University of Leuven (Belgium) Academic Center for ECT and Neuromodulation.
Dr. Sienaert noted that the relapse rate in the ECT metaanalysis is nearly identical to that reported in the landmark Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial in real-world patients with major depression who achieved remission in response to second-step or later antidepressant medication.
“It’s a common misconception that relapse is higher after ECT than medication,” the psychiatrist said.
In the ECT metaanalysis, continuation ECT after induction of remission did not substantially affect the relapse risk. But that’s because the prevailing maintenance ECT strategy in the studies included in the 2013 metaanalysis relied upon a fixed-dose treatment schedule, according to Dr. Sienaert.
“In most studies, fixed-schedule maintenance ECT is used and with rather high relapse rates. Most clinicians have the experience that flexible, clinically driven on an as-needed-basis maintenance ECT has lower relapse rates,” he said. “Still, relapse remains the most pressing issue in the field, and it is very difficult for us as clinicians to predict which patients will relapse and which will not.”
That’s where the two ResPECT studies come into play.
In one of the studies, 116 patients with major depression at three tertiary psychiatric hospitals were randomized double blind to twice-weekly high-dose ultrabrief pulse (0.3-0.4 milliseconds) right unilateral or high-dose brief pulse (1.0 millisecond) right unilateral ECT. The dosing was at eight times the seizure threshold until remission as defined by a Montgomery-Åsberg Depression Rating Scale (MADRS) score below 10 or for a maximum of 6 weeks. Among the 87 completers, the remission rate was 68% in the brief pulse group, significantly higher than the 49% rate with ultrabrief ECT. Cognitive effects on semantic and lexical memory, and retrograde amnesia were the same in the two groups (J Clin Psychiatry. 2013 Nov;74[11]:e1029-36).
Dr. Sienaert and his coinvestigators then prospectively followed the 50 remitters for 6 months, during which all but one patient remained on antidepressant medication. The relapse rate, defined as rehospitalization for depression, restart of ECT, suicide, or a MADRS score above 15, was 25% at 3 months and about 40% at 6 months. The investigators found several predictors of a lower relapse rate. The strongest was early complete remission as defined by a Clinical Global Impressions Scale score of 1 out of a maximum of a possible 7 points within the first four ECT sessions: The 6-month relapse rate was 10% among those early complete remitters versus 63% in the other remitters (J Affect Disord. 2015 Sep 15;184:137-44).
“These are very small numbers in these groups, but the signal that emerges is the same as we have seen in the Irish metaanalysis: Early complete remitters were older, had shorter current episodes of depression, and showed more baseline psychotic features,” Dr. Sienaert said.
In a more recent ResPECT consortium study, the Mood Disorders in Elderly Treated With ECT (MODECT) study, 110 patients aged 55 and older with unipolar depression treated by ECT were followed with serial brain imaging studies prior to and for 6 months post treatment in an effort to gain insight into the mechanism of the particularly strong benefit of ECT in late-life depression. The response rate to ECT was significantly higher in those with onset of depression at age 55 or older than in those with disease onset before age 55, by a margin of 87% vs. 67%. The presence of baseline psychotic symptoms also was associated with a higher response rate.
In contrast, treatment response proved unrelated to changes in hippocampal volume, white matter hypersensitivities, amyloid load, or serum brain-derived neurotrophic factor, which is believed to be an important mediator of neuroplasticity. Thus, ECT’s mechanism of action in late-life depression remains elusive, the authors reported (Am J Geriatr Psychiatry. 2017 Feb;25[2]:178-89).
In a separate study, Dr. Sienaert and his colleagues found that ECT’s superior efficacy, compared with antidepressant medication in patients with late-life depression, was independent of their vascular disease burden. The study population was comprised of 81 patients in an antidepressant drug trial and 43 in an ECT trial, all of whom were inpatients with unipolar major depression. Their mean age was in the mid-70s.
The investigators gauged vascular burden by adding up each patient’s number of vascular risk factors, namely, diabetes, hypertension, smoking, hypercholesterolemia, known cardiovascular disease, and cerebrovascular disease. The depression remission rate was 80% in the ECT patients with no vascular risk factors, dropping to 58% in those with one or more. In the antidepressant drug trial participants, the remission rate was 38% in those with no vascular risk factors, compared with 32% in patients with one or more. Using different cutoffs for the number of vascular risk factors did not significantly alter the results (Int J Geriatr Psychiatry. 2017 Jun 28. doi: 10.1002/gps.4754).
At present, once a patient has achieved remission in response to ECT, most psychiatrists stop the therapy altogether. That’s often a mistake, according to session cochair Eduard Vieta, MD, PhD.
“. In many cases you need to continue ECT. Especially in patients who are refractory or treatment resistant, I don’t see a reason why maintenance ECT shouldn’t be the first choice. Yet in the guidelines, ECT is always the third- or fourth-line therapy,” said Dr. Vieta, professor of psychiatry at the University of Barcelona and scientific director of the Spanish Research Network on Mental Diseases.
Dr. Sienaert concurred, adding that he has patients who are on weekly maintenance ECT for as long as 16 years, with continued good results.
He reported having received honoraria from Mecta, a manufacturer of ECT equipment.
[email protected]
REPORTING FROM THE ECNP CONGRESS
MRI-guided neurofeedback improves ADHD long term in adolescent boys
PARIS – Neurofeedback based upon real-time functional magnetic resonance imaging resulted in long-term reduction in attention-deficit/hyperactivity disorder symptoms in adolescents in a randomized controlled proof-of-concept study, Katya Rubia, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
The effect size of the improvement when measured at follow-up 11 months after completing the functional MRI-based neurofeedback (fMRI-NF) training exercises was moderate to large and comparable to that of psychostimulant medication in published placebo-controlled clinical trials. But the effects of the medications last only 24 hours after administration, and the drugs have side effects.
Neurofeedback is an operant conditioning procedure, which, through trial and error, teaches patients to self-regulate specific areas of the brain involved in psychopathology. EEG-based neurofeedback for ADHD has been extensively studied, with generally small to medium effect sizes being reported. Morever, patients need to be very highly motivated in order to succeed at EEG-NF: It takes 30-40 EEG-NF sessions, each an hour long, in order to learn targeted brain self-control in ADHD, whereas in Dr. Rubia’s study, patients learned to self-regulate brain activity in an average of eight fMRI sessions, each lasting 8.5 minutes, over the course of 2 weeks. The far speedier learning curve is probably tied to the superior specificity of spatial localization afforded by fMRI neurofeedback, according to the neuroscientist.
Also, fMRI-NF can reach certain key regions of the brain involved in ADHD that EEG-NF cannot, most notably the inferior frontal cortex (IFC) and basal ganglia, she added.
The target region in the proof-of-concept study was the right IFC, an area important for cognitive control, attention, and timing. Functional neuroimaging studies consistently have shown that the right IFC is underactive in ADHD, and that psychostimulant medications upregulate this area. A dysfunctional right IFC is an ADHD-specific abnormality not present in children with obessive-compulsive disorder (JAMA Psychiatry. 2016 Aug 1;73[8]:815-25), conduct disorder, or autism.
“The IFC seems to be a very good functional biomarker for ADHD,” Dr. Rubia said.
The proof-of-concept study, published in Human Brain Mapping, included 31 boys with a DSM-5 diagnosis of ADHD, aged 12-17, who were randomized to fMRI-NF of the right IFC or, as a control condition, to fMRI-NF targeting the left parahippocampal gyrus. Two patients had the inattentive subtype of ADHD; the rest had the combined hyperactive/inattentive form. Parents and patients were blinded as to their study arm.
So this program uses neuroimaging as a treatment. It is neuroimaging employed as neurotherapy. To make the training experience more attractive to young patients, it was presented as a computer game: By making progress in controlling their brain activity, patients could launch a rocket ship on the screen. With further progress, they could send the rocket through the atmosphere into space and eventually land it on another planet.
The primary study endpoint was change in the ADHD Rating Scale. The group that targeted self-upregulation of right IFC activity showed roughly a 20% improvement in scores, from a baseline mean total score of 36.7 to 30.2 immediately post treatment, further improving to a score of 26.7 at roughly 11 months of follow-up. Mean scores on the inattention subscale improved from 19.8 to 15.9 immediately post treatment and 15.3 at follow-up. Scores on the hyperactivity/impulsivity subscale went from 16.9 before treatment to 14.2 after treatment and 11.5 at follow-up.
There were no side effects of fMRI-NF in either study arm.
However, a degree of uncertainty exists regarding the clinical significance of the results, Dr. Rubia said. That’s because the control group showed a similar degree of improvement in ADHD symptoms immediately after learning to upregulate the left parahippocampal gyrus, although their scores did backslide modestly during 11 months of follow-up, while the IFC group continued to improve.
Dr. Rubia acknowledged that this raises the possibility that the observed improvement in clinical symptoms achieved through fMRI-NF could be attributable to a placebo effect. However, she said she believes this is unlikely for several reasons. For one, brain scans showed that targeting either the right IFC or the left parahippocampal gyrus not only resulted in upregulation of activity in those specific regions, but throughout the broader neural networks of which they are a part. The right IFC upregulators showed activation of a bilateral dorsolateral prefrontal cortex/IFC-insular-striato-cerebellar cognitive control network. In contrast, the boys who targeted the left parahippocampal gyrus experienced activation of associated posterior visual-spatial attention regions, which are relevant to ADHD. This made for a far from ideal control group.
Also, the amount of improvement in ADHD symptoms in the right IFC-targeted group correlated with the degree of activation of that region, indicative of a brain-behavior correlation that speaks against a nonspecific effect.
Because this was a small, unpowered pilot study and interest remains intense in potential nonpharmacologic treatments for ADHD, the U.K. Medical Research Council is funding Dr. Rubia and her colleagues for a new 100-patient study – including a sham fMRI-NF arm – in order to definitively address the possibility of a placebo effect. The study also will attempt to pin down the patient population most likely to benefit from fMRI-NF. “It’s possible that the inattentive subtype of ADHD will respond best. Neurofeedback is, after all, a form of attention training,” she noted.
While real-time fMRI-NF might sound prohibitively expensive for widespread use in clinical practice for a disorder as common as ADHD, which has an estimated prevalence of about 7%, it might actually stack up reasonably well in a cost-benefit analysis, compared with ongoing medication costs and side effects or with a year’s worth of weekly psychotherapy, according to Dr. Rubia.
In parallel with the ongoing sham-controlled fMRI-NF study, Dr. Rubia also is conducting a clinical trial of transcranial direct current stimulation of the right IFC in combination with cognitive training. The idea is to study the clinical impact of directly upregulating activity in this area of the brain, bypassing the added step of training patients to gain self-control over this dysregulated region. The early findings, she said, look promising.
The fMRI-NF study (Hum Brain Mapp. 2017 Jun;38[6]:3190-209) was sponsored by the U.K. National Institute for Health Research and the Maudsley NHS Foundation Trust. Dr. Rubia reported receiving speakers honoraria from Lilly, Shire, and Medice.
Source: Rubia K et al. European College of Neuropsychopharmacology.
PARIS – Neurofeedback based upon real-time functional magnetic resonance imaging resulted in long-term reduction in attention-deficit/hyperactivity disorder symptoms in adolescents in a randomized controlled proof-of-concept study, Katya Rubia, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
The effect size of the improvement when measured at follow-up 11 months after completing the functional MRI-based neurofeedback (fMRI-NF) training exercises was moderate to large and comparable to that of psychostimulant medication in published placebo-controlled clinical trials. But the effects of the medications last only 24 hours after administration, and the drugs have side effects.
Neurofeedback is an operant conditioning procedure, which, through trial and error, teaches patients to self-regulate specific areas of the brain involved in psychopathology. EEG-based neurofeedback for ADHD has been extensively studied, with generally small to medium effect sizes being reported. Morever, patients need to be very highly motivated in order to succeed at EEG-NF: It takes 30-40 EEG-NF sessions, each an hour long, in order to learn targeted brain self-control in ADHD, whereas in Dr. Rubia’s study, patients learned to self-regulate brain activity in an average of eight fMRI sessions, each lasting 8.5 minutes, over the course of 2 weeks. The far speedier learning curve is probably tied to the superior specificity of spatial localization afforded by fMRI neurofeedback, according to the neuroscientist.
Also, fMRI-NF can reach certain key regions of the brain involved in ADHD that EEG-NF cannot, most notably the inferior frontal cortex (IFC) and basal ganglia, she added.
The target region in the proof-of-concept study was the right IFC, an area important for cognitive control, attention, and timing. Functional neuroimaging studies consistently have shown that the right IFC is underactive in ADHD, and that psychostimulant medications upregulate this area. A dysfunctional right IFC is an ADHD-specific abnormality not present in children with obessive-compulsive disorder (JAMA Psychiatry. 2016 Aug 1;73[8]:815-25), conduct disorder, or autism.
“The IFC seems to be a very good functional biomarker for ADHD,” Dr. Rubia said.
The proof-of-concept study, published in Human Brain Mapping, included 31 boys with a DSM-5 diagnosis of ADHD, aged 12-17, who were randomized to fMRI-NF of the right IFC or, as a control condition, to fMRI-NF targeting the left parahippocampal gyrus. Two patients had the inattentive subtype of ADHD; the rest had the combined hyperactive/inattentive form. Parents and patients were blinded as to their study arm.
So this program uses neuroimaging as a treatment. It is neuroimaging employed as neurotherapy. To make the training experience more attractive to young patients, it was presented as a computer game: By making progress in controlling their brain activity, patients could launch a rocket ship on the screen. With further progress, they could send the rocket through the atmosphere into space and eventually land it on another planet.
The primary study endpoint was change in the ADHD Rating Scale. The group that targeted self-upregulation of right IFC activity showed roughly a 20% improvement in scores, from a baseline mean total score of 36.7 to 30.2 immediately post treatment, further improving to a score of 26.7 at roughly 11 months of follow-up. Mean scores on the inattention subscale improved from 19.8 to 15.9 immediately post treatment and 15.3 at follow-up. Scores on the hyperactivity/impulsivity subscale went from 16.9 before treatment to 14.2 after treatment and 11.5 at follow-up.
There were no side effects of fMRI-NF in either study arm.
However, a degree of uncertainty exists regarding the clinical significance of the results, Dr. Rubia said. That’s because the control group showed a similar degree of improvement in ADHD symptoms immediately after learning to upregulate the left parahippocampal gyrus, although their scores did backslide modestly during 11 months of follow-up, while the IFC group continued to improve.
Dr. Rubia acknowledged that this raises the possibility that the observed improvement in clinical symptoms achieved through fMRI-NF could be attributable to a placebo effect. However, she said she believes this is unlikely for several reasons. For one, brain scans showed that targeting either the right IFC or the left parahippocampal gyrus not only resulted in upregulation of activity in those specific regions, but throughout the broader neural networks of which they are a part. The right IFC upregulators showed activation of a bilateral dorsolateral prefrontal cortex/IFC-insular-striato-cerebellar cognitive control network. In contrast, the boys who targeted the left parahippocampal gyrus experienced activation of associated posterior visual-spatial attention regions, which are relevant to ADHD. This made for a far from ideal control group.
Also, the amount of improvement in ADHD symptoms in the right IFC-targeted group correlated with the degree of activation of that region, indicative of a brain-behavior correlation that speaks against a nonspecific effect.
Because this was a small, unpowered pilot study and interest remains intense in potential nonpharmacologic treatments for ADHD, the U.K. Medical Research Council is funding Dr. Rubia and her colleagues for a new 100-patient study – including a sham fMRI-NF arm – in order to definitively address the possibility of a placebo effect. The study also will attempt to pin down the patient population most likely to benefit from fMRI-NF. “It’s possible that the inattentive subtype of ADHD will respond best. Neurofeedback is, after all, a form of attention training,” she noted.
While real-time fMRI-NF might sound prohibitively expensive for widespread use in clinical practice for a disorder as common as ADHD, which has an estimated prevalence of about 7%, it might actually stack up reasonably well in a cost-benefit analysis, compared with ongoing medication costs and side effects or with a year’s worth of weekly psychotherapy, according to Dr. Rubia.
