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MDMA – the love drug – makes a therapeutic comeback
VIENNA – What a difference a decade can make in the world of psychiatry.
Take, for example, the case of 3,4-methylenedioxymethamphetamine, better known as MDMA or, when used recreationally, as ecstasy, the love drug.
“Ten years ago at pretty much every scientific meeting where MDMA was being discussed, people were looking to find problems with it. People were dredging around trying to vilify this drug, because there was a hope that it might cause brain damage, which would justify having made its use illicit. Ten years later, we’ve changed direction completely, from fear and hating MDMA to loving it. Now we’re talking about the possibility that MDMA might actually heal the brain, and restoring MDMA to the therapeutic armamentarium,” David Nutt, MD, observed at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the drug’s potential as an adjunct to psychotherapy in patients with posttraumatic stress disorder was the topic of a packed-to-the-gills session in the largest hall at the ECNP Congress, where Dr. Nutt highlighted recent insights into the psychopharmacology of MDMA and other speakers described evidence of the drug’s salutary effects on autobiographical memory and social cognition.
“The biggest problem with MDMA is its name,” quipped Dr. Nutt, professor of neuropsychopharmacology at Imperial College London.
“It used to be called ‘empathy,’ but when it started being used recreationally at raves and in the clubs, the dealers decided to change its name to ‘ecstasy.’ And that created havoc, because there’s nothing that aged editors of newspapers hate more than young people having ecstasy. They hated the term, and so the drug had to go,” according to the psychiatrist.
MDMA’s comeback as a potentially valuable medication in psychiatry can be traced to the first report of the drug’s impressive success when used as an adjunct to psychotherapy in a randomized, placebo-controlled pilot study. Michael C. Mithoefer, MD, a psychiatrist in private practice in South Carolina, and his coinvestigators stunned the psychiatric world by reporting that 10 of 12 patients with chronic PTSD refractory to both medications and psychotherapy showed significant clinical improvement in response to just two sessions of MDMA-assisted psychotherapy supplementing a more conventional course of psychotherapy (J Psychopharmacology. 2011 Apr;25[4]:439-52).
Moreover, the benefits proved durable: In a subsequent paper, the investigators reported the clinical benefit of this two-dose treatment program persisted at a mean 3.8 years of follow-up and no safety concerns had been seen (J Psychopharmacol. 2013 Jan;27[1]:28-39).
This study, which eventually drew the attention of military veterans’ groups with political clout, proved hugely influential, especially since PTSD is so common and often is highly treatment resistant.
“We’re now living in a very strange world where trauma has in some ways become the No. 1 problem facing many societies,” Dr. Nutt observed.
He predicted that with the Food and Drug Administration’s recent approval of clinical trials of MDMA in patients with PTSD, the drug will be licensed for that indication “within the next couple years.”
How MDMA works
The pharmacology of MDMA is complex, he continued. The drug is chiefly a serotonin-releasing agent and 5HT reuptake blocker, but it also acts as an agonist on alpha-adrenergic receptors, has muscarinic and histamine-blocking effects, and promotes release of oxytocin.
Animal studies have demonstrated that MDMA facilitates extinction of fear memories through a mechanism involving changes in levels of brain-derived neurotrophic factor. Experience in humans has shown that the drug has diverse pro-social effects: It is activating, enhances mood, promotes more flexible thinking, boosts tactile experiences, and increases empathy, which in turn aids patients in bonding with their therapists.
Dr. Nutt and his coinvestigators performed the first whole-brain study of the effects of MDMA using functional MRI. This double-blind, placebo-controlled, crossover study in healthy volunteers used measurements obtained through arterial spin labeling and analysis of blood oxygen level–dependent resting state functional connectivity. The investigators documented that the marked increase in positive mood and decreased magnitude of negative personal memories produced by MDMA was accompanied by profound reduction of cerebral blood flow in the right amygdala and hippocampus. Cerebral blood flow also was reduced in the right medial temporal lobe, thalamus, and inferior visual cortex. MDMA also resulted in decreased amygdala-cortical connectivity (Biol Psychiatry. 2015 Oct 15;78[8]:554-62; Int J Neuropsychopharmacol. 2014 Apr;17[4]:527-40).
The changes in those particular brain systems are consistent with and most likely underlie the drug’s therapeutic effects, he said. Taken together, they could serve to assist a patient in re-engaging with traumatic memories with less interference from emotional centers, thereby helping to gain executive control of the memory of the trauma.
H. Valerie Curran, PhD, a coinvestigator in the brain imaging study, cautioned the rapt audience that while there are abundant favorable anecdotal reports from psychotherapists going back as far as the 1970s, the actual evidence base for MDMA as a therapeutic adjunct to psychotherapy for PTSD is still pretty thin. She noted that in their groundbreaking study, Dr. Mithoefer and his colleagues used an unconventional form of psychotherapy modeled on the LSD therapy developed by Stanislav Grof, MD, PhD. The two MDMA-assisted sessions were each 8 hours long and included shamanistic techniques and specialized breathing to promote diminished oxygen to the brain. Also, the patient sat on a futon listening to music with a male therapist on one side and a female therapist on the other. As a clinical psychologist herself, she assured the audience that this is not standard practice in her field.
Only one other randomized, double-blind, placebo-controlled study of MDMA-assisted psychotherapy has been published to date (J Psychopharmacol. 2013 Jan;27[1]:40-52). With just 12 participants, it was too small to be conclusive. So there is a definite need for additional controlled studies on the interaction between MDMA and evidence-based forms of psychotherapy. Fortunately, additional clinical trials are ongoing, noted Dr. Curran, professor of psychopharmacology at University College London.
She presented highlights of a study she and her coinvestigators carried out to determine how MDMA affects the encoding and recall of emotional autobiographical memories, since the core of most psychotherapy for PTSD entails controlled revisiting of traumatic memories. The nonblinded study included a group of recreational MDMA users who – on two separate occasions, one under the influence of street-quality MDMA of uncertain dose and purity, the other on placebo – were tasked with responding to self-threatening scenarios, exposure to compassionate imagery, and a large series of positive and negative adjectives addressed at themselves or another person (J Psychopharmacol. 2015 Sep;29[9]:961-70).
The investigators found that MDMA enhanced the emotional intensity, vividness, and positivity of the subjects’ best autobiographical memories while modestly reducing the negativity of their worst memories. Structured ratings of compassion markedly increased while on MDMA. Overall, the drug’s effects were similar to those obtained through rigorous cognitive training methods developed in venerable Eastern contemplative practices in pursuit of a compassionate mindset, according to Dr. Curran.
The study results suggest a mechanism by which MDMA might enhance psychotherapy not only by improving the therapeutic alliance but also by reducing self-referential emotional processing without diminishing declarative memory, she added.
Findings of Swiss studies
Matthias E. Liechti, MD, head of the psychopharmacology research unit at the University of Basel, explained that at present Switzerland is the only country in the world where it’s legal to prescribe MDMA. Ditto LSD. Psychiatrists can do so on a case-by-case basis outside of a clinical trial setting in patients with treatment-resistant PTSD or anxiety disorders.
Dr. Liechti and his coinvestigators are interested in examining how MDMA affects social cognition as assessed by outcome measures, including a structured face emotion recognition test, the multifaceted empathy test, and a sexual arousal task.
In a series of studies in which they exposed subjects to MDMA, alcohol, methamphetamine, or LSD, they have established that both MDMA and LSD produce empathogenic effects that are possibly serotonin mediated. On a visual analog scale, subjects on those drugs gave high marks for feeling happy, open, trusting, and extroverted, and having a sense of well-being. MDMA impaired recognition of fearful, angry, and sad faces.
In contrast, methamphetamine, a pure stimulant that activates the norepinephrine/dopamine system, produced no empathogenic effects, but it enhanced recognition of sad or fearful faces. Alcohol slightly increased self-ratings for trust, happiness, and openness.
Methamphetamine increased ratings of sexual arousal in response to explicit sexual stimuli, while MDMA had no effect on sexual arousal.
MDMA and LSD increased oxytocin, prolactin, and cortisol levels consistent with their serotonergic effects. Methylphenidate did not, Dr. Liechti said.
A neuroscientist in the audience raised a possible safety concern regarding MDMA: If the drug has an agonist effect on serotonin receptors, couldn’t it have cardiac side effects similar to those of fenfluramine, a drug now banned because it stimulated the abundant 5HT-2b receptors present in the heart, resulting in increased risk of pulmonary hypertension and other adverse cardiovascular effects?
Dr. Nutt replied that there are multitudes of serotonin receptor subtypes, and it’s not yet known whether MDMA acts upon the 5HT-2b receptor. In any case, it shouldn’t be an issue for the drug’s medicinal use.
“Luckily, the effects of MDMA wear off quickly, and when it’s used with psychotherapy we may be giving only one or two doses in a lifetime, so it shouldn’t be a concern,” he said.
Dr. Nutt reported that the functional MRI brain imaging study was funded by a British television station and a private foundation.
“The reason for that is we’ve found it impossible to get any money from any traditional government funders to study drugs like MDMA unless you write grants to show they’re harmful,” he asserted.
Dr. Curran reported having no financial conflicts of interest regarding her studies. Dr. Liechti’s work is supported by the Swiss National Science Foundation.
VIENNA – What a difference a decade can make in the world of psychiatry.
Take, for example, the case of 3,4-methylenedioxymethamphetamine, better known as MDMA or, when used recreationally, as ecstasy, the love drug.
“Ten years ago at pretty much every scientific meeting where MDMA was being discussed, people were looking to find problems with it. People were dredging around trying to vilify this drug, because there was a hope that it might cause brain damage, which would justify having made its use illicit. Ten years later, we’ve changed direction completely, from fear and hating MDMA to loving it. Now we’re talking about the possibility that MDMA might actually heal the brain, and restoring MDMA to the therapeutic armamentarium,” David Nutt, MD, observed at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the drug’s potential as an adjunct to psychotherapy in patients with posttraumatic stress disorder was the topic of a packed-to-the-gills session in the largest hall at the ECNP Congress, where Dr. Nutt highlighted recent insights into the psychopharmacology of MDMA and other speakers described evidence of the drug’s salutary effects on autobiographical memory and social cognition.
“The biggest problem with MDMA is its name,” quipped Dr. Nutt, professor of neuropsychopharmacology at Imperial College London.
“It used to be called ‘empathy,’ but when it started being used recreationally at raves and in the clubs, the dealers decided to change its name to ‘ecstasy.’ And that created havoc, because there’s nothing that aged editors of newspapers hate more than young people having ecstasy. They hated the term, and so the drug had to go,” according to the psychiatrist.
MDMA’s comeback as a potentially valuable medication in psychiatry can be traced to the first report of the drug’s impressive success when used as an adjunct to psychotherapy in a randomized, placebo-controlled pilot study. Michael C. Mithoefer, MD, a psychiatrist in private practice in South Carolina, and his coinvestigators stunned the psychiatric world by reporting that 10 of 12 patients with chronic PTSD refractory to both medications and psychotherapy showed significant clinical improvement in response to just two sessions of MDMA-assisted psychotherapy supplementing a more conventional course of psychotherapy (J Psychopharmacology. 2011 Apr;25[4]:439-52).
Moreover, the benefits proved durable: In a subsequent paper, the investigators reported the clinical benefit of this two-dose treatment program persisted at a mean 3.8 years of follow-up and no safety concerns had been seen (J Psychopharmacol. 2013 Jan;27[1]:28-39).
This study, which eventually drew the attention of military veterans’ groups with political clout, proved hugely influential, especially since PTSD is so common and often is highly treatment resistant.
“We’re now living in a very strange world where trauma has in some ways become the No. 1 problem facing many societies,” Dr. Nutt observed.
He predicted that with the Food and Drug Administration’s recent approval of clinical trials of MDMA in patients with PTSD, the drug will be licensed for that indication “within the next couple years.”
How MDMA works
The pharmacology of MDMA is complex, he continued. The drug is chiefly a serotonin-releasing agent and 5HT reuptake blocker, but it also acts as an agonist on alpha-adrenergic receptors, has muscarinic and histamine-blocking effects, and promotes release of oxytocin.
Animal studies have demonstrated that MDMA facilitates extinction of fear memories through a mechanism involving changes in levels of brain-derived neurotrophic factor. Experience in humans has shown that the drug has diverse pro-social effects: It is activating, enhances mood, promotes more flexible thinking, boosts tactile experiences, and increases empathy, which in turn aids patients in bonding with their therapists.
Dr. Nutt and his coinvestigators performed the first whole-brain study of the effects of MDMA using functional MRI. This double-blind, placebo-controlled, crossover study in healthy volunteers used measurements obtained through arterial spin labeling and analysis of blood oxygen level–dependent resting state functional connectivity. The investigators documented that the marked increase in positive mood and decreased magnitude of negative personal memories produced by MDMA was accompanied by profound reduction of cerebral blood flow in the right amygdala and hippocampus. Cerebral blood flow also was reduced in the right medial temporal lobe, thalamus, and inferior visual cortex. MDMA also resulted in decreased amygdala-cortical connectivity (Biol Psychiatry. 2015 Oct 15;78[8]:554-62; Int J Neuropsychopharmacol. 2014 Apr;17[4]:527-40).
The changes in those particular brain systems are consistent with and most likely underlie the drug’s therapeutic effects, he said. Taken together, they could serve to assist a patient in re-engaging with traumatic memories with less interference from emotional centers, thereby helping to gain executive control of the memory of the trauma.
H. Valerie Curran, PhD, a coinvestigator in the brain imaging study, cautioned the rapt audience that while there are abundant favorable anecdotal reports from psychotherapists going back as far as the 1970s, the actual evidence base for MDMA as a therapeutic adjunct to psychotherapy for PTSD is still pretty thin. She noted that in their groundbreaking study, Dr. Mithoefer and his colleagues used an unconventional form of psychotherapy modeled on the LSD therapy developed by Stanislav Grof, MD, PhD. The two MDMA-assisted sessions were each 8 hours long and included shamanistic techniques and specialized breathing to promote diminished oxygen to the brain. Also, the patient sat on a futon listening to music with a male therapist on one side and a female therapist on the other. As a clinical psychologist herself, she assured the audience that this is not standard practice in her field.
Only one other randomized, double-blind, placebo-controlled study of MDMA-assisted psychotherapy has been published to date (J Psychopharmacol. 2013 Jan;27[1]:40-52). With just 12 participants, it was too small to be conclusive. So there is a definite need for additional controlled studies on the interaction between MDMA and evidence-based forms of psychotherapy. Fortunately, additional clinical trials are ongoing, noted Dr. Curran, professor of psychopharmacology at University College London.
She presented highlights of a study she and her coinvestigators carried out to determine how MDMA affects the encoding and recall of emotional autobiographical memories, since the core of most psychotherapy for PTSD entails controlled revisiting of traumatic memories. The nonblinded study included a group of recreational MDMA users who – on two separate occasions, one under the influence of street-quality MDMA of uncertain dose and purity, the other on placebo – were tasked with responding to self-threatening scenarios, exposure to compassionate imagery, and a large series of positive and negative adjectives addressed at themselves or another person (J Psychopharmacol. 2015 Sep;29[9]:961-70).
The investigators found that MDMA enhanced the emotional intensity, vividness, and positivity of the subjects’ best autobiographical memories while modestly reducing the negativity of their worst memories. Structured ratings of compassion markedly increased while on MDMA. Overall, the drug’s effects were similar to those obtained through rigorous cognitive training methods developed in venerable Eastern contemplative practices in pursuit of a compassionate mindset, according to Dr. Curran.
The study results suggest a mechanism by which MDMA might enhance psychotherapy not only by improving the therapeutic alliance but also by reducing self-referential emotional processing without diminishing declarative memory, she added.
Findings of Swiss studies
Matthias E. Liechti, MD, head of the psychopharmacology research unit at the University of Basel, explained that at present Switzerland is the only country in the world where it’s legal to prescribe MDMA. Ditto LSD. Psychiatrists can do so on a case-by-case basis outside of a clinical trial setting in patients with treatment-resistant PTSD or anxiety disorders.
Dr. Liechti and his coinvestigators are interested in examining how MDMA affects social cognition as assessed by outcome measures, including a structured face emotion recognition test, the multifaceted empathy test, and a sexual arousal task.
In a series of studies in which they exposed subjects to MDMA, alcohol, methamphetamine, or LSD, they have established that both MDMA and LSD produce empathogenic effects that are possibly serotonin mediated. On a visual analog scale, subjects on those drugs gave high marks for feeling happy, open, trusting, and extroverted, and having a sense of well-being. MDMA impaired recognition of fearful, angry, and sad faces.
In contrast, methamphetamine, a pure stimulant that activates the norepinephrine/dopamine system, produced no empathogenic effects, but it enhanced recognition of sad or fearful faces. Alcohol slightly increased self-ratings for trust, happiness, and openness.
Methamphetamine increased ratings of sexual arousal in response to explicit sexual stimuli, while MDMA had no effect on sexual arousal.
MDMA and LSD increased oxytocin, prolactin, and cortisol levels consistent with their serotonergic effects. Methylphenidate did not, Dr. Liechti said.
A neuroscientist in the audience raised a possible safety concern regarding MDMA: If the drug has an agonist effect on serotonin receptors, couldn’t it have cardiac side effects similar to those of fenfluramine, a drug now banned because it stimulated the abundant 5HT-2b receptors present in the heart, resulting in increased risk of pulmonary hypertension and other adverse cardiovascular effects?
Dr. Nutt replied that there are multitudes of serotonin receptor subtypes, and it’s not yet known whether MDMA acts upon the 5HT-2b receptor. In any case, it shouldn’t be an issue for the drug’s medicinal use.
“Luckily, the effects of MDMA wear off quickly, and when it’s used with psychotherapy we may be giving only one or two doses in a lifetime, so it shouldn’t be a concern,” he said.
Dr. Nutt reported that the functional MRI brain imaging study was funded by a British television station and a private foundation.
“The reason for that is we’ve found it impossible to get any money from any traditional government funders to study drugs like MDMA unless you write grants to show they’re harmful,” he asserted.
Dr. Curran reported having no financial conflicts of interest regarding her studies. Dr. Liechti’s work is supported by the Swiss National Science Foundation.
VIENNA – What a difference a decade can make in the world of psychiatry.
Take, for example, the case of 3,4-methylenedioxymethamphetamine, better known as MDMA or, when used recreationally, as ecstasy, the love drug.
“Ten years ago at pretty much every scientific meeting where MDMA was being discussed, people were looking to find problems with it. People were dredging around trying to vilify this drug, because there was a hope that it might cause brain damage, which would justify having made its use illicit. Ten years later, we’ve changed direction completely, from fear and hating MDMA to loving it. Now we’re talking about the possibility that MDMA might actually heal the brain, and restoring MDMA to the therapeutic armamentarium,” David Nutt, MD, observed at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the drug’s potential as an adjunct to psychotherapy in patients with posttraumatic stress disorder was the topic of a packed-to-the-gills session in the largest hall at the ECNP Congress, where Dr. Nutt highlighted recent insights into the psychopharmacology of MDMA and other speakers described evidence of the drug’s salutary effects on autobiographical memory and social cognition.