In parallel with the ongoing sham-controlled fMRI-NF study, Dr. Rubia also is conducting a clinical trial of transcranial direct current stimulation of the right IFC in combination with cognitive training. The idea is to study the clinical impact of directly upregulating activity in this area of the brain, bypassing the added step of training patients to gain self-control over this dysregulated region. The early findings, she said, look promising.
The fMRI-NF study (Hum Brain Mapp. 2017 Jun;38[6]:3190-209) was sponsored by the U.K. National Institute for Health Research and the Maudsley NHS Foundation Trust. Dr. Rubia reported receiving speakers honoraria from Lilly, Shire, and Medice.
Source: Rubia K et al. European College of Neuropsychopharmacology.
PARIS – Neurofeedback based upon real-time functional magnetic resonance imaging resulted in long-term reduction in attention-deficit/hyperactivity disorder symptoms in adolescents in a randomized controlled proof-of-concept study, Katya Rubia, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
The effect size of the improvement when measured at follow-up 11 months after completing the functional MRI-based neurofeedback (fMRI-NF) training exercises was moderate to large and comparable to that of psychostimulant medication in published placebo-controlled clinical trials. But the effects of the medications last only 24 hours after administration, and the drugs have side effects.
Neurofeedback is an operant conditioning procedure, which, through trial and error, teaches patients to self-regulate specific areas of the brain involved in psychopathology. EEG-based neurofeedback for ADHD has been extensively studied, with generally small to medium effect sizes being reported. Morever, patients need to be very highly motivated in order to succeed at EEG-NF: It takes 30-40 EEG-NF sessions, each an hour long, in order to learn targeted brain self-control in ADHD, whereas in Dr. Rubia’s study, patients learned to self-regulate brain activity in an average of eight fMRI sessions, each lasting 8.5 minutes, over the course of 2 weeks. The far speedier learning curve is probably tied to the superior specificity of spatial localization afforded by fMRI neurofeedback, according to the neuroscientist.
Also, fMRI-NF can reach certain key regions of the brain involved in ADHD that EEG-NF cannot, most notably the inferior frontal cortex (IFC) and basal ganglia, she added.
The target region in the proof-of-concept study was the right IFC, an area important for cognitive control, attention, and timing. Functional neuroimaging studies consistently have shown that the right IFC is underactive in ADHD, and that psychostimulant medications upregulate this area. A dysfunctional right IFC is an ADHD-specific abnormality not present in children with obessive-compulsive disorder (JAMA Psychiatry. 2016 Aug 1;73[8]:815-25), conduct disorder, or autism.
“The IFC seems to be a very good functional biomarker for ADHD,” Dr. Rubia said.
The proof-of-concept study, published in Human Brain Mapping, included 31 boys with a DSM-5 diagnosis of ADHD, aged 12-17, who were randomized to fMRI-NF of the right IFC or, as a control condition, to fMRI-NF targeting the left parahippocampal gyrus. Two patients had the inattentive subtype of ADHD; the rest had the combined hyperactive/inattentive form. Parents and patients were blinded as to their study arm.
So this program uses neuroimaging as a treatment. It is neuroimaging employed as neurotherapy. To make the training experience more attractive to young patients, it was presented as a computer game: By making progress in controlling their brain activity, patients could launch a rocket ship on the screen. With further progress, they could send the rocket through the atmosphere into space and eventually land it on another planet.
The primary study endpoint was change in the ADHD Rating Scale. The group that targeted self-upregulation of right IFC activity showed roughly a 20% improvement in scores, from a baseline mean total score of 36.7 to 30.2 immediately post treatment, further improving to a score of 26.7 at roughly 11 months of follow-up. Mean scores on the inattention subscale improved from 19.8 to 15.9 immediately post treatment and 15.3 at follow-up. Scores on the hyperactivity/impulsivity subscale went from 16.9 before treatment to 14.2 after treatment and 11.5 at follow-up.
There were no side effects of fMRI-NF in either study arm.
However, a degree of uncertainty exists regarding the clinical significance of the results, Dr. Rubia said. That’s because the control group showed a similar degree of improvement in ADHD symptoms immediately after learning to upregulate the left parahippocampal gyrus, although their scores did backslide modestly during 11 months of follow-up, while the IFC group continued to improve.
Dr. Rubia acknowledged that this raises the possibility that the observed improvement in clinical symptoms achieved through fMRI-NF could be attributable to a placebo effect. However, she said she believes this is unlikely for several reasons. For one, brain scans showed that targeting either the right IFC or the left parahippocampal gyrus not only resulted in upregulation of activity in those specific regions, but throughout the broader neural networks of which they are a part. The right IFC upregulators showed activation of a bilateral dorsolateral prefrontal cortex/IFC-insular-striato-cerebellar cognitive control network. In contrast, the boys who targeted the left parahippocampal gyrus experienced activation of associated posterior visual-spatial attention regions, which are relevant to ADHD. This made for a far from ideal control group.
Also, the amount of improvement in ADHD symptoms in the right IFC-targeted group correlated with the degree of activation of that region, indicative of a brain-behavior correlation that speaks against a nonspecific effect.
Because this was a small, unpowered pilot study and interest remains intense in potential nonpharmacologic treatments for ADHD, the U.K. Medical Research Council is funding Dr. Rubia and her colleagues for a new 100-patient study – including a sham fMRI-NF arm – in order to definitively address the possibility of a placebo effect. The study also will attempt to pin down the patient population most likely to benefit from fMRI-NF. “It’s possible that the inattentive subtype of ADHD will respond best. Neurofeedback is, after all, a form of attention training,” she noted.
While real-time fMRI-NF might sound prohibitively expensive for widespread use in clinical practice for a disorder as common as ADHD, which has an estimated prevalence of about 7%, it might actually stack up reasonably well in a cost-benefit analysis, compared with ongoing medication costs and side effects or with a year’s worth of weekly psychotherapy, according to Dr. Rubia.
In parallel with the ongoing sham-controlled fMRI-NF study, Dr. Rubia also is conducting a clinical trial of transcranial direct current stimulation of the right IFC in combination with cognitive training. The idea is to study the clinical impact of directly upregulating activity in this area of the brain, bypassing the added step of training patients to gain self-control over this dysregulated region. The early findings, she said, look promising.
The fMRI-NF study (Hum Brain Mapp. 2017 Jun;38[6]:3190-209) was sponsored by the U.K. National Institute for Health Research and the Maudsley NHS Foundation Trust. Dr. Rubia reported receiving speakers honoraria from Lilly, Shire, and Medice.
Source: Rubia K et al. European College of Neuropsychopharmacology.
REPORTING FROM THE ECNP CONGRESS
Key clinical point: Neuroimaging can be employed as neurotherapy to improve ADHD nonpharmacologically.
Major finding: Adolescents with ADHD who learned via functional MRI neurofeedback to upregulate activity in their right inferior frontal cortex showed significant improvement in scores on the ADHD Rating Scale, from a baseline mean total score of 36.7 to 30.2 immediately after the training program, further improving to 26.7 at roughly 11 months of follow-up.
Study details: A prospective, randomized, single-blind study of 31 boys aged 12-17 with ADHD.
Disclosures: The study was sponsored by the U.K. National Institute for Health Research and the Maudsley NHS Foundation Trust. The presenter reported receiving speakers honoraria from Lilly, Shire, and Medice.
Source: Rubia K et al. European College of Neuropsychopharmacology.
The year’s Top 10 in addiction medicine
PARIS – Genetic studies are finally making an impact in addiction medicine, as evidenced by the inclusion of three genomewide association studies in one expert’s list of the year’s top 10 developments in the field.
The three genetic studies that made their way onto this admittedly personal top 10 list of advances in addiction medicine include the surprising results of the first-ever genomewide association study of pathological gambling, a methylomic profiling study implicating a gene that regulates low-density lipoprotein cholesterol in the pathogenesis of alcohol use disorder, and a study that identified a specific microRNA as a regulator of motivation for cocaine, Philip Gorwood, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“This was an extremely important development, because it means pathologic gambling is a behavioral addiction,” said Dr. Gorwood, also head of the Clinic for Mental Illness and the Brain at Sainte-Anne Central Hospital in Paris. “This makes a difference to research because it means what we observe in the brain is really due to the patient’s behavior, to his or her choice to gamble, and not because they’re taking alcohol or cocaine or nicotine.”
His list of the year’s top 10 studies in addiction medicine follows:
Deep TMS in AUD
There is a general sense within the field of addiction medicine that transcranial magnetic stimulation (TMS) might have efficacy in some addictive disorders, but it has been hard to make a convincing case for the therapy when the mechanism is unknown.
Italian investigators have brought clarity in a study published in European Psychopharmacology (2017 May;27[5]:450-61) in which they randomized 11 patients with alcohol use disorder (AUD) to 4 weeks of real or sham deep TMS sessions, coupled with baseline and follow-up single-photon emission computed tomography (SPECT) imaging of dopamine transporter availability in the striatum of the dorsolateral prefrontal cortex. After 4 weeks, the group receiving real TMS showed a clinically important reduction in alcohol intake accompanied by a significant decrease in their elevated strial dopamine transporter availability, while sham-treated controls were unchanged. “This was a small study, but I loved the way the investigators merged a pilot clinical study with a biologic mechanism study,” Dr. Gorwood commented.
Coffee drinking and mortality
Investigators for a prospective cohort study of 521,330 people enrolled in the 10-country European Prospective Investigation into Cancer and Nutrition concluded that, during a mean 16.4 years of follow-up, participants in the top quartile of coffee consumption had a significantly lower risk of all-cause mortality, compared with those who did not drink coffee: a 12% reduction in men and a 7% reduction in women.
Moreover, the risk of mortality tied to digestive disease was reduced by 59% in high– versus non–coffee-consuming men and by 40% in women in this report from the International Agency for Research on Cancer, in Lyon, France . High–coffee-consuming women, but not men, also had a significant 22% reduction in circulatory disease mortality and a 30% lower risk of cerebrovascular disease mortality, compared with those who did not drink coffee.
Of particular interest to psychiatrists, the investigators also examined suicide risk. In a multivariate analysis, men in the third and fourth quartiles of coffee consumption were at 36% and 29% lower risk of death by suicide than those who did not drink coffee. Suicide in women occurred less frequently and was not related to coffee intake.
These various associations did not vary by country, even though coffee preparation methods vary considerably across Europe. And when the investigators excluded participants who died within 8 years of baseline, the results were unchanged, a finding that makes bias tied to reverse causality less likely as explanation for the results, the findings published in the Annals of Internal Medicine (2017 Aug 15;167[4]:236-47) showed.
“As addiction specialists, our patients often complain that we are forbidding everything. We are the bad guys: Don’t drink too much, don’t eat too much, and so on. The key finding in this European study is that you will not die of coffee drinking, even if you are having 8 cups a day. Yes, we know that coffee has a psychotropic effect, we know that you have a tendency to repeat its consumption, but it is really quite readily distinguishable from other addictive substances,” the psychiatrist said.
Smoking and violence
A few years ago when smoke-free policies were proposed in psychiatric inpatient settings, there was an uproar from staff.
“That was a huge mess,” Dr. Gorwood recalled. “The staff said, ‘Whoa, if you do that, I’m going to be killed by my patients. They are extremely addicted to cigarettes, and if they stop smoking tobacco during their hospitalization – when they already have very high anxiety – we are going to have an increase in violence.’ ”
Not so, as convincingly shown by investigators at King’s College London. They analyzed incident reports of physical assault 30 months before and 12 months after implementation of a no-smoking policy on the inpatient wards of a large London mental health organization. They scrutinized the 4,550 physical assaults that took place during the study period, 4.9% of which were smoking related and found that the number of physical assaults per month fell by 39% after the smoking policy change, according to the study, which was published in the Lancet Psychiatry (2017 Jul;4[7]:540-6).
When an audience member said this reduction in ward violence struck him as counterintuitive and asked for an explanation, Dr. Gorwood noted that the London study wasn’t designed to address the mechanism of benefit. However, he speculated that a reasonable hypothesis prevalent among addiction specialists: Once an addict is no longer being triggered by an addictive substance, he or she will feel better.
“This is why we ask patients with any kind of dependence to stop doing it. They will feel better in terms of mood, well being, and optimistically in terms of violence,” Dr. Gordon said.
Skyrocketing alcohol misuse
The National Epidemiologic Survey on Alcohol and Related Conditions, conducted every 5-6 years by the U.S. National Institute on Alcohol Abuse and Alcoholism, enjoys great respect among addiction medicine specialists worldwide because it surveys tens of thousands of individuals and consistently employs the same methodology and definitions each time. This provides a degree of confidence regarding big-picture trends that’s not often found in European studies. The latest report from the survey is deeply concerning, according to Dr. Gorwood.
Investigators charted changing trends in 12-month rates of alcohol use, high-risk drinking, and AUD between the 2001-2002 survey, which included 43,093 subjects, and the 2012-2013 version, which included 36,309. The rate of alcohol use during the past 12 months increased by 11.2% across this 11-year time span, from 65.4% to 72.7%. Far more troubling: The rate of high-risk drinking climbed by 29.9%, from 9.7% to 12.6%; and the proportion of individuals meeting DSM-IV criteria for AUD jumped by roughly 50%, from 8.5% in 2001-2002 to 12.7% in 2012-2013.
Disproportionate increases in AUD were documented in women, with an 84% jump between the two survey periods; African Americans, with a 93% increase; Asian or Pacific Islanders, 78%; middle-aged individuals ages 45-65, with an 82% increase; and Americans aged 65 or older, with a whopping 107% increase.
These data “constitute a public health crisis,” according to the investigators. “Taken together, these findings portend increases in many chronic comorbidities in which alcohol use has a substantial role,” they added in the article, published in JAMA Psychiatry (2017 Sep 1;74[9]:911-23).
This unwelcome trend is surely not unique to the United States, in Dr. Gorwood’s view. “We need to figure out why we have such a big increase and what we should be doing about it,” he said.
Smoking cessation in pregnancy
A large Finnish prospective study in which virtually all births in the country’s two northernmost provinces in 1986 have been followed from pregnancy onward provides an optimistic new message regarding prevention of teenage smoking.
The adolescent offspring of Finnish women who quit smoking before becoming pregnant and continued to shun smoking as their child achieved age 15-16 years had the same low rate of daily smoking as those whose mothers never smoked: 10%. If the moms quit smoking during their first trimester, the rate of daily smoking by their teenage offspring at age 15-16 years was higher – 16% – but nonetheless lower than if she continued smoking beyond the first trimester – 25% – even if neither she nor the father smoked during their offspring’s teen years. If the mother continued to smoke after the first trimester and either she or the father smoked as their child grew up, the rate of daily smoking at age 15-16 years climbed to 37%; if both parents smoked, it was 41%, according to results of the study published in the journal Addiction (2017 Jan;112[1]:134-43).
“A take-home message: If you are a smoker and you quit before pregnancy, you abolish the increased risk, just as if you’d never been smoking in your life. It’s definitely good news,” Dr. Gorwood said.
ADHD medication and SUDs
All physicians who treat patients with attention-deficit/hyperactivity disorder get an earful from parents and patients who fear that the drugs will lead to addiction to stimulants. Reassuring evidence that this isn’t the case comes from a massive study of nearly 3 million adolescent and adult ADHD patients, median age 21, in a U.S. commercial health care claims database. The study endpoint was visits to emergency departments related to substance use disorders during 16 months of follow-up.
In within-individual comparisons, male patients had an adjusted 35% reduction in the likelihood of trips to the ED for substance use events during the months they received stimulant medications or atomoxetine, compared with the months they were off ADHD medication. Females had a 31% reduction during their on-treatment months (Am J Psychiatry. 2017 Sep 1;174[9]:877-85).
“That’s the kind of information I like to share with my patients,” Dr. Gorwood commented. “It’s very easy to understand, and it gives them objective information that – although they may find surprising – treatment protects against addiction rather than leading to addiction.”
Divorce and new AUD
A Swedish national registry study of 942,366 married people born in 1960-1990, none with a history of AUD when they tied the knot, documented that divorce predicted a six- to sevenfold increase in new-onset AUD, compared with that of individuals who stayed married. Remarriage cut that risk by 50%-60% relative to those who did not remarry.