“The biggest problem with MDMA is its name,” quipped Dr. Nutt, professor of neuropsychopharmacology at Imperial College London.
“It used to be called ‘empathy,’ but when it started being used recreationally at raves and in the clubs, the dealers decided to change its name to ‘ecstasy.’ And that created havoc, because there’s nothing that aged editors of newspapers hate more than young people having ecstasy. They hated the term, and so the drug had to go,” according to the psychiatrist.
MDMA’s comeback as a potentially valuable medication in psychiatry can be traced to the first report of the drug’s impressive success when used as an adjunct to psychotherapy in a randomized, placebo-controlled pilot study. Michael C. Mithoefer, MD, a psychiatrist in private practice in South Carolina, and his coinvestigators stunned the psychiatric world by reporting that 10 of 12 patients with chronic PTSD refractory to both medications and psychotherapy showed significant clinical improvement in response to just two sessions of MDMA-assisted psychotherapy supplementing a more conventional course of psychotherapy (J Psychopharmacology. 2011 Apr;25[4]:439-52).
Moreover, the benefits proved durable: In a subsequent paper, the investigators reported the clinical benefit of this two-dose treatment program persisted at a mean 3.8 years of follow-up and no safety concerns had been seen (J Psychopharmacol. 2013 Jan;27[1]:28-39).
This study, which eventually drew the attention of military veterans’ groups with political clout, proved hugely influential, especially since PTSD is so common and often is highly treatment resistant.
“We’re now living in a very strange world where trauma has in some ways become the No. 1 problem facing many societies,” Dr. Nutt observed.
He predicted that with the Food and Drug Administration’s recent approval of clinical trials of MDMA in patients with PTSD, the drug will be licensed for that indication “within the next couple years.”
How MDMA works
The pharmacology of MDMA is complex, he continued. The drug is chiefly a serotonin-releasing agent and 5HT reuptake blocker, but it also acts as an agonist on alpha-adrenergic receptors, has muscarinic and histamine-blocking effects, and promotes release of oxytocin.
Animal studies have demonstrated that MDMA facilitates extinction of fear memories through a mechanism involving changes in levels of brain-derived neurotrophic factor. Experience in humans has shown that the drug has diverse pro-social effects: It is activating, enhances mood, promotes more flexible thinking, boosts tactile experiences, and increases empathy, which in turn aids patients in bonding with their therapists.
Dr. Nutt and his coinvestigators performed the first whole-brain study of the effects of MDMA using functional MRI. This double-blind, placebo-controlled, crossover study in healthy volunteers used measurements obtained through arterial spin labeling and analysis of blood oxygen level–dependent resting state functional connectivity. The investigators documented that the marked increase in positive mood and decreased magnitude of negative personal memories produced by MDMA was accompanied by profound reduction of cerebral blood flow in the right amygdala and hippocampus. Cerebral blood flow also was reduced in the right medial temporal lobe, thalamus, and inferior visual cortex. MDMA also resulted in decreased amygdala-cortical connectivity (Biol Psychiatry. 2015 Oct 15;78[8]:554-62; Int J Neuropsychopharmacol. 2014 Apr;17[4]:527-40).
The changes in those particular brain systems are consistent with and most likely underlie the drug’s therapeutic effects, he said. Taken together, they could serve to assist a patient in re-engaging with traumatic memories with less interference from emotional centers, thereby helping to gain executive control of the memory of the trauma.
H. Valerie Curran, PhD, a coinvestigator in the brain imaging study, cautioned the rapt audience that while there are abundant favorable anecdotal reports from psychotherapists going back as far as the 1970s, the actual evidence base for MDMA as a therapeutic adjunct to psychotherapy for PTSD is still pretty thin. She noted that in their groundbreaking study, Dr. Mithoefer and his colleagues used an unconventional form of psychotherapy modeled on the LSD therapy developed by Stanislav Grof, MD, PhD. The two MDMA-assisted sessions were each 8 hours long and included shamanistic techniques and specialized breathing to promote diminished oxygen to the brain. Also, the patient sat on a futon listening to music with a male therapist on one side and a female therapist on the other. As a clinical psychologist herself, she assured the audience that this is not standard practice in her field.
Only one other randomized, double-blind, placebo-controlled study of MDMA-assisted psychotherapy has been published to date (J Psychopharmacol. 2013 Jan;27[1]:40-52). With just 12 participants, it was too small to be conclusive. So there is a definite need for additional controlled studies on the interaction between MDMA and evidence-based forms of psychotherapy. Fortunately, additional clinical trials are ongoing, noted Dr. Curran, professor of psychopharmacology at University College London.
She presented highlights of a study she and her coinvestigators carried out to determine how MDMA affects the encoding and recall of emotional autobiographical memories, since the core of most psychotherapy for PTSD entails controlled revisiting of traumatic memories. The nonblinded study included a group of recreational MDMA users who – on two separate occasions, one under the influence of street-quality MDMA of uncertain dose and purity, the other on placebo – were tasked with responding to self-threatening scenarios, exposure to compassionate imagery, and a large series of positive and negative adjectives addressed at themselves or another person (J Psychopharmacol. 2015 Sep;29[9]:961-70).
The investigators found that MDMA enhanced the emotional intensity, vividness, and positivity of the subjects’ best autobiographical memories while modestly reducing the negativity of their worst memories. Structured ratings of compassion markedly increased while on MDMA. Overall, the drug’s effects were similar to those obtained through rigorous cognitive training methods developed in venerable Eastern contemplative practices in pursuit of a compassionate mindset, according to Dr. Curran.
The study results suggest a mechanism by which MDMA might enhance psychotherapy not only by improving the therapeutic alliance but also by reducing self-referential emotional processing without diminishing declarative memory, she added.
Findings of Swiss studies
Matthias E. Liechti, MD, head of the psychopharmacology research unit at the University of Basel, explained that at present Switzerland is the only country in the world where it’s legal to prescribe MDMA. Ditto LSD. Psychiatrists can do so on a case-by-case basis outside of a clinical trial setting in patients with treatment-resistant PTSD or anxiety disorders.
Dr. Liechti and his coinvestigators are interested in examining how MDMA affects social cognition as assessed by outcome measures, including a structured face emotion recognition test, the multifaceted empathy test, and a sexual arousal task.
In a series of studies in which they exposed subjects to MDMA, alcohol, methamphetamine, or LSD, they have established that both MDMA and LSD produce empathogenic effects that are possibly serotonin mediated. On a visual analog scale, subjects on those drugs gave high marks for feeling happy, open, trusting, and extroverted, and having a sense of well-being. MDMA impaired recognition of fearful, angry, and sad faces.
In contrast, methamphetamine, a pure stimulant that activates the norepinephrine/dopamine system, produced no empathogenic effects, but it enhanced recognition of sad or fearful faces. Alcohol slightly increased self-ratings for trust, happiness, and openness.
Methamphetamine increased ratings of sexual arousal in response to explicit sexual stimuli, while MDMA had no effect on sexual arousal.
MDMA and LSD increased oxytocin, prolactin, and cortisol levels consistent with their serotonergic effects. Methylphenidate did not, Dr. Liechti said.
A neuroscientist in the audience raised a possible safety concern regarding MDMA: If the drug has an agonist effect on serotonin receptors, couldn’t it have cardiac side effects similar to those of fenfluramine, a drug now banned because it stimulated the abundant 5HT-2b receptors present in the heart, resulting in increased risk of pulmonary hypertension and other adverse cardiovascular effects?
Dr. Nutt replied that there are multitudes of serotonin receptor subtypes, and it’s not yet known whether MDMA acts upon the 5HT-2b receptor. In any case, it shouldn’t be an issue for the drug’s medicinal use.
“Luckily, the effects of MDMA wear off quickly, and when it’s used with psychotherapy we may be giving only one or two doses in a lifetime, so it shouldn’t be a concern,” he said.
Dr. Nutt reported that the functional MRI brain imaging study was funded by a British television station and a private foundation.
“The reason for that is we’ve found it impossible to get any money from any traditional government funders to study drugs like MDMA unless you write grants to show they’re harmful,” he asserted.
Dr. Curran reported having no financial conflicts of interest regarding her studies. Dr. Liechti’s work is supported by the Swiss National Science Foundation.
What’s next for deep brain stimulation in OCD?
VIENNA – Even though deep brain stimulation has been used to treat obsessive-compulsive disorder in fewer than 300 patients worldwide, the therapy has had a huge impact on understanding of the disorder, Damiaan Denys, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the efficacy of deep brain stimulation (DBS) in the most severe, treatment-refractory cases of OCD casts doubt upon the fundamental construct clinicians have relied upon for decades to comprehend OCD: Namely, that affected patients first experience obsessions, which induce anxiety, which then stimulates compulsions, and engaging in those compulsions brings relief and reward, and then the whole cycle starts over again.
That construct may not actually be true.
“Deep brain stimulation will force us to rethink OCD,” predicted Dr. Denys, professor and head of psychiatry at the University of Amsterdam.
What does DBS change, and is there a temporal order? It varies, the psychiatrist said.
“In some patients, anxiety is the first thing that changes. In others, it starts with obsessions. Compulsions do decrease, but it’s difficult. It takes some time, and often we need supplemental cognitive-behavioral therapy (CBT). What changes, mainly, in my experience, is not symptoms, but something outside of OCD: namely, mood. Deep brain stimulation has a huge impact on mood. That’s an interesting finding, because it suggests the possibility that you can change a psychiatric disorder by changing symptoms that are thought of as being outside the disorder,” Dr. Denys observed.
“Another interesting thing is that deep brain stimulation changes things that are not even within psychiatry. When we ask our patients what has been the most profound impact deep brain stimulation has had on their lives, all of them say, ‘It increases my self-confidence.’ And that’s not something that is included in our scales. We assess patients using the HAM-D [Hamilton Rating Scale for Depression] and Y-BOCS [Yale-Brown Obsessive Compulsive Scale] and other measures, but there are still some very important aspects we are not taking into account and that have a profound effect on symptoms. In this case, using deep brain stimulation, we improve self-confidence and thereby change a whole chain of symptoms,” he continued.
Among the 60 highly refractory OCD patients treated by DBS by Dr. Denys and his colleagues at the Amsterdam center over the past 15 years, 15% were cured as a result.
“I purposely use the word ‘cured,’ because they don’t have obsessive-compulsive symptoms, anymore, which is, of course, extraordinary,” Dr. Denys noted.
An additional 35% of patients had a good response, defined as 60%-80% improvement on the Y-BOCS. Ten percent of patients were partial responders, with a 20%-40% improvement on the Y-BOCS. And 15% were nonresponders.
Closed-loop system coming
DBS entails implantation of electrodes deep within the brain to interrupt dysfunctional brain signals in local areas and across neural networks. This dysfunctional brain activity is expressed as symptoms. To date, DBS has been used in what’s called an open-loop system: Patients report the symptoms they’re experiencing and the clinician then adjusts the electrode settings in order to quell those symptoms. This approach is about to change. The technology has improved vastly since the early days, when the electrodes had four contact points. Now they have 64 contact points, and are capable of sending and receiving electrical signals.
“The next step in deep brain stimulation will be a closed-loop system. We will remove the clinician and the patient, and attempt to use a device capable of recording what happens in the brain and then changing electrical activity in response to the recordings. Our purpose will be to block these brain signals in advance of obsessions and compulsions so patients don’t have these symptoms. It’s technically possible. It has been done in Parkinson’s, and I think it’s the next step in psychiatry,” Dr. Denys said.
Indeed, he and his coinvestigators are planning formal studies of closed-loop DBS. For him, the prospect raises three key questions: What are the neural correlates of OCD symptoms? What about the ethics of implanting a device in the brain which by itself results in different life experiences? And will closed-loop DBS have superior efficacy, compared with open-loop DBS?
“How is the mind rooted in the brain, and how is the brain expressed in the mind? It’s the most fascinating question; it’s why we all love psychiatry, and up until now, there are no answers,” he observed.
Significant progress already has been made on the neural correlates question. Dr. Denys and his colleagues have found that when OCD patients with deep brain electrodes engage in cleaning compulsions, their local field potentials in the striatal area show peaks of roughly 9 Hz in the alpha range and in the beta/low gamma range. These patterns may represent compulsive behavior and likely could be useful in steering a closed-loop system. Also, the Dutch investigators have found that 3- to 8-Hz theta oscillations in local field potentials in the striatal area may represent a neural signature for anxiety and/or obsessions.
Using a closed-loop system, he continued, investigators plan to test two quite different hypotheses about the fundamental nature of OCD. One is that obsessions, anxiety, compulsions, and relief are each separately related to different brain areas. The other hypothesis is that one central brain stimulus drives the chain of symptoms that characterize OCD, and that by identifying and blocking that primary signal, the whole pathologic process can be stopped.
Current status of procedure
While Dr. Denys focused on the near future of DBS for OCD, another speaker at the session, Sina Kohl, PhD, addressed DBS for OCD as it exists today, particularly the who, how, and where.
The “who” is the relatively rare patient with truly refractory OCD after multiple drug trials of agents in different antidepressant classes, one of which should be clomipramine, as well as a failed course of CBT provided by an expert in CBT for OCD, of which there are relatively few. In a study led by investigators at Brown University, Providence, R.I., only 2 of 325 patients with OCD were deemed truly refractory (J Neuropsychiatry Clin Neurosci. 2014 Winter;26[1]:81-6). That sounds about right, according to Dr. Kohl, a psychologist at the University of Cologne, in Germany.
The “how” is to deliver DBS in conjunction with CBT. Response rates are higher at centers where that practice is routine, she added.
The “where” is an unsettled question. In Dr. Kohl’s meta-analysis of 25 published DBS studies, electrode placement in four different DBS target structures produced similar results: the nucleus accumbens, the anterior limb of the internal capsule, the ventral striatum, and the subthalamic nucleus. Stimulation of the inferior thalamic peduncle appeared to achieve better results, but this is a sketchy conclusion based upon two studies totaling just six patients (BMC Psychiatry. 2014 Aug 2;14:214. doi: 10.1186/s12888-014-0214-y).
Recently, Belgian investigators have reported particularly promising results – the best so far – for DBS targeting the bed nucleus of the stria terminalis (Mol Psychiatry. 2016 Sep;21[9]:1272-80).
Bilateral DBS appears to be more effective than unilateral.
Dr. Kohl and her colleagues in Cologne recently completed a study of DBS in 20 patients. She noted that it took 5 years to collect these 20 patients, underscoring the high bar that’s appropriate for resort to DBS, even though the therapy is approved for OCD by both the Food and Drug Administration and European regulatory authorities. Forty percent of the patients were DBS responders, with a mean 30% improvement in Y-BOCS scores. That’s a lower responder rate than in Dr. Denys’s and some other series, which Dr. Kohl attributed to the fact that in Germany, postimplantation CBT is not yet routine.
Asked about DBS side effects, the speakers agreed that they’re transient and fall off after initial stimulation parameters are changed.
“The most consistent and impressive side effect is that initially after surgical implantation of the electrodes and stimulation of the nucleus accumbens, patients experience 3 or 4 days of hypomania, which then disappears,” Dr. Denys said. “It causes a kind of imprinting, because even a decade later, patients ask us, ‘Could you bring back that really nice feeling?’ It’s 3 days of love, peace, and hypomania. It’s a side effect, but people like it.”
Dr. Denys and Dr. Kohl reported no financial conflicts of interest regarding their presentations.
VIENNA – Even though deep brain stimulation has been used to treat obsessive-compulsive disorder in fewer than 300 patients worldwide, the therapy has had a huge impact on understanding of the disorder, Damiaan Denys, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the efficacy of deep brain stimulation (DBS) in the most severe, treatment-refractory cases of OCD casts doubt upon the fundamental construct clinicians have relied upon for decades to comprehend OCD: Namely, that affected patients first experience obsessions, which induce anxiety, which then stimulates compulsions, and engaging in those compulsions brings relief and reward, and then the whole cycle starts over again.
That construct may not actually be true.
“Deep brain stimulation will force us to rethink OCD,” predicted Dr. Denys, professor and head of psychiatry at the University of Amsterdam.
What does DBS change, and is there a temporal order? It varies, the psychiatrist said.
“In some patients, anxiety is the first thing that changes. In others, it starts with obsessions. Compulsions do decrease, but it’s difficult. It takes some time, and often we need supplemental cognitive-behavioral therapy (CBT). What changes, mainly, in my experience, is not symptoms, but something outside of OCD: namely, mood. Deep brain stimulation has a huge impact on mood. That’s an interesting finding, because it suggests the possibility that you can change a psychiatric disorder by changing symptoms that are thought of as being outside the disorder,” Dr. Denys observed.
“Another interesting thing is that deep brain stimulation changes things that are not even within psychiatry. When we ask our patients what has been the most profound impact deep brain stimulation has had on their lives, all of them say, ‘It increases my self-confidence.’ And that’s not something that is included in our scales. We assess patients using the HAM-D [Hamilton Rating Scale for Depression] and Y-BOCS [Yale-Brown Obsessive Compulsive Scale] and other measures, but there are still some very important aspects we are not taking into account and that have a profound effect on symptoms. In this case, using deep brain stimulation, we improve self-confidence and thereby change a whole chain of symptoms,” he continued.
Among the 60 highly refractory OCD patients treated by DBS by Dr. Denys and his colleagues at the Amsterdam center over the past 15 years, 15% were cured as a result.
“I purposely use the word ‘cured,’ because they don’t have obsessive-compulsive symptoms, anymore, which is, of course, extraordinary,” Dr. Denys noted.
An additional 35% of patients had a good response, defined as 60%-80% improvement on the Y-BOCS. Ten percent of patients were partial responders, with a 20%-40% improvement on the Y-BOCS. And 15% were nonresponders.
Closed-loop system coming
DBS entails implantation of electrodes deep within the brain to interrupt dysfunctional brain signals in local areas and across neural networks. This dysfunctional brain activity is expressed as symptoms. To date, DBS has been used in what’s called an open-loop system: Patients report the symptoms they’re experiencing and the clinician then adjusts the electrode settings in order to quell those symptoms. This approach is about to change. The technology has improved vastly since the early days, when the electrodes had four contact points. Now they have 64 contact points, and are capable of sending and receiving electrical signals.
“The next step in deep brain stimulation will be a closed-loop system. We will remove the clinician and the patient, and attempt to use a device capable of recording what happens in the brain and then changing electrical activity in response to the recordings. Our purpose will be to block these brain signals in advance of obsessions and compulsions so patients don’t have these symptoms. It’s technically possible. It has been done in Parkinson’s, and I think it’s the next step in psychiatry,” Dr. Denys said.
Indeed, he and his coinvestigators are planning formal studies of closed-loop DBS. For him, the prospect raises three key questions: What are the neural correlates of OCD symptoms? What about the ethics of implanting a device in the brain which by itself results in different life experiences? And will closed-loop DBS have superior efficacy, compared with open-loop DBS?
“How is the mind rooted in the brain, and how is the brain expressed in the mind? It’s the most fascinating question; it’s why we all love psychiatry, and up until now, there are no answers,” he observed.