The relationship between marriage, divorce, and AUD was more complex than that, however. The level of drinking actually started to increase several years before divorce.
“A lot of patients will say, ‘Doctor, I’m drinking so much now because I’ve lost my wife, my life is miserable, and the only thing I have now is alcohol to make things feel better.’ But we could propose a different statement: ‘Maybe you got divorced because you drank too much alcohol.’ We wouldn’t say that to patients, of course, but we could help them to recognize their own paradoxical approach,” Dr. Gorwood said.
Widowhood was associated with a roughly fourfold increased risk of new-onset AUD, according to an article in the American Journal of Psychiatry (2017 May 1;174[5]:451-8).
Study of pathological gambling
A German multicenter team set out to identify genetic pathways involved in pathological gambling. They found a strong association with alcohol dependence, providing novel evidence of genetic overlap between a substance- and non–substance-related addiction. Unexpectedly, they also identified a shared genetic pathway between pathological gambling and Huntington’s disease that will provide a rich new avenue of research. Their results were published in the journal European Psychiatry (2016 Aug;36:38-46).
Gene implicated in alcohol use disorder
For several years, cardiologists have been agog over the unprecedented LDL cholesterol–lowering ability of a novel class of medications that inhibit the protein produced by the PCSK9 (proprotein convertase subtilisin/kexin 9) gene, which slows removal of LDL from the circulation. Ongoing studies of the PCSK9 inhibitors evolocumab and alirocumab are widely expected to report reductions in cardiovascular event rates far beyond what is achievable with statins.
Now investigators at the U.S. National Institute on Alcohol Abuse and Alcoholism have conducted a genomewide methylomic variation study that showed PCSK9 expression in the liver is dysregulated in patients with alcohol use disorder. They coupled this finding with a translational study in a mouse model of alcohol use disorder in which they demonstrated that alcohol exposure leads to PCSK9 downregulation, with resultant lowering of LDL.
Taken together, the results, published in Molecular Psychiatry (2017 Aug 29. doi: 10.1038/mp.2017.168), suggest that epigenetic regulation of PCSK9 by alcohol is a dynamic process in which exposure to small amounts of alcohol leads to less PCSK9 gene expression, less methylation, and lower LDL, while chronic heavy use leads to greater gene expression, unfavorable lipid levels, and eventually to low PCSK9 protein levels as a result of hepatotoxicity.
MicroRNA-495 and cocaine
Using genomewide sequencing techniques, investigators zeroed in on a specific microRNA known as miR-495 as an important posttranscriptional regulator of the expression of genes included in KARG, the Knowledgebase for Addiction Related Genes database. This small RNA is highly expressed in the nucleus accumbens, a key area of the brain involved in motivation and reward.
In rodent studies, the researchers showed that administration of cocaine rapidly downregulated miR-495 expression in the nucleus accumbens with an accompanying increase in expression of addiction-related genes known to be involved in specific substance use disorder–related biologic pathways. Moreover, when the investigators induced miR-495 overexpression in the nucleus accumbens, the animals lost motivation to seek and self-administer cocaine without having any effect on food-seeking, suggesting miR-495 selectively affects addiction-related behaviors, according to results of a study published in Molecular Psychiatry (2017 Jan 3. doi: 10.1038/mp.2016.238).
“I found this really convincing. There is converging evidence that we’re going to hear a lot more about miR-495 later on,” Dr. Gorwood said.
He reported having no financial conflicts of interest regarding his presentation.
PARIS – Genetic studies are finally making an impact in addiction medicine, as evidenced by the inclusion of three genomewide association studies in one expert’s list of the year’s top 10 developments in the field.
The three genetic studies that made their way onto this admittedly personal top 10 list of advances in addiction medicine include the surprising results of the first-ever genomewide association study of pathological gambling, a methylomic profiling study implicating a gene that regulates low-density lipoprotein cholesterol in the pathogenesis of alcohol use disorder, and a study that identified a specific microRNA as a regulator of motivation for cocaine, Philip Gorwood, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“This was an extremely important development, because it means pathologic gambling is a behavioral addiction,” said Dr. Gorwood, also head of the Clinic for Mental Illness and the Brain at Sainte-Anne Central Hospital in Paris. “This makes a difference to research because it means what we observe in the brain is really due to the patient’s behavior, to his or her choice to gamble, and not because they’re taking alcohol or cocaine or nicotine.”
His list of the year’s top 10 studies in addiction medicine follows:
Deep TMS in AUD
There is a general sense within the field of addiction medicine that transcranial magnetic stimulation (TMS) might have efficacy in some addictive disorders, but it has been hard to make a convincing case for the therapy when the mechanism is unknown.
Italian investigators have brought clarity in a study published in European Psychopharmacology (2017 May;27[5]:450-61) in which they randomized 11 patients with alcohol use disorder (AUD) to 4 weeks of real or sham deep TMS sessions, coupled with baseline and follow-up single-photon emission computed tomography (SPECT) imaging of dopamine transporter availability in the striatum of the dorsolateral prefrontal cortex. After 4 weeks, the group receiving real TMS showed a clinically important reduction in alcohol intake accompanied by a significant decrease in their elevated strial dopamine transporter availability, while sham-treated controls were unchanged. “This was a small study, but I loved the way the investigators merged a pilot clinical study with a biologic mechanism study,” Dr. Gorwood commented.
Coffee drinking and mortality
Investigators for a prospective cohort study of 521,330 people enrolled in the 10-country European Prospective Investigation into Cancer and Nutrition concluded that, during a mean 16.4 years of follow-up, participants in the top quartile of coffee consumption had a significantly lower risk of all-cause mortality, compared with those who did not drink coffee: a 12% reduction in men and a 7% reduction in women.
Moreover, the risk of mortality tied to digestive disease was reduced by 59% in high– versus non–coffee-consuming men and by 40% in women in this report from the International Agency for Research on Cancer, in Lyon, France . High–coffee-consuming women, but not men, also had a significant 22% reduction in circulatory disease mortality and a 30% lower risk of cerebrovascular disease mortality, compared with those who did not drink coffee.
Of particular interest to psychiatrists, the investigators also examined suicide risk. In a multivariate analysis, men in the third and fourth quartiles of coffee consumption were at 36% and 29% lower risk of death by suicide than those who did not drink coffee. Suicide in women occurred less frequently and was not related to coffee intake.
These various associations did not vary by country, even though coffee preparation methods vary considerably across Europe. And when the investigators excluded participants who died within 8 years of baseline, the results were unchanged, a finding that makes bias tied to reverse causality less likely as explanation for the results, the findings published in the Annals of Internal Medicine (2017 Aug 15;167[4]:236-47) showed.
“As addiction specialists, our patients often complain that we are forbidding everything. We are the bad guys: Don’t drink too much, don’t eat too much, and so on. The key finding in this European study is that you will not die of coffee drinking, even if you are having 8 cups a day. Yes, we know that coffee has a psychotropic effect, we know that you have a tendency to repeat its consumption, but it is really quite readily distinguishable from other addictive substances,” the psychiatrist said.
Smoking and violence
A few years ago when smoke-free policies were proposed in psychiatric inpatient settings, there was an uproar from staff.
“That was a huge mess,” Dr. Gorwood recalled. “The staff said, ‘Whoa, if you do that, I’m going to be killed by my patients. They are extremely addicted to cigarettes, and if they stop smoking tobacco during their hospitalization – when they already have very high anxiety – we are going to have an increase in violence.’ ”
Not so, as convincingly shown by investigators at King’s College London. They analyzed incident reports of physical assault 30 months before and 12 months after implementation of a no-smoking policy on the inpatient wards of a large London mental health organization. They scrutinized the 4,550 physical assaults that took place during the study period, 4.9% of which were smoking related and found that the number of physical assaults per month fell by 39% after the smoking policy change, according to the study, which was published in the Lancet Psychiatry (2017 Jul;4[7]:540-6).
When an audience member said this reduction in ward violence struck him as counterintuitive and asked for an explanation, Dr. Gorwood noted that the London study wasn’t designed to address the mechanism of benefit. However, he speculated that a reasonable hypothesis prevalent among addiction specialists: Once an addict is no longer being triggered by an addictive substance, he or she will feel better.
“This is why we ask patients with any kind of dependence to stop doing it. They will feel better in terms of mood, well being, and optimistically in terms of violence,” Dr. Gordon said.
Skyrocketing alcohol misuse
The National Epidemiologic Survey on Alcohol and Related Conditions, conducted every 5-6 years by the U.S. National Institute on Alcohol Abuse and Alcoholism, enjoys great respect among addiction medicine specialists worldwide because it surveys tens of thousands of individuals and consistently employs the same methodology and definitions each time. This provides a degree of confidence regarding big-picture trends that’s not often found in European studies. The latest report from the survey is deeply concerning, according to Dr. Gorwood.
Investigators charted changing trends in 12-month rates of alcohol use, high-risk drinking, and AUD between the 2001-2002 survey, which included 43,093 subjects, and the 2012-2013 version, which included 36,309. The rate of alcohol use during the past 12 months increased by 11.2% across this 11-year time span, from 65.4% to 72.7%. Far more troubling: The rate of high-risk drinking climbed by 29.9%, from 9.7% to 12.6%; and the proportion of individuals meeting DSM-IV criteria for AUD jumped by roughly 50%, from 8.5% in 2001-2002 to 12.7% in 2012-2013.
Disproportionate increases in AUD were documented in women, with an 84% jump between the two survey periods; African Americans, with a 93% increase; Asian or Pacific Islanders, 78%; middle-aged individuals ages 45-65, with an 82% increase; and Americans aged 65 or older, with a whopping 107% increase.
These data “constitute a public health crisis,” according to the investigators. “Taken together, these findings portend increases in many chronic comorbidities in which alcohol use has a substantial role,” they added in the article, published in JAMA Psychiatry (2017 Sep 1;74[9]:911-23).
This unwelcome trend is surely not unique to the United States, in Dr. Gorwood’s view. “We need to figure out why we have such a big increase and what we should be doing about it,” he said.
Smoking cessation in pregnancy
A large Finnish prospective study in which virtually all births in the country’s two northernmost provinces in 1986 have been followed from pregnancy onward provides an optimistic new message regarding prevention of teenage smoking.
The adolescent offspring of Finnish women who quit smoking before becoming pregnant and continued to shun smoking as their child achieved age 15-16 years had the same low rate of daily smoking as those whose mothers never smoked: 10%. If the moms quit smoking during their first trimester, the rate of daily smoking by their teenage offspring at age 15-16 years was higher – 16% – but nonetheless lower than if she continued smoking beyond the first trimester – 25% – even if neither she nor the father smoked during their offspring’s teen years. If the mother continued to smoke after the first trimester and either she or the father smoked as their child grew up, the rate of daily smoking at age 15-16 years climbed to 37%; if both parents smoked, it was 41%, according to results of the study published in the journal Addiction (2017 Jan;112[1]:134-43).
“A take-home message: If you are a smoker and you quit before pregnancy, you abolish the increased risk, just as if you’d never been smoking in your life. It’s definitely good news,” Dr. Gorwood said.
ADHD medication and SUDs
All physicians who treat patients with attention-deficit/hyperactivity disorder get an earful from parents and patients who fear that the drugs will lead to addiction to stimulants. Reassuring evidence that this isn’t the case comes from a massive study of nearly 3 million adolescent and adult ADHD patients, median age 21, in a U.S. commercial health care claims database. The study endpoint was visits to emergency departments related to substance use disorders during 16 months of follow-up.
In within-individual comparisons, male patients had an adjusted 35% reduction in the likelihood of trips to the ED for substance use events during the months they received stimulant medications or atomoxetine, compared with the months they were off ADHD medication. Females had a 31% reduction during their on-treatment months (Am J Psychiatry. 2017 Sep 1;174[9]:877-85).
“That’s the kind of information I like to share with my patients,” Dr. Gorwood commented. “It’s very easy to understand, and it gives them objective information that – although they may find surprising – treatment protects against addiction rather than leading to addiction.”
Divorce and new AUD
A Swedish national registry study of 942,366 married people born in 1960-1990, none with a history of AUD when they tied the knot, documented that divorce predicted a six- to sevenfold increase in new-onset AUD, compared with that of individuals who stayed married. Remarriage cut that risk by 50%-60% relative to those who did not remarry.
The relationship between marriage, divorce, and AUD was more complex than that, however. The level of drinking actually started to increase several years before divorce.
“A lot of patients will say, ‘Doctor, I’m drinking so much now because I’ve lost my wife, my life is miserable, and the only thing I have now is alcohol to make things feel better.’ But we could propose a different statement: ‘Maybe you got divorced because you drank too much alcohol.’ We wouldn’t say that to patients, of course, but we could help them to recognize their own paradoxical approach,” Dr. Gorwood said.
Widowhood was associated with a roughly fourfold increased risk of new-onset AUD, according to an article in the American Journal of Psychiatry (2017 May 1;174[5]:451-8).
Study of pathological gambling
A German multicenter team set out to identify genetic pathways involved in pathological gambling. They found a strong association with alcohol dependence, providing novel evidence of genetic overlap between a substance- and non–substance-related addiction. Unexpectedly, they also identified a shared genetic pathway between pathological gambling and Huntington’s disease that will provide a rich new avenue of research. Their results were published in the journal European Psychiatry (2016 Aug;36:38-46).
Gene implicated in alcohol use disorder
For several years, cardiologists have been agog over the unprecedented LDL cholesterol–lowering ability of a novel class of medications that inhibit the protein produced by the PCSK9 (proprotein convertase subtilisin/kexin 9) gene, which slows removal of LDL from the circulation. Ongoing studies of the PCSK9 inhibitors evolocumab and alirocumab are widely expected to report reductions in cardiovascular event rates far beyond what is achievable with statins.
Now investigators at the U.S. National Institute on Alcohol Abuse and Alcoholism have conducted a genomewide methylomic variation study that showed PCSK9 expression in the liver is dysregulated in patients with alcohol use disorder. They coupled this finding with a translational study in a mouse model of alcohol use disorder in which they demonstrated that alcohol exposure leads to PCSK9 downregulation, with resultant lowering of LDL.
Taken together, the results, published in Molecular Psychiatry (2017 Aug 29. doi: 10.1038/mp.2017.168), suggest that epigenetic regulation of PCSK9 by alcohol is a dynamic process in which exposure to small amounts of alcohol leads to less PCSK9 gene expression, less methylation, and lower LDL, while chronic heavy use leads to greater gene expression, unfavorable lipid levels, and eventually to low PCSK9 protein levels as a result of hepatotoxicity.
MicroRNA-495 and cocaine
Using genomewide sequencing techniques, investigators zeroed in on a specific microRNA known as miR-495 as an important posttranscriptional regulator of the expression of genes included in KARG, the Knowledgebase for Addiction Related Genes database. This small RNA is highly expressed in the nucleus accumbens, a key area of the brain involved in motivation and reward.
In rodent studies, the researchers showed that administration of cocaine rapidly downregulated miR-495 expression in the nucleus accumbens with an accompanying increase in expression of addiction-related genes known to be involved in specific substance use disorder–related biologic pathways. Moreover, when the investigators induced miR-495 overexpression in the nucleus accumbens, the animals lost motivation to seek and self-administer cocaine without having any effect on food-seeking, suggesting miR-495 selectively affects addiction-related behaviors, according to results of a study published in Molecular Psychiatry (2017 Jan 3. doi: 10.1038/mp.2016.238).
“I found this really convincing. There is converging evidence that we’re going to hear a lot more about miR-495 later on,” Dr. Gorwood said.
He reported having no financial conflicts of interest regarding his presentation.
PARIS – Genetic studies are finally making an impact in addiction medicine, as evidenced by the inclusion of three genomewide association studies in one expert’s list of the year’s top 10 developments in the field.