Significant progress already has been made on the neural correlates question. Dr. Denys and his colleagues have found that when OCD patients with deep brain electrodes engage in cleaning compulsions, their local field potentials in the striatal area show peaks of roughly 9 Hz in the alpha range and in the beta/low gamma range. These patterns may represent compulsive behavior and likely could be useful in steering a closed-loop system. Also, the Dutch investigators have found that 3- to 8-Hz theta oscillations in local field potentials in the striatal area may represent a neural signature for anxiety and/or obsessions.
Using a closed-loop system, he continued, investigators plan to test two quite different hypotheses about the fundamental nature of OCD. One is that obsessions, anxiety, compulsions, and relief are each separately related to different brain areas. The other hypothesis is that one central brain stimulus drives the chain of symptoms that characterize OCD, and that by identifying and blocking that primary signal, the whole pathologic process can be stopped.
Current status of procedure
While Dr. Denys focused on the near future of DBS for OCD, another speaker at the session, Sina Kohl, PhD, addressed DBS for OCD as it exists today, particularly the who, how, and where.
The “who” is the relatively rare patient with truly refractory OCD after multiple drug trials of agents in different antidepressant classes, one of which should be clomipramine, as well as a failed course of CBT provided by an expert in CBT for OCD, of which there are relatively few. In a study led by investigators at Brown University, Providence, R.I., only 2 of 325 patients with OCD were deemed truly refractory (J Neuropsychiatry Clin Neurosci. 2014 Winter;26[1]:81-6). That sounds about right, according to Dr. Kohl, a psychologist at the University of Cologne, in Germany.
The “how” is to deliver DBS in conjunction with CBT. Response rates are higher at centers where that practice is routine, she added.
The “where” is an unsettled question. In Dr. Kohl’s meta-analysis of 25 published DBS studies, electrode placement in four different DBS target structures produced similar results: the nucleus accumbens, the anterior limb of the internal capsule, the ventral striatum, and the subthalamic nucleus. Stimulation of the inferior thalamic peduncle appeared to achieve better results, but this is a sketchy conclusion based upon two studies totaling just six patients (BMC Psychiatry. 2014 Aug 2;14:214. doi: 10.1186/s12888-014-0214-y).
Recently, Belgian investigators have reported particularly promising results – the best so far – for DBS targeting the bed nucleus of the stria terminalis (Mol Psychiatry. 2016 Sep;21[9]:1272-80).
Bilateral DBS appears to be more effective than unilateral.
Dr. Kohl and her colleagues in Cologne recently completed a study of DBS in 20 patients. She noted that it took 5 years to collect these 20 patients, underscoring the high bar that’s appropriate for resort to DBS, even though the therapy is approved for OCD by both the Food and Drug Administration and European regulatory authorities. Forty percent of the patients were DBS responders, with a mean 30% improvement in Y-BOCS scores. That’s a lower responder rate than in Dr. Denys’s and some other series, which Dr. Kohl attributed to the fact that in Germany, postimplantation CBT is not yet routine.
Asked about DBS side effects, the speakers agreed that they’re transient and fall off after initial stimulation parameters are changed.
“The most consistent and impressive side effect is that initially after surgical implantation of the electrodes and stimulation of the nucleus accumbens, patients experience 3 or 4 days of hypomania, which then disappears,” Dr. Denys said. “It causes a kind of imprinting, because even a decade later, patients ask us, ‘Could you bring back that really nice feeling?’ It’s 3 days of love, peace, and hypomania. It’s a side effect, but people like it.”
Dr. Denys and Dr. Kohl reported no financial conflicts of interest regarding their presentations.
VIENNA – Even though deep brain stimulation has been used to treat obsessive-compulsive disorder in fewer than 300 patients worldwide, the therapy has had a huge impact on understanding of the disorder, Damiaan Denys, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the efficacy of deep brain stimulation (DBS) in the most severe, treatment-refractory cases of OCD casts doubt upon the fundamental construct clinicians have relied upon for decades to comprehend OCD: Namely, that affected patients first experience obsessions, which induce anxiety, which then stimulates compulsions, and engaging in those compulsions brings relief and reward, and then the whole cycle starts over again.
That construct may not actually be true.
“Deep brain stimulation will force us to rethink OCD,” predicted Dr. Denys, professor and head of psychiatry at the University of Amsterdam.
What does DBS change, and is there a temporal order? It varies, the psychiatrist said.
“In some patients, anxiety is the first thing that changes. In others, it starts with obsessions. Compulsions do decrease, but it’s difficult. It takes some time, and often we need supplemental cognitive-behavioral therapy (CBT). What changes, mainly, in my experience, is not symptoms, but something outside of OCD: namely, mood. Deep brain stimulation has a huge impact on mood. That’s an interesting finding, because it suggests the possibility that you can change a psychiatric disorder by changing symptoms that are thought of as being outside the disorder,” Dr. Denys observed.
“Another interesting thing is that deep brain stimulation changes things that are not even within psychiatry. When we ask our patients what has been the most profound impact deep brain stimulation has had on their lives, all of them say, ‘It increases my self-confidence.’ And that’s not something that is included in our scales. We assess patients using the HAM-D [Hamilton Rating Scale for Depression] and Y-BOCS [Yale-Brown Obsessive Compulsive Scale] and other measures, but there are still some very important aspects we are not taking into account and that have a profound effect on symptoms. In this case, using deep brain stimulation, we improve self-confidence and thereby change a whole chain of symptoms,” he continued.
Among the 60 highly refractory OCD patients treated by DBS by Dr. Denys and his colleagues at the Amsterdam center over the past 15 years, 15% were cured as a result.
“I purposely use the word ‘cured,’ because they don’t have obsessive-compulsive symptoms, anymore, which is, of course, extraordinary,” Dr. Denys noted.
An additional 35% of patients had a good response, defined as 60%-80% improvement on the Y-BOCS. Ten percent of patients were partial responders, with a 20%-40% improvement on the Y-BOCS. And 15% were nonresponders.
Closed-loop system coming
DBS entails implantation of electrodes deep within the brain to interrupt dysfunctional brain signals in local areas and across neural networks. This dysfunctional brain activity is expressed as symptoms. To date, DBS has been used in what’s called an open-loop system: Patients report the symptoms they’re experiencing and the clinician then adjusts the electrode settings in order to quell those symptoms. This approach is about to change. The technology has improved vastly since the early days, when the electrodes had four contact points. Now they have 64 contact points, and are capable of sending and receiving electrical signals.
“The next step in deep brain stimulation will be a closed-loop system. We will remove the clinician and the patient, and attempt to use a device capable of recording what happens in the brain and then changing electrical activity in response to the recordings. Our purpose will be to block these brain signals in advance of obsessions and compulsions so patients don’t have these symptoms. It’s technically possible. It has been done in Parkinson’s, and I think it’s the next step in psychiatry,” Dr. Denys said.
Indeed, he and his coinvestigators are planning formal studies of closed-loop DBS. For him, the prospect raises three key questions: What are the neural correlates of OCD symptoms? What about the ethics of implanting a device in the brain which by itself results in different life experiences? And will closed-loop DBS have superior efficacy, compared with open-loop DBS?
“How is the mind rooted in the brain, and how is the brain expressed in the mind? It’s the most fascinating question; it’s why we all love psychiatry, and up until now, there are no answers,” he observed.
Significant progress already has been made on the neural correlates question. Dr. Denys and his colleagues have found that when OCD patients with deep brain electrodes engage in cleaning compulsions, their local field potentials in the striatal area show peaks of roughly 9 Hz in the alpha range and in the beta/low gamma range. These patterns may represent compulsive behavior and likely could be useful in steering a closed-loop system. Also, the Dutch investigators have found that 3- to 8-Hz theta oscillations in local field potentials in the striatal area may represent a neural signature for anxiety and/or obsessions.
Using a closed-loop system, he continued, investigators plan to test two quite different hypotheses about the fundamental nature of OCD. One is that obsessions, anxiety, compulsions, and relief are each separately related to different brain areas. The other hypothesis is that one central brain stimulus drives the chain of symptoms that characterize OCD, and that by identifying and blocking that primary signal, the whole pathologic process can be stopped.
Current status of procedure
While Dr. Denys focused on the near future of DBS for OCD, another speaker at the session, Sina Kohl, PhD, addressed DBS for OCD as it exists today, particularly the who, how, and where.
The “who” is the relatively rare patient with truly refractory OCD after multiple drug trials of agents in different antidepressant classes, one of which should be clomipramine, as well as a failed course of CBT provided by an expert in CBT for OCD, of which there are relatively few. In a study led by investigators at Brown University, Providence, R.I., only 2 of 325 patients with OCD were deemed truly refractory (J Neuropsychiatry Clin Neurosci. 2014 Winter;26[1]:81-6). That sounds about right, according to Dr. Kohl, a psychologist at the University of Cologne, in Germany.
The “how” is to deliver DBS in conjunction with CBT. Response rates are higher at centers where that practice is routine, she added.
The “where” is an unsettled question. In Dr. Kohl’s meta-analysis of 25 published DBS studies, electrode placement in four different DBS target structures produced similar results: the nucleus accumbens, the anterior limb of the internal capsule, the ventral striatum, and the subthalamic nucleus. Stimulation of the inferior thalamic peduncle appeared to achieve better results, but this is a sketchy conclusion based upon two studies totaling just six patients (BMC Psychiatry. 2014 Aug 2;14:214. doi: 10.1186/s12888-014-0214-y).
Recently, Belgian investigators have reported particularly promising results – the best so far – for DBS targeting the bed nucleus of the stria terminalis (Mol Psychiatry. 2016 Sep;21[9]:1272-80).