The three genetic studies that made their way onto this admittedly personal top 10 list of advances in addiction medicine include the surprising results of the first-ever genomewide association study of pathological gambling, a methylomic profiling study implicating a gene that regulates low-density lipoprotein cholesterol in the pathogenesis of alcohol use disorder, and a study that identified a specific microRNA as a regulator of motivation for cocaine, Philip Gorwood, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“This was an extremely important development, because it means pathologic gambling is a behavioral addiction,” said Dr. Gorwood, also head of the Clinic for Mental Illness and the Brain at Sainte-Anne Central Hospital in Paris. “This makes a difference to research because it means what we observe in the brain is really due to the patient’s behavior, to his or her choice to gamble, and not because they’re taking alcohol or cocaine or nicotine.”
His list of the year’s top 10 studies in addiction medicine follows:
Deep TMS in AUD
There is a general sense within the field of addiction medicine that transcranial magnetic stimulation (TMS) might have efficacy in some addictive disorders, but it has been hard to make a convincing case for the therapy when the mechanism is unknown.
Italian investigators have brought clarity in a study published in European Psychopharmacology (2017 May;27[5]:450-61) in which they randomized 11 patients with alcohol use disorder (AUD) to 4 weeks of real or sham deep TMS sessions, coupled with baseline and follow-up single-photon emission computed tomography (SPECT) imaging of dopamine transporter availability in the striatum of the dorsolateral prefrontal cortex. After 4 weeks, the group receiving real TMS showed a clinically important reduction in alcohol intake accompanied by a significant decrease in their elevated strial dopamine transporter availability, while sham-treated controls were unchanged. “This was a small study, but I loved the way the investigators merged a pilot clinical study with a biologic mechanism study,” Dr. Gorwood commented.
Coffee drinking and mortality
Investigators for a prospective cohort study of 521,330 people enrolled in the 10-country European Prospective Investigation into Cancer and Nutrition concluded that, during a mean 16.4 years of follow-up, participants in the top quartile of coffee consumption had a significantly lower risk of all-cause mortality, compared with those who did not drink coffee: a 12% reduction in men and a 7% reduction in women.
Moreover, the risk of mortality tied to digestive disease was reduced by 59% in high– versus non–coffee-consuming men and by 40% in women in this report from the International Agency for Research on Cancer, in Lyon, France . High–coffee-consuming women, but not men, also had a significant 22% reduction in circulatory disease mortality and a 30% lower risk of cerebrovascular disease mortality, compared with those who did not drink coffee.
Of particular interest to psychiatrists, the investigators also examined suicide risk. In a multivariate analysis, men in the third and fourth quartiles of coffee consumption were at 36% and 29% lower risk of death by suicide than those who did not drink coffee. Suicide in women occurred less frequently and was not related to coffee intake.
These various associations did not vary by country, even though coffee preparation methods vary considerably across Europe. And when the investigators excluded participants who died within 8 years of baseline, the results were unchanged, a finding that makes bias tied to reverse causality less likely as explanation for the results, the findings published in the Annals of Internal Medicine (2017 Aug 15;167[4]:236-47) showed.
“As addiction specialists, our patients often complain that we are forbidding everything. We are the bad guys: Don’t drink too much, don’t eat too much, and so on. The key finding in this European study is that you will not die of coffee drinking, even if you are having 8 cups a day. Yes, we know that coffee has a psychotropic effect, we know that you have a tendency to repeat its consumption, but it is really quite readily distinguishable from other addictive substances,” the psychiatrist said.
Smoking and violence
A few years ago when smoke-free policies were proposed in psychiatric inpatient settings, there was an uproar from staff.
“That was a huge mess,” Dr. Gorwood recalled. “The staff said, ‘Whoa, if you do that, I’m going to be killed by my patients. They are extremely addicted to cigarettes, and if they stop smoking tobacco during their hospitalization – when they already have very high anxiety – we are going to have an increase in violence.’ ”
Not so, as convincingly shown by investigators at King’s College London. They analyzed incident reports of physical assault 30 months before and 12 months after implementation of a no-smoking policy on the inpatient wards of a large London mental health organization. They scrutinized the 4,550 physical assaults that took place during the study period, 4.9% of which were smoking related and found that the number of physical assaults per month fell by 39% after the smoking policy change, according to the study, which was published in the Lancet Psychiatry (2017 Jul;4[7]:540-6).
When an audience member said this reduction in ward violence struck him as counterintuitive and asked for an explanation, Dr. Gorwood noted that the London study wasn’t designed to address the mechanism of benefit. However, he speculated that a reasonable hypothesis prevalent among addiction specialists: Once an addict is no longer being triggered by an addictive substance, he or she will feel better.
“This is why we ask patients with any kind of dependence to stop doing it. They will feel better in terms of mood, well being, and optimistically in terms of violence,” Dr. Gordon said.
Skyrocketing alcohol misuse
The National Epidemiologic Survey on Alcohol and Related Conditions, conducted every 5-6 years by the U.S. National Institute on Alcohol Abuse and Alcoholism, enjoys great respect among addiction medicine specialists worldwide because it surveys tens of thousands of individuals and consistently employs the same methodology and definitions each time. This provides a degree of confidence regarding big-picture trends that’s not often found in European studies. The latest report from the survey is deeply concerning, according to Dr. Gorwood.
Investigators charted changing trends in 12-month rates of alcohol use, high-risk drinking, and AUD between the 2001-2002 survey, which included 43,093 subjects, and the 2012-2013 version, which included 36,309. The rate of alcohol use during the past 12 months increased by 11.2% across this 11-year time span, from 65.4% to 72.7%. Far more troubling: The rate of high-risk drinking climbed by 29.9%, from 9.7% to 12.6%; and the proportion of individuals meeting DSM-IV criteria for AUD jumped by roughly 50%, from 8.5% in 2001-2002 to 12.7% in 2012-2013.
Disproportionate increases in AUD were documented in women, with an 84% jump between the two survey periods; African Americans, with a 93% increase; Asian or Pacific Islanders, 78%; middle-aged individuals ages 45-65, with an 82% increase; and Americans aged 65 or older, with a whopping 107% increase.
These data “constitute a public health crisis,” according to the investigators. “Taken together, these findings portend increases in many chronic comorbidities in which alcohol use has a substantial role,” they added in the article, published in JAMA Psychiatry (2017 Sep 1;74[9]:911-23).
This unwelcome trend is surely not unique to the United States, in Dr. Gorwood’s view. “We need to figure out why we have such a big increase and what we should be doing about it,” he said.
Smoking cessation in pregnancy
A large Finnish prospective study in which virtually all births in the country’s two northernmost provinces in 1986 have been followed from pregnancy onward provides an optimistic new message regarding prevention of teenage smoking.
The adolescent offspring of Finnish women who quit smoking before becoming pregnant and continued to shun smoking as their child achieved age 15-16 years had the same low rate of daily smoking as those whose mothers never smoked: 10%. If the moms quit smoking during their first trimester, the rate of daily smoking by their teenage offspring at age 15-16 years was higher – 16% – but nonetheless lower than if she continued smoking beyond the first trimester – 25% – even if neither she nor the father smoked during their offspring’s teen years. If the mother continued to smoke after the first trimester and either she or the father smoked as their child grew up, the rate of daily smoking at age 15-16 years climbed to 37%; if both parents smoked, it was 41%, according to results of the study published in the journal Addiction (2017 Jan;112[1]:134-43).
“A take-home message: If you are a smoker and you quit before pregnancy, you abolish the increased risk, just as if you’d never been smoking in your life. It’s definitely good news,” Dr. Gorwood said.
ADHD medication and SUDs
All physicians who treat patients with attention-deficit/hyperactivity disorder get an earful from parents and patients who fear that the drugs will lead to addiction to stimulants. Reassuring evidence that this isn’t the case comes from a massive study of nearly 3 million adolescent and adult ADHD patients, median age 21, in a U.S. commercial health care claims database. The study endpoint was visits to emergency departments related to substance use disorders during 16 months of follow-up.
In within-individual comparisons, male patients had an adjusted 35% reduction in the likelihood of trips to the ED for substance use events during the months they received stimulant medications or atomoxetine, compared with the months they were off ADHD medication. Females had a 31% reduction during their on-treatment months (Am J Psychiatry. 2017 Sep 1;174[9]:877-85).
“That’s the kind of information I like to share with my patients,” Dr. Gorwood commented. “It’s very easy to understand, and it gives them objective information that – although they may find surprising – treatment protects against addiction rather than leading to addiction.”
Divorce and new AUD
A Swedish national registry study of 942,366 married people born in 1960-1990, none with a history of AUD when they tied the knot, documented that divorce predicted a six- to sevenfold increase in new-onset AUD, compared with that of individuals who stayed married. Remarriage cut that risk by 50%-60% relative to those who did not remarry.
The relationship between marriage, divorce, and AUD was more complex than that, however. The level of drinking actually started to increase several years before divorce.
“A lot of patients will say, ‘Doctor, I’m drinking so much now because I’ve lost my wife, my life is miserable, and the only thing I have now is alcohol to make things feel better.’ But we could propose a different statement: ‘Maybe you got divorced because you drank too much alcohol.’ We wouldn’t say that to patients, of course, but we could help them to recognize their own paradoxical approach,” Dr. Gorwood said.
Widowhood was associated with a roughly fourfold increased risk of new-onset AUD, according to an article in the American Journal of Psychiatry (2017 May 1;174[5]:451-8).
Study of pathological gambling
A German multicenter team set out to identify genetic pathways involved in pathological gambling. They found a strong association with alcohol dependence, providing novel evidence of genetic overlap between a substance- and non–substance-related addiction. Unexpectedly, they also identified a shared genetic pathway between pathological gambling and Huntington’s disease that will provide a rich new avenue of research. Their results were published in the journal European Psychiatry (2016 Aug;36:38-46).
Gene implicated in alcohol use disorder
For several years, cardiologists have been agog over the unprecedented LDL cholesterol–lowering ability of a novel class of medications that inhibit the protein produced by the PCSK9 (proprotein convertase subtilisin/kexin 9) gene, which slows removal of LDL from the circulation. Ongoing studies of the PCSK9 inhibitors evolocumab and alirocumab are widely expected to report reductions in cardiovascular event rates far beyond what is achievable with statins.
Now investigators at the U.S. National Institute on Alcohol Abuse and Alcoholism have conducted a genomewide methylomic variation study that showed PCSK9 expression in the liver is dysregulated in patients with alcohol use disorder. They coupled this finding with a translational study in a mouse model of alcohol use disorder in which they demonstrated that alcohol exposure leads to PCSK9 downregulation, with resultant lowering of LDL.
Taken together, the results, published in Molecular Psychiatry (2017 Aug 29. doi: 10.1038/mp.2017.168), suggest that epigenetic regulation of PCSK9 by alcohol is a dynamic process in which exposure to small amounts of alcohol leads to less PCSK9 gene expression, less methylation, and lower LDL, while chronic heavy use leads to greater gene expression, unfavorable lipid levels, and eventually to low PCSK9 protein levels as a result of hepatotoxicity.
MicroRNA-495 and cocaine
Using genomewide sequencing techniques, investigators zeroed in on a specific microRNA known as miR-495 as an important posttranscriptional regulator of the expression of genes included in KARG, the Knowledgebase for Addiction Related Genes database. This small RNA is highly expressed in the nucleus accumbens, a key area of the brain involved in motivation and reward.
In rodent studies, the researchers showed that administration of cocaine rapidly downregulated miR-495 expression in the nucleus accumbens with an accompanying increase in expression of addiction-related genes known to be involved in specific substance use disorder–related biologic pathways. Moreover, when the investigators induced miR-495 overexpression in the nucleus accumbens, the animals lost motivation to seek and self-administer cocaine without having any effect on food-seeking, suggesting miR-495 selectively affects addiction-related behaviors, according to results of a study published in Molecular Psychiatry (2017 Jan 3. doi: 10.1038/mp.2016.238).
“I found this really convincing. There is converging evidence that we’re going to hear a lot more about miR-495 later on,” Dr. Gorwood said.
He reported having no financial conflicts of interest regarding his presentation.
EXPERT ANALYSIS FROM THE ECNP CONGRESS
Early inguinal hernia linked to schizophrenia
PARIS – One of the most unexpected and intriguing new developments in the field of schizophrenia has to be the discovery that the risk of the disease is significantly increased in men who were diagnosed with inguinal hernia before they were 13 years old.
“I think this is interesting because inguinal hernia in boys has to do with fibroblasts producing abnormal collagen structure,” according to Kristina Melkersson, MD, PhD, who presented her study findings at the annual congress of the European College of Neuropsychopharmacology.
She first detected a signal for a potential relationship in an earlier, small interview study in which she noticed that men with schizophrenia were more likely to have a history of inguinal hernia surgery than did men in the general population. This prompted her to try to confirm this preliminary observation in a large Swedish registry-based cohort study.
Among the nearly 1.3 million Swedes born during 1987-1999, there were 20,705 who were diagnosed with inguinal hernia before age 13 years. During a median 9.9 years of follow-up starting at age 13 years, 1,294 of these individuals were diagnosed with schizophrenia or schizoaffective disorder at a mean age of 21.4 years.
Among men, a history of inguinal hernia diagnosed before age 13 years was associated with a 56% increase in subsequent risk of schizophrenia or schizoaffective disorder, compared with men without such a history.
Women with a history of having inguinal hernia before age 13 years were at 16% increased risk; however, this modest increase in risk was not statistically significant, possibly because of small numbers. Inguinal hernia is 25 times more common in men than women.
Dr. Melkersson reported having no financial conflicts of interest regarding her study, which was supported by a grant from the Swedish Society of Medicine.
PARIS – One of the most unexpected and intriguing new developments in the field of schizophrenia has to be the discovery that the risk of the disease is significantly increased in men who were diagnosed with inguinal hernia before they were 13 years old.
“I think this is interesting because inguinal hernia in boys has to do with fibroblasts producing abnormal collagen structure,” according to Kristina Melkersson, MD, PhD, who presented her study findings at the annual congress of the European College of Neuropsychopharmacology.
She first detected a signal for a potential relationship in an earlier, small interview study in which she noticed that men with schizophrenia were more likely to have a history of inguinal hernia surgery than did men in the general population. This prompted her to try to confirm this preliminary observation in a large Swedish registry-based cohort study.
Among the nearly 1.3 million Swedes born during 1987-1999, there were 20,705 who were diagnosed with inguinal hernia before age 13 years. During a median 9.9 years of follow-up starting at age 13 years, 1,294 of these individuals were diagnosed with schizophrenia or schizoaffective disorder at a mean age of 21.4 years.
Among men, a history of inguinal hernia diagnosed before age 13 years was associated with a 56% increase in subsequent risk of schizophrenia or schizoaffective disorder, compared with men without such a history.
Women with a history of having inguinal hernia before age 13 years were at 16% increased risk; however, this modest increase in risk was not statistically significant, possibly because of small numbers. Inguinal hernia is 25 times more common in men than women.
Dr. Melkersson reported having no financial conflicts of interest regarding her study, which was supported by a grant from the Swedish Society of Medicine.
PARIS – One of the most unexpected and intriguing new developments in the field of schizophrenia has to be the discovery that the risk of the disease is significantly increased in men who were diagnosed with inguinal hernia before they were 13 years old.
“I think this is interesting because inguinal hernia in boys has to do with fibroblasts producing abnormal collagen structure,” according to Kristina Melkersson, MD, PhD, who presented her study findings at the annual congress of the European College of Neuropsychopharmacology.
She first detected a signal for a potential relationship in an earlier, small interview study in which she noticed that men with schizophrenia were more likely to have a history of inguinal hernia surgery than did men in the general population. This prompted her to try to confirm this preliminary observation in a large Swedish registry-based cohort study.
Among the nearly 1.3 million Swedes born during 1987-1999, there were 20,705 who were diagnosed with inguinal hernia before age 13 years. During a median 9.9 years of follow-up starting at age 13 years, 1,294 of these individuals were diagnosed with schizophrenia or schizoaffective disorder at a mean age of 21.4 years.
Among men, a history of inguinal hernia diagnosed before age 13 years was associated with a 56% increase in subsequent risk of schizophrenia or schizoaffective disorder, compared with men without such a history.
Women with a history of having inguinal hernia before age 13 years were at 16% increased risk; however, this modest increase in risk was not statistically significant, possibly because of small numbers. Inguinal hernia is 25 times more common in men than women.
Dr. Melkersson reported having no financial conflicts of interest regarding her study, which was supported by a grant from the Swedish Society of Medicine.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Swedish boys diagnosed with inguinal hernia before age 13 years were 56% more likely to be diagnosed with schizophrenia or schizoaffective disorder later in life.
Data source: This retrospective cohort study included nearly 1.3 million Swedes, 20,705 of whom were diagnosed with an inguinal hernia before age 13 years.
Disclosures: The study was supported by a grant from the Swedish Society of Medicine. The presenter reported having no financial conflicts.
Antidepressant therapy is too often tardy
PARIS – Forty percent of patients with major depressive disorder who receive a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor (SNRI) as their initial pharmacotherapy do not achieve the minimum therapeutic dose within 4 weeks of diagnosis, according to a real-world study of U.S. practice patterns.
This finding from a retrospective analysis of more than 60,000 adults diagnosed with major depressive disorder (MDD) during 2010-2015 and newly treated with an SSRI or SNRI as their first-line medication highlights an area where improved treatment delivery could lead to better outcomes, Rita Prieto, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
It’s noteworthy that, in this study of 60,433 adult outpatients with MDD – 15% of whom also had a diagnosis of an anxiety disorder – those who reached the minimum therapeutic dose (MTD) of their SSRI or SNRI within 4 weeks of diagnosis had significantly better medication adherence than those who arrived at the MTD later. Eighty percent of the early achievers filled their prescriptions regularly enough that it could reasonably be inferred they were taking their medication more than 80% of the time, as was the case for only 71% of the late achievers, she continued.
The mean time to reach the MTD was 1.5 weeks in the early achievers and 23.1 weeks in the later achievers. More than 80% of the study group as a whole had achieved the MTD for their SSRI or SNRI by 3 months after diagnosis of MDD. However, by the end of 6 months, 12% of patients still were not there.
Time to initiation of first-line SSRI or SNRI therapy left something to be desired as well: 60% of patients were on medication within 2 weeks after diagnosis. An additional 22% initiated pharmacotherapy during weeks 3-12. After 6 months, however, 10% of the patients who eventually went on medication still had not started pharmacotherapy.
Early treatment initiators exhibited better treatment adherence: 80% of them took their daily medication more than 80% of the time, compared with 68% of the late initiators.
It’s possible that the early treatment initiators and MTD achievers were more severely ill. That’s suggested by the fact that 23% of the early MTD achievers received combination therapy with an additional antidepressant or antipsychotic agent for more than 30 days, compared with only 17% of the late achievers.
This study used claims data obtained from the Truven Health Analytics MarketScan Commercial and Medicare Supplement database. Dr. Prieto noted that an important study limitation was that the database did not yield information on remission rates and other clinical outcomes.
The study was funded by Pfizer.
PARIS – Forty percent of patients with major depressive disorder who receive a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor (SNRI) as their initial pharmacotherapy do not achieve the minimum therapeutic dose within 4 weeks of diagnosis, according to a real-world study of U.S. practice patterns.
This finding from a retrospective analysis of more than 60,000 adults diagnosed with major depressive disorder (MDD) during 2010-2015 and newly treated with an SSRI or SNRI as their first-line medication highlights an area where improved treatment delivery could lead to better outcomes, Rita Prieto, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
It’s noteworthy that, in this study of 60,433 adult outpatients with MDD – 15% of whom also had a diagnosis of an anxiety disorder – those who reached the minimum therapeutic dose (MTD) of their SSRI or SNRI within 4 weeks of diagnosis had significantly better medication adherence than those who arrived at the MTD later. Eighty percent of the early achievers filled their prescriptions regularly enough that it could reasonably be inferred they were taking their medication more than 80% of the time, as was the case for only 71% of the late achievers, she continued.
The mean time to reach the MTD was 1.5 weeks in the early achievers and 23.1 weeks in the later achievers. More than 80% of the study group as a whole had achieved the MTD for their SSRI or SNRI by 3 months after diagnosis of MDD. However, by the end of 6 months, 12% of patients still were not there.
Time to initiation of first-line SSRI or SNRI therapy left something to be desired as well: 60% of patients were on medication within 2 weeks after diagnosis. An additional 22% initiated pharmacotherapy during weeks 3-12. After 6 months, however, 10% of the patients who eventually went on medication still had not started pharmacotherapy.
Early treatment initiators exhibited better treatment adherence: 80% of them took their daily medication more than 80% of the time, compared with 68% of the late initiators.
It’s possible that the early treatment initiators and MTD achievers were more severely ill. That’s suggested by the fact that 23% of the early MTD achievers received combination therapy with an additional antidepressant or antipsychotic agent for more than 30 days, compared with only 17% of the late achievers.
This study used claims data obtained from the Truven Health Analytics MarketScan Commercial and Medicare Supplement database. Dr. Prieto noted that an important study limitation was that the database did not yield information on remission rates and other clinical outcomes.
The study was funded by Pfizer.
PARIS – Forty percent of patients with major depressive disorder who receive a selective serotonin reuptake inhibitor or serotonin norepinephrine reuptake inhibitor (SNRI) as their initial pharmacotherapy do not achieve the minimum therapeutic dose within 4 weeks of diagnosis, according to a real-world study of U.S. practice patterns.
This finding from a retrospective analysis of more than 60,000 adults diagnosed with major depressive disorder (MDD) during 2010-2015 and newly treated with an SSRI or SNRI as their first-line medication highlights an area where improved treatment delivery could lead to better outcomes, Rita Prieto, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
It’s noteworthy that, in this study of 60,433 adult outpatients with MDD – 15% of whom also had a diagnosis of an anxiety disorder – those who reached the minimum therapeutic dose (MTD) of their SSRI or SNRI within 4 weeks of diagnosis had significantly better medication adherence than those who arrived at the MTD later. Eighty percent of the early achievers filled their prescriptions regularly enough that it could reasonably be inferred they were taking their medication more than 80% of the time, as was the case for only 71% of the late achievers, she continued.
The mean time to reach the MTD was 1.5 weeks in the early achievers and 23.1 weeks in the later achievers. More than 80% of the study group as a whole had achieved the MTD for their SSRI or SNRI by 3 months after diagnosis of MDD. However, by the end of 6 months, 12% of patients still were not there.
Time to initiation of first-line SSRI or SNRI therapy left something to be desired as well: 60% of patients were on medication within 2 weeks after diagnosis. An additional 22% initiated pharmacotherapy during weeks 3-12. After 6 months, however, 10% of the patients who eventually went on medication still had not started pharmacotherapy.
Early treatment initiators exhibited better treatment adherence: 80% of them took their daily medication more than 80% of the time, compared with 68% of the late initiators.
It’s possible that the early treatment initiators and MTD achievers were more severely ill. That’s suggested by the fact that 23% of the early MTD achievers received combination therapy with an additional antidepressant or antipsychotic agent for more than 30 days, compared with only 17% of the late achievers.
This study used claims data obtained from the Truven Health Analytics MarketScan Commercial and Medicare Supplement database. Dr. Prieto noted that an important study limitation was that the database did not yield information on remission rates and other clinical outcomes.
The study was funded by Pfizer.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Forty percent of U.S. adults diagnosed with major depressive disorder who received an SSRI or an SNRI as initial pharmacotherapy weren’t on the minimum therapeutic dose within 4 weeks of diagnosis.
Data source: A retrospective real-world analysis of claims data on 60,433 U.S. adult outpatients diagnosed with major depressive disorder.
Disclosures: The study was funded by Pfizer and presented by a company employee.
ADHD and insomnia appear intertwined
PARIS – Converging evidence suggests that attention-deficit/hyperactivity disorder and sleep difficulties share a common underlying etiology involving circadian rhythm disturbance, J.J. Sandra Kooij, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.
“If you review the evidence, it looks more and more like ADHD and sleeplessness are two sides of the same physiological and mental coin,” said Dr. Kooij, a psychiatrist at VU University Medical Center, Amsterdam, and chair of the European Network Adult ADHD.
Since this study remains ongoing, Dr. Kooij focused instead on the evidence suggesting that ADHD and sleep problems have a shared etiology.
Multiple studies have shown that roughly 75% of children and adults with ADHD have sleep-onset insomnia. It takes them longer to fall asleep, and they have a shorter than normal sleep duration because they have to get up in the morning for school or work. Dr. Kooij and her colleagues have shown that in adult ADHD patients with delayed sleep onset syndrome, their evening dim light melatonin onset, change in core body temperature, and other physiologic harbingers of sleep are delayed by an average of 1.5 hours (J Sleep Res. 2013 Dec;22[6]:607-16).
“My ADHD patients sleep a mean of 5-6 hours per night on a chronic basis, versus 7-8 hours in normal individuals. It leads to daytime sleepiness and dysfunction due to inattentiveness and social problems,” the psychiatrist said.
Other investigators have demonstrated that the prevalence of ADHD varies across the United States and that geographic differences in solar intensity explain 34%-57% of this variance in ADHD rates. The investigators postulated that the ADHD-preventive effect of high solar irradiation might be tied to improvement in circadian clock disturbances (Biol Psychiatry. 2013 Oct 15;74[8]:585-90).
In a study of 2,090 adult participants in The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues showed that ADHD, depression, anxiety, and circadian rhythm sleep problems are fellow travelers.
The prevalence of sleep duration of fewer than 6 hours per night was 15% in subjects with high ADHD symptoms and a lifetime history of an anxiety and/or depression diagnosis, 5% in those with lifetime anxiety/depression but no ADHD, and 4% in healthy controls. Delayed sleep phase syndrome was present in 16% of individuals with ADHD and a history of depression and/or anxiety, 8% in those with a lifetime history of anxiety/depression without ADHD, and 5% of healthy controls. The take-home message: Circadian rhythm sleep disorders in patients with ADHD are not necessarily attributable to comorbid anxiety and/or depression (J Affect Disord. 2016 Aug;200:74-81).
Seasonal affective disorder is commonly comorbid with ADHD. In another analysis from The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues determined that the prevalence of probable seasonal affective disorder using the Seasonal Pattern Assessment Questionnaire was 9.9% in participants with clinically significant ADHD symptoms, compared with 3.3% in the non-ADHD subjects. Self-reported delayed sleep onset was extremely common in participants with ADHD as well as in those with probable seasonal affective disorder (J Psychiat Res. 2016 Oct;81:87-94).
Patients with ADHD have an increased prevalence of obesity. Their chronic short sleep pushes them toward an unstable eating pattern in which they skip breakfast, then engage in binge eating later in the day. The hope is that treating the circadian rhythm disruption associated with ADHD will prevent obesity in this population (J Psychosom Res. 2015 Nov;79[5]:443-50).
“If you mess up sleep, you mess up the body: bowel movements, blood pressure, body temperature, the leptin/ghrelin ratio, reaction time, coordination. That’s why I call my patients chronically jet-lagged,” Dr. Kooij said.
She reported having no financial conflicts regarding her presentation.
PARIS – Converging evidence suggests that attention-deficit/hyperactivity disorder and sleep difficulties share a common underlying etiology involving circadian rhythm disturbance, J.J. Sandra Kooij, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.
“If you review the evidence, it looks more and more like ADHD and sleeplessness are two sides of the same physiological and mental coin,” said Dr. Kooij, a psychiatrist at VU University Medical Center, Amsterdam, and chair of the European Network Adult ADHD.
Since this study remains ongoing, Dr. Kooij focused instead on the evidence suggesting that ADHD and sleep problems have a shared etiology.
Multiple studies have shown that roughly 75% of children and adults with ADHD have sleep-onset insomnia. It takes them longer to fall asleep, and they have a shorter than normal sleep duration because they have to get up in the morning for school or work. Dr. Kooij and her colleagues have shown that in adult ADHD patients with delayed sleep onset syndrome, their evening dim light melatonin onset, change in core body temperature, and other physiologic harbingers of sleep are delayed by an average of 1.5 hours (J Sleep Res. 2013 Dec;22[6]:607-16).
“My ADHD patients sleep a mean of 5-6 hours per night on a chronic basis, versus 7-8 hours in normal individuals. It leads to daytime sleepiness and dysfunction due to inattentiveness and social problems,” the psychiatrist said.
Other investigators have demonstrated that the prevalence of ADHD varies across the United States and that geographic differences in solar intensity explain 34%-57% of this variance in ADHD rates. The investigators postulated that the ADHD-preventive effect of high solar irradiation might be tied to improvement in circadian clock disturbances (Biol Psychiatry. 2013 Oct 15;74[8]:585-90).
In a study of 2,090 adult participants in The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues showed that ADHD, depression, anxiety, and circadian rhythm sleep problems are fellow travelers.
The prevalence of sleep duration of fewer than 6 hours per night was 15% in subjects with high ADHD symptoms and a lifetime history of an anxiety and/or depression diagnosis, 5% in those with lifetime anxiety/depression but no ADHD, and 4% in healthy controls. Delayed sleep phase syndrome was present in 16% of individuals with ADHD and a history of depression and/or anxiety, 8% in those with a lifetime history of anxiety/depression without ADHD, and 5% of healthy controls. The take-home message: Circadian rhythm sleep disorders in patients with ADHD are not necessarily attributable to comorbid anxiety and/or depression (J Affect Disord. 2016 Aug;200:74-81).
Seasonal affective disorder is commonly comorbid with ADHD. In another analysis from The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues determined that the prevalence of probable seasonal affective disorder using the Seasonal Pattern Assessment Questionnaire was 9.9% in participants with clinically significant ADHD symptoms, compared with 3.3% in the non-ADHD subjects. Self-reported delayed sleep onset was extremely common in participants with ADHD as well as in those with probable seasonal affective disorder (J Psychiat Res. 2016 Oct;81:87-94).
Patients with ADHD have an increased prevalence of obesity. Their chronic short sleep pushes them toward an unstable eating pattern in which they skip breakfast, then engage in binge eating later in the day. The hope is that treating the circadian rhythm disruption associated with ADHD will prevent obesity in this population (J Psychosom Res. 2015 Nov;79[5]:443-50).
“If you mess up sleep, you mess up the body: bowel movements, blood pressure, body temperature, the leptin/ghrelin ratio, reaction time, coordination. That’s why I call my patients chronically jet-lagged,” Dr. Kooij said.
She reported having no financial conflicts regarding her presentation.
PARIS – Converging evidence suggests that attention-deficit/hyperactivity disorder and sleep difficulties share a common underlying etiology involving circadian rhythm disturbance, J.J. Sandra Kooij, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.
“If you review the evidence, it looks more and more like ADHD and sleeplessness are two sides of the same physiological and mental coin,” said Dr. Kooij, a psychiatrist at VU University Medical Center, Amsterdam, and chair of the European Network Adult ADHD.
Since this study remains ongoing, Dr. Kooij focused instead on the evidence suggesting that ADHD and sleep problems have a shared etiology.
Multiple studies have shown that roughly 75% of children and adults with ADHD have sleep-onset insomnia. It takes them longer to fall asleep, and they have a shorter than normal sleep duration because they have to get up in the morning for school or work. Dr. Kooij and her colleagues have shown that in adult ADHD patients with delayed sleep onset syndrome, their evening dim light melatonin onset, change in core body temperature, and other physiologic harbingers of sleep are delayed by an average of 1.5 hours (J Sleep Res. 2013 Dec;22[6]:607-16).
“My ADHD patients sleep a mean of 5-6 hours per night on a chronic basis, versus 7-8 hours in normal individuals. It leads to daytime sleepiness and dysfunction due to inattentiveness and social problems,” the psychiatrist said.
Other investigators have demonstrated that the prevalence of ADHD varies across the United States and that geographic differences in solar intensity explain 34%-57% of this variance in ADHD rates. The investigators postulated that the ADHD-preventive effect of high solar irradiation might be tied to improvement in circadian clock disturbances (Biol Psychiatry. 2013 Oct 15;74[8]:585-90).
In a study of 2,090 adult participants in The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues showed that ADHD, depression, anxiety, and circadian rhythm sleep problems are fellow travelers.