Bilateral DBS appears to be more effective than unilateral.
Dr. Kohl and her colleagues in Cologne recently completed a study of DBS in 20 patients. She noted that it took 5 years to collect these 20 patients, underscoring the high bar that’s appropriate for resort to DBS, even though the therapy is approved for OCD by both the Food and Drug Administration and European regulatory authorities. Forty percent of the patients were DBS responders, with a mean 30% improvement in Y-BOCS scores. That’s a lower responder rate than in Dr. Denys’s and some other series, which Dr. Kohl attributed to the fact that in Germany, postimplantation CBT is not yet routine.
Asked about DBS side effects, the speakers agreed that they’re transient and fall off after initial stimulation parameters are changed.
“The most consistent and impressive side effect is that initially after surgical implantation of the electrodes and stimulation of the nucleus accumbens, patients experience 3 or 4 days of hypomania, which then disappears,” Dr. Denys said. “It causes a kind of imprinting, because even a decade later, patients ask us, ‘Could you bring back that really nice feeling?’ It’s 3 days of love, peace, and hypomania. It’s a side effect, but people like it.”
Dr. Denys and Dr. Kohl reported no financial conflicts of interest regarding their presentations.
Ketamine emerging as top treatment for cocaine dependence
VIENNA – The prospect on the horizon of two new effective therapies for chronic cocaine dependence – sustained-release dextroamphetamine and subanesthetic ketamine infusions – was among the top developments of the year in addiction medicine, Wim van den Brink, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Other highlights on his list included:
• Studies establishing that comorbid attention-deficit/hyperactivity disorder (ADHD) and substance use disorder now can be treated effectively with either extended-release mixed amphetamine salts or high-dose methylphenidate.
• Evidence that the alpha-1 blocker doxazosin is an effective treatment for alcoholism in a specific well-defined subset of patients, opening the door to a personalized medicine approach to this disease.
• Release of a puzzling array of conflicting studies on the use of high-dose baclofen for treatment of alcohol dependence. It’s tough to reconcile this mishmash of polar opposite results. And that dictates it’s time to declare a moratorium on the use of this therapy in clinical practice, which in many places is now widespread, said Dr. van den Brink, professor of psychiatry and addiction at the University of Amsterdam and director of the Amsterdam Institute for Addiction Research.
“It’s too strange that we have such conflicting evidence out there. Too many people are prescribing crazy-high doses of baclofen with no strong supporting evidence,” Dr. van den Brink said.
Cocaine dependence
Dr. van den Brink was a coinvestigator in a Dutch multicenter randomized, double-blind, placebo-controlled trial of multitreatment-refractory comorbid cocaine dependence in 73 heroin-dependent patients in heroin-assisted treatment. Patients assigned to 60 mg/day of sustained-release dextroamphetamine, in addition to the background methadone and diacetylmorphine all participants were on for their heroin dependence, had significantly fewer days of cocaine use in the 12-week study: a mean of 44.9 days, compared with 60.6 days in placebo-treated controls. Adverse events were transient and well tolerated (Lancet. 2016 May 28;387[10034]:2226-34).
“A lot of medications have been tried for treatment of cocaine dependence, but actually none of them has been shown to be effective with the exception of substitution treatment with stimulants. Ours is one of the most successful trials. These patients were using cocaine an average of 24 days per month along with a lot of other drugs, despite being in heroin treatment for 4 years,” Dr. van den Brink said. “Patients were very willing to take the sustained-release dextroamphetamine. In the last 4 weeks, 84% of them used at least 80% of their medication. And they were blinded to what they were using.
“We saw good effect sizes: 0.6-0.7 for self-report measures and 0.31 for negative urine samples. So this is a very promising approach. But it also means that, like with tobacco dependence or alcohol dependence, we have to start thinking about substitution therapy in stimulant-dependent patients,” he said.
Dr. van den Brink said subanesthetic ketamine as a novel treatment for cocaine dependence is not yet ready for prime time use in clinical practice, because it’s just not practical to bring patients in for a roughly hour-long intravenous infusion on a daily basis, as was done in a highly impressive proof-of-concept study. But new formulations of ketamine are under development that should better lend themselves to use in clinical practice.
In the proof-of-concept study, investigators at the New York State Psychiatric Institute brought into the laboratory cocaine-dependent volunteers not seeking treatment or abstinence and administered 52-minute infusions of ketamine at 0.41 or 71 mg/kg or lorazepam at 2 mg (Biol Psychiatry. 2014 Jul 1;76[1]:40-6). Lorazepam had absolutely no effect on motivation to change, but ketamine was a different story.
“As soon as you give a low dose of ketamine, you see a wonderful effect on motivation to change and on craving ratings in assessments at 24 hours post infusion. This looks like another promising way of treating cocaine dependence,” he said.
Doxazosin for alcoholism
Investigators at the National Institute on Alcohol Abuse and Alcoholism and several U.S. universities hypothesized that the norepinephrine system could be an important treatment target in alcohol dependence. They conducted a double-blind, placebo-controlled randomized trial in which alcohol-dependent patients seeking outpatient treatment were assigned to the alpha1-adrenergic blocker doxazosin (Cardura) titrated to a maximum of 16 mg/day or placebo. They found doxazosin significantly reduced drinks per week and the number of heavy drinking days per week, but only in the subgroup of patients with a strong family history of alcoholism. In patients without such a family history, doxazosin paradoxically increased drinking (Addict Biol. 2016 Jul;21[4]:904-14).
One of the reasons adult ADHD is greatly underrecognized is that it tends to occur in combination with flashier substance use disorders. “Addiction is very comorbid with all kinds of disorders, but especially with externalizing childhood disorders like conduct disorder and ADHD,” Dr. van den Brink said.
It was shown half-a-decade ago that normal doses of methylphenidate have no effect on ADHD symptoms or substance use in comorbid adults. Then Swedish investigators reported that treating criminal offenders with high-dose methylphenidate – roughly three times greater than standard dosing – was effective in reducing both ADHD symptoms and comorbid substance use in criminal offenders. Those findings prompted investigators at the New York State Psychiatric Institute and the University of Minnesota to examine whether prescribing extended-release mixed amphetamine salts in adults with comorbid cocaine use disorder and ADHD would achieve improvement in both conditions. Indeed, it did, Dr. van den Brink said.
One hundred twenty-six affected patients were randomized to 60 or 80 mg/day of extended-release mixed amphetamine salts or placebo for 13 weeks coupled with weekly individual cognitive-behavioral therapy for all in this double-blind, three-arm clinical trial.
“They showed a number-needed-to-treat of about 2.5 in order to achieve a significant reduction in cocaine use and a very nice reduction in ADHD symptoms with a number-needed-to-treat of 3,” Dr. van den Brink said.
The rate of continuous cocaine abstinence in the last 3 weeks of the trial was 30% in the 80-mg group and 17.5% with 60 mg of extended-release mixed amphetamine salts, compared with just 7% with placebo (JAMA Psychiatry. 2015 Jun;72[6]:593-602).
Interpreting baclofen studies
The first high-quality multicenter, randomized, placebo-controlled, double-blind clinical trial, conducted in Germany, showed baclofen (Lioresal) at a mean dose of 180 mg/day was effective in maintaining alcohol abstinence (Eur Neuropsychopharmacol. 2015 Aug;25[8]:1167-77).
“They got wonderful results, with a number-needed-to-treat of 2.3. That is something we’re not used to seeing in the treatment of alcoholism. But there was no dose-response effect, which is a little unusual,” the psychiatrist observed.
Then a multicenter group of Dutch investigators, including Dr. van den Brink, carried out what they believed would be a confirmatory randomized, double-blind, placebo-controlled trial. However, it showed no difference between high- or low-dose baclofen and placebo in time to relapse (Eur Neuropsychopharmacol. 2016 Dec;26[12]:1950-9).
Little further light was shed by the two large French randomized, placebo-controlled clinical trials presented at the 2016 World Congress for Alcohol and Alcoholism in Berlin. One, the BACLOVILLE trial, included 320 patients treated in 60 family practice clinics; it showed strongly positive results for high-dose baclofen. In contrast, the 316-patient ALPADIR study proved negative. These conflicting results were particularly disappointing because France has been at the forefront of using high-dose baclofen to treat alcoholism, Dr. van den Brink said.
“Maybe some 100,000 people have been treated with high-dose baclofen for alcoholism in France,” he said. “What is the conclusion from all these baclofen studies? You can interpret them in many ways. Maybe there are two positive trials and two negative trials, or maybe there are two positive trials and two failed trials. The debate is not closed, even after four randomized trials.”
Dr. van den Brink reported receiving research funding from and/or serving as a consultant to more than half a dozen pharmaceutical companies.
VIENNA – The prospect on the horizon of two new effective therapies for chronic cocaine dependence – sustained-release dextroamphetamine and subanesthetic ketamine infusions – was among the top developments of the year in addiction medicine, Wim van den Brink, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Other highlights on his list included:
• Studies establishing that comorbid attention-deficit/hyperactivity disorder (ADHD) and substance use disorder now can be treated effectively with either extended-release mixed amphetamine salts or high-dose methylphenidate.
• Evidence that the alpha-1 blocker doxazosin is an effective treatment for alcoholism in a specific well-defined subset of patients, opening the door to a personalized medicine approach to this disease.
• Release of a puzzling array of conflicting studies on the use of high-dose baclofen for treatment of alcohol dependence. It’s tough to reconcile this mishmash of polar opposite results. And that dictates it’s time to declare a moratorium on the use of this therapy in clinical practice, which in many places is now widespread, said Dr. van den Brink, professor of psychiatry and addiction at the University of Amsterdam and director of the Amsterdam Institute for Addiction Research.