The prevalence of sleep duration of fewer than 6 hours per night was 15% in subjects with high ADHD symptoms and a lifetime history of an anxiety and/or depression diagnosis, 5% in those with lifetime anxiety/depression but no ADHD, and 4% in healthy controls. Delayed sleep phase syndrome was present in 16% of individuals with ADHD and a history of depression and/or anxiety, 8% in those with a lifetime history of anxiety/depression without ADHD, and 5% of healthy controls. The take-home message: Circadian rhythm sleep disorders in patients with ADHD are not necessarily attributable to comorbid anxiety and/or depression (J Affect Disord. 2016 Aug;200:74-81).
Seasonal affective disorder is commonly comorbid with ADHD. In another analysis from The Netherlands Study of Depression and Anxiety, Dr. Kooij and her colleagues determined that the prevalence of probable seasonal affective disorder using the Seasonal Pattern Assessment Questionnaire was 9.9% in participants with clinically significant ADHD symptoms, compared with 3.3% in the non-ADHD subjects. Self-reported delayed sleep onset was extremely common in participants with ADHD as well as in those with probable seasonal affective disorder (J Psychiat Res. 2016 Oct;81:87-94).
Patients with ADHD have an increased prevalence of obesity. Their chronic short sleep pushes them toward an unstable eating pattern in which they skip breakfast, then engage in binge eating later in the day. The hope is that treating the circadian rhythm disruption associated with ADHD will prevent obesity in this population (J Psychosom Res. 2015 Nov;79[5]:443-50).
“If you mess up sleep, you mess up the body: bowel movements, blood pressure, body temperature, the leptin/ghrelin ratio, reaction time, coordination. That’s why I call my patients chronically jet-lagged,” Dr. Kooij said.
She reported having no financial conflicts regarding her presentation.
EXPERT ANALYSIS FROM THE ECNP CONGRESS
Inhaled loxapine quells agitation in personality disorders
PARIS – The inhaled powder formulation of loxapine appears to be a safe and effective treatment for acute agitation in patients with personality disorders, Diego R. Mendez Mareque, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
Inhaled loxapine is approved for the treatment of acute agitation associated with schizophrenia or bipolar I disorder. Its use in patients with borderline personality and other personality disorders is off label. But this inhaled typical antipsychotic shows promise in filling an unmet need for a rapid-acting, minimally invasive treatment for acute agitation in patients with personality disorders, a very common scenario in psychiatric wards and emergency departments, and one that can quickly escalate to aggression and violence, noted Dr. Mendez Mareque of the Galician Health Service in Ferrol, Spain.
He presented a prospective, longitudinal, observational pilot study of 14 patients with personality disorders treated with a single 10-mg dose of inhaled loxapine while experiencing acute agitation in a psychiatric emergency department or psychiatric ward. Their mean baseline score on the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) was 20.8 out of a possible 35 points. The scale assesses five domains: excitement, tension, uncooperativeness, hostility, and poor impulse control.
Within 10 minutes after administration of inhaled loxapine by a health care professional, 11 patients showed a significant drop on the PANSS-EC. They were calm, nonsedated, and ready for assessment. Within 20 minutes, their PANSS-EC scores were reduced by roughly half, compared with baseline.
Three patients were nonresponders. They received rescue treatment with oral or injectable antipsychotics and benzodiazepines.
None of the 14 patients had a history of airway disease, and none experienced bronchospasm, a known possible side effect of inhaled loxapine, the psychiatrist noted.
The results of this Spanish observational study confirm the benefits of inhaled loxapine for treating agitation in patients with borderline personality disorder previously described in a German case series (J Clin Psychopharmacol. 2015 Dec;35[6]:741-3).
Dr. Mendez Mareque reported having no financial conflicts of interest regarding his study.
PARIS – The inhaled powder formulation of loxapine appears to be a safe and effective treatment for acute agitation in patients with personality disorders, Diego R. Mendez Mareque, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
Inhaled loxapine is approved for the treatment of acute agitation associated with schizophrenia or bipolar I disorder. Its use in patients with borderline personality and other personality disorders is off label. But this inhaled typical antipsychotic shows promise in filling an unmet need for a rapid-acting, minimally invasive treatment for acute agitation in patients with personality disorders, a very common scenario in psychiatric wards and emergency departments, and one that can quickly escalate to aggression and violence, noted Dr. Mendez Mareque of the Galician Health Service in Ferrol, Spain.
He presented a prospective, longitudinal, observational pilot study of 14 patients with personality disorders treated with a single 10-mg dose of inhaled loxapine while experiencing acute agitation in a psychiatric emergency department or psychiatric ward. Their mean baseline score on the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) was 20.8 out of a possible 35 points. The scale assesses five domains: excitement, tension, uncooperativeness, hostility, and poor impulse control.
Within 10 minutes after administration of inhaled loxapine by a health care professional, 11 patients showed a significant drop on the PANSS-EC. They were calm, nonsedated, and ready for assessment. Within 20 minutes, their PANSS-EC scores were reduced by roughly half, compared with baseline.
Three patients were nonresponders. They received rescue treatment with oral or injectable antipsychotics and benzodiazepines.
None of the 14 patients had a history of airway disease, and none experienced bronchospasm, a known possible side effect of inhaled loxapine, the psychiatrist noted.
The results of this Spanish observational study confirm the benefits of inhaled loxapine for treating agitation in patients with borderline personality disorder previously described in a German case series (J Clin Psychopharmacol. 2015 Dec;35[6]:741-3).
Dr. Mendez Mareque reported having no financial conflicts of interest regarding his study.
PARIS – The inhaled powder formulation of loxapine appears to be a safe and effective treatment for acute agitation in patients with personality disorders, Diego R. Mendez Mareque, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
Inhaled loxapine is approved for the treatment of acute agitation associated with schizophrenia or bipolar I disorder. Its use in patients with borderline personality and other personality disorders is off label. But this inhaled typical antipsychotic shows promise in filling an unmet need for a rapid-acting, minimally invasive treatment for acute agitation in patients with personality disorders, a very common scenario in psychiatric wards and emergency departments, and one that can quickly escalate to aggression and violence, noted Dr. Mendez Mareque of the Galician Health Service in Ferrol, Spain.
He presented a prospective, longitudinal, observational pilot study of 14 patients with personality disorders treated with a single 10-mg dose of inhaled loxapine while experiencing acute agitation in a psychiatric emergency department or psychiatric ward. Their mean baseline score on the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) was 20.8 out of a possible 35 points. The scale assesses five domains: excitement, tension, uncooperativeness, hostility, and poor impulse control.
Within 10 minutes after administration of inhaled loxapine by a health care professional, 11 patients showed a significant drop on the PANSS-EC. They were calm, nonsedated, and ready for assessment. Within 20 minutes, their PANSS-EC scores were reduced by roughly half, compared with baseline.
Three patients were nonresponders. They received rescue treatment with oral or injectable antipsychotics and benzodiazepines.
None of the 14 patients had a history of airway disease, and none experienced bronchospasm, a known possible side effect of inhaled loxapine, the psychiatrist noted.
The results of this Spanish observational study confirm the benefits of inhaled loxapine for treating agitation in patients with borderline personality disorder previously described in a German case series (J Clin Psychopharmacol. 2015 Dec;35[6]:741-3).
Dr. Mendez Mareque reported having no financial conflicts of interest regarding his study.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Eleven of 14 acutely agitated patients with various personality disorders were calm, nonsedated, and ready for assessment within 10 minutes after a single dose of inhaled loxapine.
Data source: A prospective observational pilot study of inhaled loxapine in 14 acutely agitated patients with personality disorders.
Disclosures: The study presenter reported having no financial conflicts of interest.
Treatment-resistant depression boosts early mortality
PARIS – Young adults with treatment-resistant depression have more than double the risk of all-cause mortality, compared with their peers with major depressive disorder that’s not treatment resistant, Johan Reutfors, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
Across the full age spectrum of adults with treatment-resistant depression, however, the magnitude of the increased risk associated with treatment-resistant depression is less extreme than in the 18- to 29-year-olds. Yet, the moderate overall 11% increased risk of all-cause mortality in adults with treatment-resistant depression, compared with those with non–treatment-resistant major depressive disorder remains both statistically significant and clinically meaningful, observed Dr. Reutfors, a psychiatrist at the Karolinska Institute in Stockholm.
During a mean 4.1 years of follow-up, 4,662 patients died. The all-cause mortality adjusted for age, gender, and a history of substance use disorders or self-harm was 2.17-fold greater in 18- to 29-year-olds who had treatment-resistant depression, compared with those with nonresistant major depressive disorder, 1.51-fold greater in 30- to 49-year-olds with treatment-resistant depression, and 1.18-fold greater in 50- to 69-year-olds with treatment-resistant depression.
In contrast, patients aged 70 or older with treatment-resistant depression had a significant 17% lower risk of all-cause mortality than those with non-TRD major depression. In an interview, Dr. Reutfors said this apparent protective effect was probably tied to survival bias.
“If you have lived so long that perhaps during your lifetime you’ve already had many depressive episodes, maybe only the healthier ones have survived,” he explained.
The all-cause mortality in patients with treatment-resistant depression and a history of self-harm was 37% greater than in patients without treatment-resistant depression.
The causes of excess mortality in the treatment-resistant depression group were quite different in the younger and older patients. In younger patients, the increased mortality was attributed mainly to suicides and accidents. In the older group, where the degree of excess risk was more modest, a variety of fatal illnesses figured more prominently.
The study was supported by Janssen. Dr. Reutfors reported having served as a paid speaker for Eli Lilly and receiving unrestricted grant support from Schering-Plough.
PARIS – Young adults with treatment-resistant depression have more than double the risk of all-cause mortality, compared with their peers with major depressive disorder that’s not treatment resistant, Johan Reutfors, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
Across the full age spectrum of adults with treatment-resistant depression, however, the magnitude of the increased risk associated with treatment-resistant depression is less extreme than in the 18- to 29-year-olds. Yet, the moderate overall 11% increased risk of all-cause mortality in adults with treatment-resistant depression, compared with those with non–treatment-resistant major depressive disorder remains both statistically significant and clinically meaningful, observed Dr. Reutfors, a psychiatrist at the Karolinska Institute in Stockholm.
During a mean 4.1 years of follow-up, 4,662 patients died. The all-cause mortality adjusted for age, gender, and a history of substance use disorders or self-harm was 2.17-fold greater in 18- to 29-year-olds who had treatment-resistant depression, compared with those with nonresistant major depressive disorder, 1.51-fold greater in 30- to 49-year-olds with treatment-resistant depression, and 1.18-fold greater in 50- to 69-year-olds with treatment-resistant depression.
In contrast, patients aged 70 or older with treatment-resistant depression had a significant 17% lower risk of all-cause mortality than those with non-TRD major depression. In an interview, Dr. Reutfors said this apparent protective effect was probably tied to survival bias.
“If you have lived so long that perhaps during your lifetime you’ve already had many depressive episodes, maybe only the healthier ones have survived,” he explained.
The all-cause mortality in patients with treatment-resistant depression and a history of self-harm was 37% greater than in patients without treatment-resistant depression.
The causes of excess mortality in the treatment-resistant depression group were quite different in the younger and older patients. In younger patients, the increased mortality was attributed mainly to suicides and accidents. In the older group, where the degree of excess risk was more modest, a variety of fatal illnesses figured more prominently.
The study was supported by Janssen. Dr. Reutfors reported having served as a paid speaker for Eli Lilly and receiving unrestricted grant support from Schering-Plough.
PARIS – Young adults with treatment-resistant depression have more than double the risk of all-cause mortality, compared with their peers with major depressive disorder that’s not treatment resistant, Johan Reutfors, MD, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
Across the full age spectrum of adults with treatment-resistant depression, however, the magnitude of the increased risk associated with treatment-resistant depression is less extreme than in the 18- to 29-year-olds. Yet, the moderate overall 11% increased risk of all-cause mortality in adults with treatment-resistant depression, compared with those with non–treatment-resistant major depressive disorder remains both statistically significant and clinically meaningful, observed Dr. Reutfors, a psychiatrist at the Karolinska Institute in Stockholm.
During a mean 4.1 years of follow-up, 4,662 patients died. The all-cause mortality adjusted for age, gender, and a history of substance use disorders or self-harm was 2.17-fold greater in 18- to 29-year-olds who had treatment-resistant depression, compared with those with nonresistant major depressive disorder, 1.51-fold greater in 30- to 49-year-olds with treatment-resistant depression, and 1.18-fold greater in 50- to 69-year-olds with treatment-resistant depression.
In contrast, patients aged 70 or older with treatment-resistant depression had a significant 17% lower risk of all-cause mortality than those with non-TRD major depression. In an interview, Dr. Reutfors said this apparent protective effect was probably tied to survival bias.
“If you have lived so long that perhaps during your lifetime you’ve already had many depressive episodes, maybe only the healthier ones have survived,” he explained.
The all-cause mortality in patients with treatment-resistant depression and a history of self-harm was 37% greater than in patients without treatment-resistant depression.
The causes of excess mortality in the treatment-resistant depression group were quite different in the younger and older patients. In younger patients, the increased mortality was attributed mainly to suicides and accidents. In the older group, where the degree of excess risk was more modest, a variety of fatal illnesses figured more prominently.
The study was supported by Janssen. Dr. Reutfors reported having served as a paid speaker for Eli Lilly and receiving unrestricted grant support from Schering-Plough.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Young adult Swedes with treatment-resistant major depressive disorder have an all-cause mortality nearly 2.2-fold higher than their peers with non–treatment-resistant major depression.
Data source: This retrospective cohort study used Swedish national databases to look at all-cause mortality in more than 127,000 adults under psychiatric care for major depressive disorder.
Disclosures: The study was supported by Janssen. The presenter reported having served as a paid speaker for Eli Lilly and receiving unrestricted grant support from Schering-Plough.
Schizophrenia’s silent epidemic: Iatrogenic sexual dysfunction
PARIS – Many psychiatrists have no inkling of how often the antipsychotic agents they prescribe cause hyperprolactinemia-related sexual dysfunction, or the serious negative consequences these common side effects have on quality of life and treatment adherence, Ángel L. Montejo, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.
Psychiatrists are largely uninformed about these matters, because for the most part, they avoid talking with their schizophrenia patients about their sexual activity or inquiring about sexual dysfunction. And they don’t perform the physical examinations that might reveal tell-tale stigmatizing gynecomastia or galactorrhea, according to Dr. Montejo, professor of psychiatry at the University of Salamanca (Spain).
The consensus report includes recommendations for the detection and management of the full range of manifestations of iatrogenic hyperprolactinemia, including osteoporosis and hip fracture, hypogonadism, premature menopause, cardiovascular disease, breast and endometrial cancer, and immunologic disorders.
However, the most common expression of antipsychotic-related hyperprolactinemia is sexual dysfunction, and that’s what Dr. Montejo focused on. This is an issue that directly relates to clinical outcomes. The literature shows that roughly 36% of male and 19% of female schizophrenia patients either stop taking their medication because of its sexual side effects, which include decreased libido, erectile difficulty, vaginal dryness, and anorgasmia, or are thinking about doing so. At least two in three schizophrenia patients engage in some sort of sexual activity. Sixty percent of patients say that having a sexual life is important to them. Yet 73% of psychiatrists in one survey indicated that they don’t interview their patients about their sexual relations.
“If sexual activity is good for you, why isn’t it good for your patients? We’re talking about love, about human relationships. Having a sexual and emotional life can help patients get the best outcomes,” said Dr. Montejo.
“If you don’t ask about sexual dysfunction, your patients won’t tell. Therefore, you may not see it, but your patients will experience it. They know the difference between their sexual life before treatment and during treatment,” he continued.
The incidence of sexual dysfunction in patients on antipsychotic therapy is a function of the agent they are on. Iatrogenic hyperprolactinemia is a consequence of intense blockade of dopamine D2 receptors. The most potent antipsychotic dopamine D2 receptor antagonists are risperidone and paliperidone, followed by haloperidol and most other first-generation antipsychotics.
A normal prolactin level is less than 25 ng/mL in women and less than 20 ng/mL in men. Endocrinologists divide hyperprolactinemia into three categories: mild hyperprolactinemia is a level of 25-50 ng/mL, moderate is 51-100 ng/mL, and severe is anything over 100 ng/mL.
In one study, 44% of patients on oral risperidone at a mean dose of 4.9 mg/day had moderate and 23% had severe hyperprolactinemia; in patients on the injectable long-acting formulation of the drug at a mean dose of 46.2 mg/month, 23% of patients had moderate and 31% had severe hyperprolactinemia. Patients on oral paliperidone at a mean dose of 8.5 mg/day had a 45% prevalence of moderate and an 18% rate of severe hyperprolactinemia, while 40% of those on long-acting injectable paliperidone at a mean of 104 mg/month had moderate and another 40% had severe hyperprolactinemia.
Sixty to 80% of patients on risperidone or paliperidone experience hyperprolactinemia-induced sexual dysfunction. At the other end of the spectrum is the prolactin-sparing antipsychotic aripiprazole, which is associated with sexual dysfunction in about 5% of treated patients. In a meta-analysis, the other prolactin-sparing antipsychotics included ziprasidone, with a 10% rate, quetiapine at 12%, and olanzapine with a 20% rate.
Screening tests for sexual dysfunction
Psychiatrists who are uncomfortable asking patients about sexual dysfunction or don’t want to take the time to do so have other good options. Four easy-to-use, validated instruments are available for free online: the four-question Arizona Sexual Experiences Scale; the Change in Sexual Function Questionnaire, or CSFQ; the Sex Effects Scale, or SexFX; and the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SALSEX).
Managing antipsychotic-induced hyperprolactinemia
The Spanish consensus panel recommended that before psychiatrists prescribe an antipsychotic, they should always explain to patients their risk of antipsychotic-related hyperprolactinemia and make an assessment of personal and family history of risk factors for its possible downstream consequences, including osteoporosis and cancer. And Dr. Montejo stressed that clinicians must “always, always, always” get a baseline serum prolactin measurement, to be repeated after increasing the drug dosage, changing antipsychotics, or upon development of symptoms of hyperprolactinemia.
When a patient’s prolactin level climbs above 50 ng/mL or symptoms of hyperprolactinemia arise, the preferred strategy is to switch to a prolactin-sparing antipsychotic. Most of the alternative options are unsatisfactory. For example, waiting for a sexual side effect to pass is pointless, because it won’t happen spontaneously. A drug holiday undermines compliance. Reducing the antipsychotic dose increases the risk of relapse.
And as for prescribing adjunctive dopamine agonist therapy, well: “Adding a dopamine agonist is not the first step. It should be one of the last steps, because it greatly increases the odds of worsening psychosis,” Dr. Montejo said.
If switching to a different antipsychotic is not possible, the expert panel recommended add-on aripiprazole, accompanied if possible by a downward dose adjustment of the offending antipsychotic. This is an effective way to lower elevated serum prolactin levels.
It’s appropriate to order a lumbar spine and proximal femur bone mineral density measurement in patients on antipsychotic agents if they are older than age 65, have had amenorrhea for at least 6 months, experienced menopause before age 35, have a body mass index below 19 kg/m2, or are experiencing any symptoms of hyperprolactinemia, including sexual dysfunction, according to the Spanish consensus algorithm.
Dr. Montejo reported receiving research grants from and/or serving as a consultant to more than half a dozen pharmaceutical companies.
PARIS – Many psychiatrists have no inkling of how often the antipsychotic agents they prescribe cause hyperprolactinemia-related sexual dysfunction, or the serious negative consequences these common side effects have on quality of life and treatment adherence, Ángel L. Montejo, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.
Psychiatrists are largely uninformed about these matters, because for the most part, they avoid talking with their schizophrenia patients about their sexual activity or inquiring about sexual dysfunction. And they don’t perform the physical examinations that might reveal tell-tale stigmatizing gynecomastia or galactorrhea, according to Dr. Montejo, professor of psychiatry at the University of Salamanca (Spain).
The consensus report includes recommendations for the detection and management of the full range of manifestations of iatrogenic hyperprolactinemia, including osteoporosis and hip fracture, hypogonadism, premature menopause, cardiovascular disease, breast and endometrial cancer, and immunologic disorders.
However, the most common expression of antipsychotic-related hyperprolactinemia is sexual dysfunction, and that’s what Dr. Montejo focused on. This is an issue that directly relates to clinical outcomes. The literature shows that roughly 36% of male and 19% of female schizophrenia patients either stop taking their medication because of its sexual side effects, which include decreased libido, erectile difficulty, vaginal dryness, and anorgasmia, or are thinking about doing so. At least two in three schizophrenia patients engage in some sort of sexual activity. Sixty percent of patients say that having a sexual life is important to them. Yet 73% of psychiatrists in one survey indicated that they don’t interview their patients about their sexual relations.
“If sexual activity is good for you, why isn’t it good for your patients? We’re talking about love, about human relationships. Having a sexual and emotional life can help patients get the best outcomes,” said Dr. Montejo.
“If you don’t ask about sexual dysfunction, your patients won’t tell. Therefore, you may not see it, but your patients will experience it. They know the difference between their sexual life before treatment and during treatment,” he continued.
The incidence of sexual dysfunction in patients on antipsychotic therapy is a function of the agent they are on. Iatrogenic hyperprolactinemia is a consequence of intense blockade of dopamine D2 receptors. The most potent antipsychotic dopamine D2 receptor antagonists are risperidone and paliperidone, followed by haloperidol and most other first-generation antipsychotics.
A normal prolactin level is less than 25 ng/mL in women and less than 20 ng/mL in men. Endocrinologists divide hyperprolactinemia into three categories: mild hyperprolactinemia is a level of 25-50 ng/mL, moderate is 51-100 ng/mL, and severe is anything over 100 ng/mL.
In one study, 44% of patients on oral risperidone at a mean dose of 4.9 mg/day had moderate and 23% had severe hyperprolactinemia; in patients on the injectable long-acting formulation of the drug at a mean dose of 46.2 mg/month, 23% of patients had moderate and 31% had severe hyperprolactinemia. Patients on oral paliperidone at a mean dose of 8.5 mg/day had a 45% prevalence of moderate and an 18% rate of severe hyperprolactinemia, while 40% of those on long-acting injectable paliperidone at a mean of 104 mg/month had moderate and another 40% had severe hyperprolactinemia.
Sixty to 80% of patients on risperidone or paliperidone experience hyperprolactinemia-induced sexual dysfunction. At the other end of the spectrum is the prolactin-sparing antipsychotic aripiprazole, which is associated with sexual dysfunction in about 5% of treated patients. In a meta-analysis, the other prolactin-sparing antipsychotics included ziprasidone, with a 10% rate, quetiapine at 12%, and olanzapine with a 20% rate.
Screening tests for sexual dysfunction
Psychiatrists who are uncomfortable asking patients about sexual dysfunction or don’t want to take the time to do so have other good options. Four easy-to-use, validated instruments are available for free online: the four-question Arizona Sexual Experiences Scale; the Change in Sexual Function Questionnaire, or CSFQ; the Sex Effects Scale, or SexFX; and the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SALSEX).
Managing antipsychotic-induced hyperprolactinemia
The Spanish consensus panel recommended that before psychiatrists prescribe an antipsychotic, they should always explain to patients their risk of antipsychotic-related hyperprolactinemia and make an assessment of personal and family history of risk factors for its possible downstream consequences, including osteoporosis and cancer. And Dr. Montejo stressed that clinicians must “always, always, always” get a baseline serum prolactin measurement, to be repeated after increasing the drug dosage, changing antipsychotics, or upon development of symptoms of hyperprolactinemia.
When a patient’s prolactin level climbs above 50 ng/mL or symptoms of hyperprolactinemia arise, the preferred strategy is to switch to a prolactin-sparing antipsychotic. Most of the alternative options are unsatisfactory. For example, waiting for a sexual side effect to pass is pointless, because it won’t happen spontaneously. A drug holiday undermines compliance. Reducing the antipsychotic dose increases the risk of relapse.
And as for prescribing adjunctive dopamine agonist therapy, well: “Adding a dopamine agonist is not the first step. It should be one of the last steps, because it greatly increases the odds of worsening psychosis,” Dr. Montejo said.
If switching to a different antipsychotic is not possible, the expert panel recommended add-on aripiprazole, accompanied if possible by a downward dose adjustment of the offending antipsychotic. This is an effective way to lower elevated serum prolactin levels.
It’s appropriate to order a lumbar spine and proximal femur bone mineral density measurement in patients on antipsychotic agents if they are older than age 65, have had amenorrhea for at least 6 months, experienced menopause before age 35, have a body mass index below 19 kg/m2, or are experiencing any symptoms of hyperprolactinemia, including sexual dysfunction, according to the Spanish consensus algorithm.
Dr. Montejo reported receiving research grants from and/or serving as a consultant to more than half a dozen pharmaceutical companies.
PARIS – Many psychiatrists have no inkling of how often the antipsychotic agents they prescribe cause hyperprolactinemia-related sexual dysfunction, or the serious negative consequences these common side effects have on quality of life and treatment adherence, Ángel L. Montejo, MD, PhD, declared at the annual congress of the European College of Neuropsychopharmacology.
Psychiatrists are largely uninformed about these matters, because for the most part, they avoid talking with their schizophrenia patients about their sexual activity or inquiring about sexual dysfunction. And they don’t perform the physical examinations that might reveal tell-tale stigmatizing gynecomastia or galactorrhea, according to Dr. Montejo, professor of psychiatry at the University of Salamanca (Spain).
The consensus report includes recommendations for the detection and management of the full range of manifestations of iatrogenic hyperprolactinemia, including osteoporosis and hip fracture, hypogonadism, premature menopause, cardiovascular disease, breast and endometrial cancer, and immunologic disorders.
However, the most common expression of antipsychotic-related hyperprolactinemia is sexual dysfunction, and that’s what Dr. Montejo focused on. This is an issue that directly relates to clinical outcomes. The literature shows that roughly 36% of male and 19% of female schizophrenia patients either stop taking their medication because of its sexual side effects, which include decreased libido, erectile difficulty, vaginal dryness, and anorgasmia, or are thinking about doing so. At least two in three schizophrenia patients engage in some sort of sexual activity. Sixty percent of patients say that having a sexual life is important to them. Yet 73% of psychiatrists in one survey indicated that they don’t interview their patients about their sexual relations.
“If sexual activity is good for you, why isn’t it good for your patients? We’re talking about love, about human relationships. Having a sexual and emotional life can help patients get the best outcomes,” said Dr. Montejo.
“If you don’t ask about sexual dysfunction, your patients won’t tell. Therefore, you may not see it, but your patients will experience it. They know the difference between their sexual life before treatment and during treatment,” he continued.
The incidence of sexual dysfunction in patients on antipsychotic therapy is a function of the agent they are on. Iatrogenic hyperprolactinemia is a consequence of intense blockade of dopamine D2 receptors. The most potent antipsychotic dopamine D2 receptor antagonists are risperidone and paliperidone, followed by haloperidol and most other first-generation antipsychotics.
A normal prolactin level is less than 25 ng/mL in women and less than 20 ng/mL in men. Endocrinologists divide hyperprolactinemia into three categories: mild hyperprolactinemia is a level of 25-50 ng/mL, moderate is 51-100 ng/mL, and severe is anything over 100 ng/mL.
In one study, 44% of patients on oral risperidone at a mean dose of 4.9 mg/day had moderate and 23% had severe hyperprolactinemia; in patients on the injectable long-acting formulation of the drug at a mean dose of 46.2 mg/month, 23% of patients had moderate and 31% had severe hyperprolactinemia. Patients on oral paliperidone at a mean dose of 8.5 mg/day had a 45% prevalence of moderate and an 18% rate of severe hyperprolactinemia, while 40% of those on long-acting injectable paliperidone at a mean of 104 mg/month had moderate and another 40% had severe hyperprolactinemia.
Sixty to 80% of patients on risperidone or paliperidone experience hyperprolactinemia-induced sexual dysfunction. At the other end of the spectrum is the prolactin-sparing antipsychotic aripiprazole, which is associated with sexual dysfunction in about 5% of treated patients. In a meta-analysis, the other prolactin-sparing antipsychotics included ziprasidone, with a 10% rate, quetiapine at 12%, and olanzapine with a 20% rate.
Screening tests for sexual dysfunction
Psychiatrists who are uncomfortable asking patients about sexual dysfunction or don’t want to take the time to do so have other good options. Four easy-to-use, validated instruments are available for free online: the four-question Arizona Sexual Experiences Scale; the Change in Sexual Function Questionnaire, or CSFQ; the Sex Effects Scale, or SexFX; and the Psychotropic-Related Sexual Dysfunction Questionnaire (PRSexDQ-SALSEX).
Managing antipsychotic-induced hyperprolactinemia
The Spanish consensus panel recommended that before psychiatrists prescribe an antipsychotic, they should always explain to patients their risk of antipsychotic-related hyperprolactinemia and make an assessment of personal and family history of risk factors for its possible downstream consequences, including osteoporosis and cancer. And Dr. Montejo stressed that clinicians must “always, always, always” get a baseline serum prolactin measurement, to be repeated after increasing the drug dosage, changing antipsychotics, or upon development of symptoms of hyperprolactinemia.
When a patient’s prolactin level climbs above 50 ng/mL or symptoms of hyperprolactinemia arise, the preferred strategy is to switch to a prolactin-sparing antipsychotic. Most of the alternative options are unsatisfactory. For example, waiting for a sexual side effect to pass is pointless, because it won’t happen spontaneously. A drug holiday undermines compliance. Reducing the antipsychotic dose increases the risk of relapse.
And as for prescribing adjunctive dopamine agonist therapy, well: “Adding a dopamine agonist is not the first step. It should be one of the last steps, because it greatly increases the odds of worsening psychosis,” Dr. Montejo said.
If switching to a different antipsychotic is not possible, the expert panel recommended add-on aripiprazole, accompanied if possible by a downward dose adjustment of the offending antipsychotic. This is an effective way to lower elevated serum prolactin levels.
It’s appropriate to order a lumbar spine and proximal femur bone mineral density measurement in patients on antipsychotic agents if they are older than age 65, have had amenorrhea for at least 6 months, experienced menopause before age 35, have a body mass index below 19 kg/m2, or are experiencing any symptoms of hyperprolactinemia, including sexual dysfunction, according to the Spanish consensus algorithm.
Dr. Montejo reported receiving research grants from and/or serving as a consultant to more than half a dozen pharmaceutical companies.
EXPERT ANALYSIS FROM THE ECNP CONGRESS
Scandinavian registries answer key questions about ADHD
PARIS – Huge longitudinal Scandinavian population registries constitute a unique data source that, in recent years, has provided new insights into attention-deficit/hyperactivity disorder and its associated risks of suicidal behavior, accidents, and early mortality, Henrik Larsson, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“Randomized, controlled trials have provided little information about real-world effectiveness of ADHD medications, such as their potential effects on adverse health outcomes,” said Dr. Larsson of the Karolinska Institute in Stockholm.
Suicidality
Dr. Larsson was senior author of a Swedish national registry study that identified 51,707 patients with ADHD matched by sex and birth year to 258,535 controls. The ADHD patients had significantly higher rates of both attempted and completed suicide.
After adjustment for socioeconomic status, these individuals were at 8.46-fold increased risk for attempted suicide. However, after further adjustment for comorbid psychiatric disorders, this dropped substantially to a 3.62-fold increased risk.
The same pattern pertained to completed suicide: The risk after adjustment for socioeconomic status was increased 12.3-fold in individuals with ADHD, compared with controls, but the risk dropped to 5.91-fold after further adjustment for comorbid psychiatric disorders (JAMA Psychiatry. 2014 Aug;71[8]:958-64).
The clinical take home point: “Detection and treatment of comorbid conditions probably will help reduce suicidal behavior in ADHD,” Dr. Larsson said.
This study also showed that increased familial risk also is a key factor in the increased risk of suicidal behavior in the ADHD population. Parents of individuals with ADHD were at 2.42-fold increased risk of attempted suicide, compared with controls, and full siblings were at 2.28-fold increased risk. In contrast, the risk in half-siblings, while significantly greater than in controls, was lower than in the genetically closer first-degree relatives: Maternal half-siblings were at 1.57-fold increased risk, and paternal half-siblings were at 1.57-fold greater risk. Cousins were at 1.39-fold increased risk.