“It’s too strange that we have such conflicting evidence out there. Too many people are prescribing crazy-high doses of baclofen with no strong supporting evidence,” Dr. van den Brink said.
Cocaine dependence
Dr. van den Brink was a coinvestigator in a Dutch multicenter randomized, double-blind, placebo-controlled trial of multitreatment-refractory comorbid cocaine dependence in 73 heroin-dependent patients in heroin-assisted treatment. Patients assigned to 60 mg/day of sustained-release dextroamphetamine, in addition to the background methadone and diacetylmorphine all participants were on for their heroin dependence, had significantly fewer days of cocaine use in the 12-week study: a mean of 44.9 days, compared with 60.6 days in placebo-treated controls. Adverse events were transient and well tolerated (Lancet. 2016 May 28;387[10034]:2226-34).
“A lot of medications have been tried for treatment of cocaine dependence, but actually none of them has been shown to be effective with the exception of substitution treatment with stimulants. Ours is one of the most successful trials. These patients were using cocaine an average of 24 days per month along with a lot of other drugs, despite being in heroin treatment for 4 years,” Dr. van den Brink said. “Patients were very willing to take the sustained-release dextroamphetamine. In the last 4 weeks, 84% of them used at least 80% of their medication. And they were blinded to what they were using.
“We saw good effect sizes: 0.6-0.7 for self-report measures and 0.31 for negative urine samples. So this is a very promising approach. But it also means that, like with tobacco dependence or alcohol dependence, we have to start thinking about substitution therapy in stimulant-dependent patients,” he said.
Dr. van den Brink said subanesthetic ketamine as a novel treatment for cocaine dependence is not yet ready for prime time use in clinical practice, because it’s just not practical to bring patients in for a roughly hour-long intravenous infusion on a daily basis, as was done in a highly impressive proof-of-concept study. But new formulations of ketamine are under development that should better lend themselves to use in clinical practice.
In the proof-of-concept study, investigators at the New York State Psychiatric Institute brought into the laboratory cocaine-dependent volunteers not seeking treatment or abstinence and administered 52-minute infusions of ketamine at 0.41 or 71 mg/kg or lorazepam at 2 mg (Biol Psychiatry. 2014 Jul 1;76[1]:40-6). Lorazepam had absolutely no effect on motivation to change, but ketamine was a different story.
“As soon as you give a low dose of ketamine, you see a wonderful effect on motivation to change and on craving ratings in assessments at 24 hours post infusion. This looks like another promising way of treating cocaine dependence,” he said.
Doxazosin for alcoholism
Investigators at the National Institute on Alcohol Abuse and Alcoholism and several U.S. universities hypothesized that the norepinephrine system could be an important treatment target in alcohol dependence. They conducted a double-blind, placebo-controlled randomized trial in which alcohol-dependent patients seeking outpatient treatment were assigned to the alpha1-adrenergic blocker doxazosin (Cardura) titrated to a maximum of 16 mg/day or placebo. They found doxazosin significantly reduced drinks per week and the number of heavy drinking days per week, but only in the subgroup of patients with a strong family history of alcoholism. In patients without such a family history, doxazosin paradoxically increased drinking (Addict Biol. 2016 Jul;21[4]:904-14).
One of the reasons adult ADHD is greatly underrecognized is that it tends to occur in combination with flashier substance use disorders. “Addiction is very comorbid with all kinds of disorders, but especially with externalizing childhood disorders like conduct disorder and ADHD,” Dr. van den Brink said.
It was shown half-a-decade ago that normal doses of methylphenidate have no effect on ADHD symptoms or substance use in comorbid adults. Then Swedish investigators reported that treating criminal offenders with high-dose methylphenidate – roughly three times greater than standard dosing – was effective in reducing both ADHD symptoms and comorbid substance use in criminal offenders. Those findings prompted investigators at the New York State Psychiatric Institute and the University of Minnesota to examine whether prescribing extended-release mixed amphetamine salts in adults with comorbid cocaine use disorder and ADHD would achieve improvement in both conditions. Indeed, it did, Dr. van den Brink said.
One hundred twenty-six affected patients were randomized to 60 or 80 mg/day of extended-release mixed amphetamine salts or placebo for 13 weeks coupled with weekly individual cognitive-behavioral therapy for all in this double-blind, three-arm clinical trial.
“They showed a number-needed-to-treat of about 2.5 in order to achieve a significant reduction in cocaine use and a very nice reduction in ADHD symptoms with a number-needed-to-treat of 3,” Dr. van den Brink said.
The rate of continuous cocaine abstinence in the last 3 weeks of the trial was 30% in the 80-mg group and 17.5% with 60 mg of extended-release mixed amphetamine salts, compared with just 7% with placebo (JAMA Psychiatry. 2015 Jun;72[6]:593-602).
Interpreting baclofen studies
The first high-quality multicenter, randomized, placebo-controlled, double-blind clinical trial, conducted in Germany, showed baclofen (Lioresal) at a mean dose of 180 mg/day was effective in maintaining alcohol abstinence (Eur Neuropsychopharmacol. 2015 Aug;25[8]:1167-77).
“They got wonderful results, with a number-needed-to-treat of 2.3. That is something we’re not used to seeing in the treatment of alcoholism. But there was no dose-response effect, which is a little unusual,” the psychiatrist observed.
Then a multicenter group of Dutch investigators, including Dr. van den Brink, carried out what they believed would be a confirmatory randomized, double-blind, placebo-controlled trial. However, it showed no difference between high- or low-dose baclofen and placebo in time to relapse (Eur Neuropsychopharmacol. 2016 Dec;26[12]:1950-9).
Little further light was shed by the two large French randomized, placebo-controlled clinical trials presented at the 2016 World Congress for Alcohol and Alcoholism in Berlin. One, the BACLOVILLE trial, included 320 patients treated in 60 family practice clinics; it showed strongly positive results for high-dose baclofen. In contrast, the 316-patient ALPADIR study proved negative. These conflicting results were particularly disappointing because France has been at the forefront of using high-dose baclofen to treat alcoholism, Dr. van den Brink said.
“Maybe some 100,000 people have been treated with high-dose baclofen for alcoholism in France,” he said. “What is the conclusion from all these baclofen studies? You can interpret them in many ways. Maybe there are two positive trials and two negative trials, or maybe there are two positive trials and two failed trials. The debate is not closed, even after four randomized trials.”
Dr. van den Brink reported receiving research funding from and/or serving as a consultant to more than half a dozen pharmaceutical companies.
VIENNA – The prospect on the horizon of two new effective therapies for chronic cocaine dependence – sustained-release dextroamphetamine and subanesthetic ketamine infusions – was among the top developments of the year in addiction medicine, Wim van den Brink, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Other highlights on his list included:
• Studies establishing that comorbid attention-deficit/hyperactivity disorder (ADHD) and substance use disorder now can be treated effectively with either extended-release mixed amphetamine salts or high-dose methylphenidate.
• Evidence that the alpha-1 blocker doxazosin is an effective treatment for alcoholism in a specific well-defined subset of patients, opening the door to a personalized medicine approach to this disease.
• Release of a puzzling array of conflicting studies on the use of high-dose baclofen for treatment of alcohol dependence. It’s tough to reconcile this mishmash of polar opposite results. And that dictates it’s time to declare a moratorium on the use of this therapy in clinical practice, which in many places is now widespread, said Dr. van den Brink, professor of psychiatry and addiction at the University of Amsterdam and director of the Amsterdam Institute for Addiction Research.
“It’s too strange that we have such conflicting evidence out there. Too many people are prescribing crazy-high doses of baclofen with no strong supporting evidence,” Dr. van den Brink said.
Cocaine dependence
Dr. van den Brink was a coinvestigator in a Dutch multicenter randomized, double-blind, placebo-controlled trial of multitreatment-refractory comorbid cocaine dependence in 73 heroin-dependent patients in heroin-assisted treatment. Patients assigned to 60 mg/day of sustained-release dextroamphetamine, in addition to the background methadone and diacetylmorphine all participants were on for their heroin dependence, had significantly fewer days of cocaine use in the 12-week study: a mean of 44.9 days, compared with 60.6 days in placebo-treated controls. Adverse events were transient and well tolerated (Lancet. 2016 May 28;387[10034]:2226-34).
“A lot of medications have been tried for treatment of cocaine dependence, but actually none of them has been shown to be effective with the exception of substitution treatment with stimulants. Ours is one of the most successful trials. These patients were using cocaine an average of 24 days per month along with a lot of other drugs, despite being in heroin treatment for 4 years,” Dr. van den Brink said. “Patients were very willing to take the sustained-release dextroamphetamine. In the last 4 weeks, 84% of them used at least 80% of their medication. And they were blinded to what they were using.
“We saw good effect sizes: 0.6-0.7 for self-report measures and 0.31 for negative urine samples. So this is a very promising approach. But it also means that, like with tobacco dependence or alcohol dependence, we have to start thinking about substitution therapy in stimulant-dependent patients,” he said.
Dr. van den Brink said subanesthetic ketamine as a novel treatment for cocaine dependence is not yet ready for prime time use in clinical practice, because it’s just not practical to bring patients in for a roughly hour-long intravenous infusion on a daily basis, as was done in a highly impressive proof-of-concept study. But new formulations of ketamine are under development that should better lend themselves to use in clinical practice.
In the proof-of-concept study, investigators at the New York State Psychiatric Institute brought into the laboratory cocaine-dependent volunteers not seeking treatment or abstinence and administered 52-minute infusions of ketamine at 0.41 or 71 mg/kg or lorazepam at 2 mg (Biol Psychiatry. 2014 Jul 1;76[1]:40-6). Lorazepam had absolutely no effect on motivation to change, but ketamine was a different story.