The same held true for completed suicide risk. And the familial associations remained significant even after excluding relatives with ADHD.
“Regarding the shared familial factors, I’m tempted to hypothesize that this might involve pleiotropic effects reflecting genetic variants associated with impulsivity,” said Dr. Larsson. To further understand the biological mechanisms underlying ADHD and associated adverse health outcomes requires multiple disciplines to work together. For such work, Dr. Larsson collaborates with international colleagues in several consortia.
ADHD medications and suicidality
Concerns regarding this question were raised by a meta-analysis based on clinical trials data that suggested patients’ increased suicidality might be caused by the effects of ADHD medications. But the meta-analysis was seriously flawed by what epidemiologists call confounding by indication, which is the potential for bias to be introduced when a group of patients on medication is compared with another group off medication. The confounding results from the fact that ADHD patients on medication are different from those who aren’t: They are likely to be more symptomatic and have more comorbidities.
To bypass the confounding issue, Dr. Larsson and his coinvestigators turned to the Swedish registries and identified 37,936 patients with ADHD with a total of 7,019 suicide-related events during nearly 151,000 person-years of follow-up. When they compared patients on drug treatment with those who were not, they found – as in the other investigators’ meta-analysis – that drug treatment was associated with a statistically significant 1.31-fold increased risk of suicide-related events. However, when they performed a more appropriate between-individual analysis, Dr. Larsson and his colleagues found that, when patients with ADHD were using stimulant medications, they had a significant 19% lower risk of suicide-related events than when they were off medication. While on nonstimulant ADHD medications, their suicidality risk was no different from when off medication (BMJ. 2014 Jun 18;348:g3769. doi: 10.1136/bmj.g3769).
ADHD and early mortality risk
Prior studies have established that ADHD is associated with a proclivity to engage in risk-taking behaviors, including substance abuse, criminality, risky sexual behavior, and accidents, which are themselves associated with early mortality.
Sure enough, when Danish investigators turned to their national registries, identified 32,061 individuals with ADHD born during 1981-2011, and followed them through 2013, they found that, during nearly 25 million person-years of follow-up, the mortality rate was 5.85 deaths per 10,000 person-years in individuals with ADHD, compared with 2.21 deaths per 10,000 person-years in controls, resulting in a fully adjusted mortality rate ratio of 2.07. The rate ratio was 1.86 for ADHD patients under age 6 years, 1.58 in those aged 6-17 years, and 4.25 for patients aged 18 years and older (Lancet. 2015 May 30;385[9983]:2190-6).
Accidents were the most common cause of death. Could ADHD medications modify this risk of fatal accidents?
Serious motor vehicle accidents
Dr. Larsson and his coinvestigators used registry data to follow 17,408 Swedish adults with ADHD for serious transport accidents involving a trip to the emergency room or death during 2006-2009. The risk was increased by an adjusted 1.47-fold in men with ADHD and by 1.45-fold in women with the disorder. However, in the within-individual analysis, men were 58% less likely to have a serious transport accident when they were on ADHD medication than when off medication. There was no statistically significant effect of ADHD medications on the risk in women with ADHD.
The investigators estimated that 41%-49% of transport accidents in men with ADHD could have been avoided had they been on drug therapy continuously throughout the follow-up period (JAMA Psychiatry. 2014 Mar;71[3]:319-25).
Similar results – that is, data showing that being on ADHD medication reduces the elevated risk of serious accidents – have been reported in four other independent studies conducted in Denmark, Germany, Hong Kong, and most recently in a U.S. analysis by Dr. Larsson and coinvestigators of more than 2.3 million patients with ADHD in a U.S. commercial health insurance claims database (JAMA Psychiatry. 2017 Jun 1;74[6]:597-603).
These findings collectively highlight the public health importance of diagnosing and treating ADHD.
But Dr. Larsson wanted his audience to take home another key lesson: “ADHD is a disorder that can be associated with serious outcomes, including suicide and accidents. It’s nevertheless important to remember that the absolute risks here are very low for any of these outcomes, so the majority of individuals with ADHD will never suffer from any of these outcomes. It’s important to keep that in mind.”
Dr. Larsson’s research is funded by the Swedish Research Council, the National Institute of Mental Health, FORTE, Horizon 2020, and Shire.
[email protected]
PARIS – Huge longitudinal Scandinavian population registries constitute a unique data source that, in recent years, has provided new insights into attention-deficit/hyperactivity disorder and its associated risks of suicidal behavior, accidents, and early mortality, Henrik Larsson, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“Randomized, controlled trials have provided little information about real-world effectiveness of ADHD medications, such as their potential effects on adverse health outcomes,” said Dr. Larsson of the Karolinska Institute in Stockholm.
Suicidality
Dr. Larsson was senior author of a Swedish national registry study that identified 51,707 patients with ADHD matched by sex and birth year to 258,535 controls. The ADHD patients had significantly higher rates of both attempted and completed suicide.
After adjustment for socioeconomic status, these individuals were at 8.46-fold increased risk for attempted suicide. However, after further adjustment for comorbid psychiatric disorders, this dropped substantially to a 3.62-fold increased risk.
The same pattern pertained to completed suicide: The risk after adjustment for socioeconomic status was increased 12.3-fold in individuals with ADHD, compared with controls, but the risk dropped to 5.91-fold after further adjustment for comorbid psychiatric disorders (JAMA Psychiatry. 2014 Aug;71[8]:958-64).
The clinical take home point: “Detection and treatment of comorbid conditions probably will help reduce suicidal behavior in ADHD,” Dr. Larsson said.
This study also showed that increased familial risk also is a key factor in the increased risk of suicidal behavior in the ADHD population. Parents of individuals with ADHD were at 2.42-fold increased risk of attempted suicide, compared with controls, and full siblings were at 2.28-fold increased risk. In contrast, the risk in half-siblings, while significantly greater than in controls, was lower than in the genetically closer first-degree relatives: Maternal half-siblings were at 1.57-fold increased risk, and paternal half-siblings were at 1.57-fold greater risk. Cousins were at 1.39-fold increased risk.
The same held true for completed suicide risk. And the familial associations remained significant even after excluding relatives with ADHD.
“Regarding the shared familial factors, I’m tempted to hypothesize that this might involve pleiotropic effects reflecting genetic variants associated with impulsivity,” said Dr. Larsson. To further understand the biological mechanisms underlying ADHD and associated adverse health outcomes requires multiple disciplines to work together. For such work, Dr. Larsson collaborates with international colleagues in several consortia.
ADHD medications and suicidality
Concerns regarding this question were raised by a meta-analysis based on clinical trials data that suggested patients’ increased suicidality might be caused by the effects of ADHD medications. But the meta-analysis was seriously flawed by what epidemiologists call confounding by indication, which is the potential for bias to be introduced when a group of patients on medication is compared with another group off medication. The confounding results from the fact that ADHD patients on medication are different from those who aren’t: They are likely to be more symptomatic and have more comorbidities.
To bypass the confounding issue, Dr. Larsson and his coinvestigators turned to the Swedish registries and identified 37,936 patients with ADHD with a total of 7,019 suicide-related events during nearly 151,000 person-years of follow-up. When they compared patients on drug treatment with those who were not, they found – as in the other investigators’ meta-analysis – that drug treatment was associated with a statistically significant 1.31-fold increased risk of suicide-related events. However, when they performed a more appropriate between-individual analysis, Dr. Larsson and his colleagues found that, when patients with ADHD were using stimulant medications, they had a significant 19% lower risk of suicide-related events than when they were off medication. While on nonstimulant ADHD medications, their suicidality risk was no different from when off medication (BMJ. 2014 Jun 18;348:g3769. doi: 10.1136/bmj.g3769).
ADHD and early mortality risk
Prior studies have established that ADHD is associated with a proclivity to engage in risk-taking behaviors, including substance abuse, criminality, risky sexual behavior, and accidents, which are themselves associated with early mortality.
Sure enough, when Danish investigators turned to their national registries, identified 32,061 individuals with ADHD born during 1981-2011, and followed them through 2013, they found that, during nearly 25 million person-years of follow-up, the mortality rate was 5.85 deaths per 10,000 person-years in individuals with ADHD, compared with 2.21 deaths per 10,000 person-years in controls, resulting in a fully adjusted mortality rate ratio of 2.07. The rate ratio was 1.86 for ADHD patients under age 6 years, 1.58 in those aged 6-17 years, and 4.25 for patients aged 18 years and older (Lancet. 2015 May 30;385[9983]:2190-6).
Accidents were the most common cause of death. Could ADHD medications modify this risk of fatal accidents?
Serious motor vehicle accidents
Dr. Larsson and his coinvestigators used registry data to follow 17,408 Swedish adults with ADHD for serious transport accidents involving a trip to the emergency room or death during 2006-2009. The risk was increased by an adjusted 1.47-fold in men with ADHD and by 1.45-fold in women with the disorder. However, in the within-individual analysis, men were 58% less likely to have a serious transport accident when they were on ADHD medication than when off medication. There was no statistically significant effect of ADHD medications on the risk in women with ADHD.
The investigators estimated that 41%-49% of transport accidents in men with ADHD could have been avoided had they been on drug therapy continuously throughout the follow-up period (JAMA Psychiatry. 2014 Mar;71[3]:319-25).
Similar results – that is, data showing that being on ADHD medication reduces the elevated risk of serious accidents – have been reported in four other independent studies conducted in Denmark, Germany, Hong Kong, and most recently in a U.S. analysis by Dr. Larsson and coinvestigators of more than 2.3 million patients with ADHD in a U.S. commercial health insurance claims database (JAMA Psychiatry. 2017 Jun 1;74[6]:597-603).
These findings collectively highlight the public health importance of diagnosing and treating ADHD.
But Dr. Larsson wanted his audience to take home another key lesson: “ADHD is a disorder that can be associated with serious outcomes, including suicide and accidents. It’s nevertheless important to remember that the absolute risks here are very low for any of these outcomes, so the majority of individuals with ADHD will never suffer from any of these outcomes. It’s important to keep that in mind.”
Dr. Larsson’s research is funded by the Swedish Research Council, the National Institute of Mental Health, FORTE, Horizon 2020, and Shire.
[email protected]
PARIS – Huge longitudinal Scandinavian population registries constitute a unique data source that, in recent years, has provided new insights into attention-deficit/hyperactivity disorder and its associated risks of suicidal behavior, accidents, and early mortality, Henrik Larsson, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
“Randomized, controlled trials have provided little information about real-world effectiveness of ADHD medications, such as their potential effects on adverse health outcomes,” said Dr. Larsson of the Karolinska Institute in Stockholm.
Suicidality
Dr. Larsson was senior author of a Swedish national registry study that identified 51,707 patients with ADHD matched by sex and birth year to 258,535 controls. The ADHD patients had significantly higher rates of both attempted and completed suicide.
After adjustment for socioeconomic status, these individuals were at 8.46-fold increased risk for attempted suicide. However, after further adjustment for comorbid psychiatric disorders, this dropped substantially to a 3.62-fold increased risk.
The same pattern pertained to completed suicide: The risk after adjustment for socioeconomic status was increased 12.3-fold in individuals with ADHD, compared with controls, but the risk dropped to 5.91-fold after further adjustment for comorbid psychiatric disorders (JAMA Psychiatry. 2014 Aug;71[8]:958-64).
The clinical take home point: “Detection and treatment of comorbid conditions probably will help reduce suicidal behavior in ADHD,” Dr. Larsson said.
This study also showed that increased familial risk also is a key factor in the increased risk of suicidal behavior in the ADHD population. Parents of individuals with ADHD were at 2.42-fold increased risk of attempted suicide, compared with controls, and full siblings were at 2.28-fold increased risk. In contrast, the risk in half-siblings, while significantly greater than in controls, was lower than in the genetically closer first-degree relatives: Maternal half-siblings were at 1.57-fold increased risk, and paternal half-siblings were at 1.57-fold greater risk. Cousins were at 1.39-fold increased risk.
The same held true for completed suicide risk. And the familial associations remained significant even after excluding relatives with ADHD.
“Regarding the shared familial factors, I’m tempted to hypothesize that this might involve pleiotropic effects reflecting genetic variants associated with impulsivity,” said Dr. Larsson. To further understand the biological mechanisms underlying ADHD and associated adverse health outcomes requires multiple disciplines to work together. For such work, Dr. Larsson collaborates with international colleagues in several consortia.
ADHD medications and suicidality
Concerns regarding this question were raised by a meta-analysis based on clinical trials data that suggested patients’ increased suicidality might be caused by the effects of ADHD medications. But the meta-analysis was seriously flawed by what epidemiologists call confounding by indication, which is the potential for bias to be introduced when a group of patients on medication is compared with another group off medication. The confounding results from the fact that ADHD patients on medication are different from those who aren’t: They are likely to be more symptomatic and have more comorbidities.
To bypass the confounding issue, Dr. Larsson and his coinvestigators turned to the Swedish registries and identified 37,936 patients with ADHD with a total of 7,019 suicide-related events during nearly 151,000 person-years of follow-up. When they compared patients on drug treatment with those who were not, they found – as in the other investigators’ meta-analysis – that drug treatment was associated with a statistically significant 1.31-fold increased risk of suicide-related events. However, when they performed a more appropriate between-individual analysis, Dr. Larsson and his colleagues found that, when patients with ADHD were using stimulant medications, they had a significant 19% lower risk of suicide-related events than when they were off medication. While on nonstimulant ADHD medications, their suicidality risk was no different from when off medication (BMJ. 2014 Jun 18;348:g3769. doi: 10.1136/bmj.g3769).
ADHD and early mortality risk
Prior studies have established that ADHD is associated with a proclivity to engage in risk-taking behaviors, including substance abuse, criminality, risky sexual behavior, and accidents, which are themselves associated with early mortality.
Sure enough, when Danish investigators turned to their national registries, identified 32,061 individuals with ADHD born during 1981-2011, and followed them through 2013, they found that, during nearly 25 million person-years of follow-up, the mortality rate was 5.85 deaths per 10,000 person-years in individuals with ADHD, compared with 2.21 deaths per 10,000 person-years in controls, resulting in a fully adjusted mortality rate ratio of 2.07. The rate ratio was 1.86 for ADHD patients under age 6 years, 1.58 in those aged 6-17 years, and 4.25 for patients aged 18 years and older (Lancet. 2015 May 30;385[9983]:2190-6).
Accidents were the most common cause of death. Could ADHD medications modify this risk of fatal accidents?
Serious motor vehicle accidents
Dr. Larsson and his coinvestigators used registry data to follow 17,408 Swedish adults with ADHD for serious transport accidents involving a trip to the emergency room or death during 2006-2009. The risk was increased by an adjusted 1.47-fold in men with ADHD and by 1.45-fold in women with the disorder. However, in the within-individual analysis, men were 58% less likely to have a serious transport accident when they were on ADHD medication than when off medication. There was no statistically significant effect of ADHD medications on the risk in women with ADHD.
The investigators estimated that 41%-49% of transport accidents in men with ADHD could have been avoided had they been on drug therapy continuously throughout the follow-up period (JAMA Psychiatry. 2014 Mar;71[3]:319-25).
Similar results – that is, data showing that being on ADHD medication reduces the elevated risk of serious accidents – have been reported in four other independent studies conducted in Denmark, Germany, Hong Kong, and most recently in a U.S. analysis by Dr. Larsson and coinvestigators of more than 2.3 million patients with ADHD in a U.S. commercial health insurance claims database (JAMA Psychiatry. 2017 Jun 1;74[6]:597-603).
These findings collectively highlight the public health importance of diagnosing and treating ADHD.
But Dr. Larsson wanted his audience to take home another key lesson: “ADHD is a disorder that can be associated with serious outcomes, including suicide and accidents. It’s nevertheless important to remember that the absolute risks here are very low for any of these outcomes, so the majority of individuals with ADHD will never suffer from any of these outcomes. It’s important to keep that in mind.”
Dr. Larsson’s research is funded by the Swedish Research Council, the National Institute of Mental Health, FORTE, Horizon 2020, and Shire.
[email protected]
expert analysis from THE ECNP CONGRESS