“As soon as you give a low dose of ketamine, you see a wonderful effect on motivation to change and on craving ratings in assessments at 24 hours post infusion. This looks like another promising way of treating cocaine dependence,” he said.
Doxazosin for alcoholism
Investigators at the National Institute on Alcohol Abuse and Alcoholism and several U.S. universities hypothesized that the norepinephrine system could be an important treatment target in alcohol dependence. They conducted a double-blind, placebo-controlled randomized trial in which alcohol-dependent patients seeking outpatient treatment were assigned to the alpha1-adrenergic blocker doxazosin (Cardura) titrated to a maximum of 16 mg/day or placebo. They found doxazosin significantly reduced drinks per week and the number of heavy drinking days per week, but only in the subgroup of patients with a strong family history of alcoholism. In patients without such a family history, doxazosin paradoxically increased drinking (Addict Biol. 2016 Jul;21[4]:904-14).
One of the reasons adult ADHD is greatly underrecognized is that it tends to occur in combination with flashier substance use disorders. “Addiction is very comorbid with all kinds of disorders, but especially with externalizing childhood disorders like conduct disorder and ADHD,” Dr. van den Brink said.
It was shown half-a-decade ago that normal doses of methylphenidate have no effect on ADHD symptoms or substance use in comorbid adults. Then Swedish investigators reported that treating criminal offenders with high-dose methylphenidate – roughly three times greater than standard dosing – was effective in reducing both ADHD symptoms and comorbid substance use in criminal offenders. Those findings prompted investigators at the New York State Psychiatric Institute and the University of Minnesota to examine whether prescribing extended-release mixed amphetamine salts in adults with comorbid cocaine use disorder and ADHD would achieve improvement in both conditions. Indeed, it did, Dr. van den Brink said.
One hundred twenty-six affected patients were randomized to 60 or 80 mg/day of extended-release mixed amphetamine salts or placebo for 13 weeks coupled with weekly individual cognitive-behavioral therapy for all in this double-blind, three-arm clinical trial.
“They showed a number-needed-to-treat of about 2.5 in order to achieve a significant reduction in cocaine use and a very nice reduction in ADHD symptoms with a number-needed-to-treat of 3,” Dr. van den Brink said.
The rate of continuous cocaine abstinence in the last 3 weeks of the trial was 30% in the 80-mg group and 17.5% with 60 mg of extended-release mixed amphetamine salts, compared with just 7% with placebo (JAMA Psychiatry. 2015 Jun;72[6]:593-602).
Interpreting baclofen studies
The first high-quality multicenter, randomized, placebo-controlled, double-blind clinical trial, conducted in Germany, showed baclofen (Lioresal) at a mean dose of 180 mg/day was effective in maintaining alcohol abstinence (Eur Neuropsychopharmacol. 2015 Aug;25[8]:1167-77).
“They got wonderful results, with a number-needed-to-treat of 2.3. That is something we’re not used to seeing in the treatment of alcoholism. But there was no dose-response effect, which is a little unusual,” the psychiatrist observed.
Then a multicenter group of Dutch investigators, including Dr. van den Brink, carried out what they believed would be a confirmatory randomized, double-blind, placebo-controlled trial. However, it showed no difference between high- or low-dose baclofen and placebo in time to relapse (Eur Neuropsychopharmacol. 2016 Dec;26[12]:1950-9).
Little further light was shed by the two large French randomized, placebo-controlled clinical trials presented at the 2016 World Congress for Alcohol and Alcoholism in Berlin. One, the BACLOVILLE trial, included 320 patients treated in 60 family practice clinics; it showed strongly positive results for high-dose baclofen. In contrast, the 316-patient ALPADIR study proved negative. These conflicting results were particularly disappointing because France has been at the forefront of using high-dose baclofen to treat alcoholism, Dr. van den Brink said.
“Maybe some 100,000 people have been treated with high-dose baclofen for alcoholism in France,” he said. “What is the conclusion from all these baclofen studies? You can interpret them in many ways. Maybe there are two positive trials and two negative trials, or maybe there are two positive trials and two failed trials. The debate is not closed, even after four randomized trials.”
Dr. van den Brink reported receiving research funding from and/or serving as a consultant to more than half a dozen pharmaceutical companies.
EXPERT ANALYSIS FROM THE ECNP CONGRESS
Adjunctive brexpiprazole improves cognitive function in major depression
VIENNA – Adjunctive brexpiprazole in patients with an inadequate response to antidepressant monotherapy for major depressive disorder resulted in clinically meaningful improvement in multiple aspects of functional impairment, including cognitive dysfunction, in three open-label exploratory studies, Ross A. Baker, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
Clinician-rated depressive symptoms also showed significant improvement once brexpiprazole (Rexulti) was on board, added Dr. Baker of Otsuka Pharmaceutical in Princeton, N.J.
But fatigue and cognitive impairment are another matter. They are now recognized as core aspects of major depression. Even after patients’ depressive symptoms have gone into remission, lingering cognitive dysfunction often impairs performance at work or school, social life, and family/home life. Antidepressants don’t improve this depression-related cognitive impairment. This was the impetus for the three open-label exploratory studies, which addressed these common problems of functional disability and cognitive impairment in different populations with major depressive disorder. The target dose of brexpiprazole in all three studies was 2 mg per day in addition to whatever antidepressant medication patients were already on.
One 12-week study included 47 young patients working at a job or in school. Their mean baseline score on the Sheehan Disability Scale (SDS) was 6.5; a score of 5 or more on the 0-10 scale indicates significant functional impairment in the three domains covered by the SDS: home responsibilities, social life, and work or school performance.
After 12 weeks of adjunctive brexpiprazole, the patients’ mean SDS score had improved by 3.7 points. The improvement was significant across all three domains in this study, as well as in the other two open-label studies.
Patients also demonstrated significant improvement on the Cognitive and Physical Functioning Questionnaire (CPFQ), a self-rated scale that addresses cognitive impairment and executive function. The CPFQ consists of seven items, each scored 1-6, with a higher score indicating worse function in that domain. After 12 weeks on adjunctive brexpiprazole, the young patients experienced a mean 8.1-point improvement from a baseline CPFQ score of 26.1.
Another study included 37 patients with prominent anxiety as a feature of their major depressive disorder. Over the course of 6 weeks of treatment, their mean SDS score improved by 3.6 points from a baseline of 6.5. Also, their CPFQ score fell by 9.9 points from a baseline of 29.3.
The third study involved 61 patients who had switched antidepressants after an inadequate response. After 6 weeks on adjunctive brexpiprazole, their mean SDS score improved from 6.3 to 3.2, and their CPFQ dropped by 9.9 points from a baseline of 29.3 points.
Increased energy and alertness were commonly reported by participants in all three studies.
MADRS scores improved by a mean of 18.1 points from 28.3 points at baseline in the youth study, by 19.8 points from a baseline of 30.1 in the high-anxiety group, and by 17.3 points from a baseline of 29.6 in the study of patients who’d switched antidepressants.
These exploratory studies were sponsored by Otsuka Pharmaceutical. Dr. Baker is a company employee.
Brexpiprazole also is FDA-approved for treatment of schizophrenia.
VIENNA – Adjunctive brexpiprazole in patients with an inadequate response to antidepressant monotherapy for major depressive disorder resulted in clinically meaningful improvement in multiple aspects of functional impairment, including cognitive dysfunction, in three open-label exploratory studies, Ross A. Baker, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
Clinician-rated depressive symptoms also showed significant improvement once brexpiprazole (Rexulti) was on board, added Dr. Baker of Otsuka Pharmaceutical in Princeton, N.J.
But fatigue and cognitive impairment are another matter. They are now recognized as core aspects of major depression. Even after patients’ depressive symptoms have gone into remission, lingering cognitive dysfunction often impairs performance at work or school, social life, and family/home life. Antidepressants don’t improve this depression-related cognitive impairment. This was the impetus for the three open-label exploratory studies, which addressed these common problems of functional disability and cognitive impairment in different populations with major depressive disorder. The target dose of brexpiprazole in all three studies was 2 mg per day in addition to whatever antidepressant medication patients were already on.
One 12-week study included 47 young patients working at a job or in school. Their mean baseline score on the Sheehan Disability Scale (SDS) was 6.5; a score of 5 or more on the 0-10 scale indicates significant functional impairment in the three domains covered by the SDS: home responsibilities, social life, and work or school performance.
After 12 weeks of adjunctive brexpiprazole, the patients’ mean SDS score had improved by 3.7 points. The improvement was significant across all three domains in this study, as well as in the other two open-label studies.
Patients also demonstrated significant improvement on the Cognitive and Physical Functioning Questionnaire (CPFQ), a self-rated scale that addresses cognitive impairment and executive function. The CPFQ consists of seven items, each scored 1-6, with a higher score indicating worse function in that domain. After 12 weeks on adjunctive brexpiprazole, the young patients experienced a mean 8.1-point improvement from a baseline CPFQ score of 26.1.
Another study included 37 patients with prominent anxiety as a feature of their major depressive disorder. Over the course of 6 weeks of treatment, their mean SDS score improved by 3.6 points from a baseline of 6.5. Also, their CPFQ score fell by 9.9 points from a baseline of 29.3.
The third study involved 61 patients who had switched antidepressants after an inadequate response. After 6 weeks on adjunctive brexpiprazole, their mean SDS score improved from 6.3 to 3.2, and their CPFQ dropped by 9.9 points from a baseline of 29.3 points.
Increased energy and alertness were commonly reported by participants in all three studies.
MADRS scores improved by a mean of 18.1 points from 28.3 points at baseline in the youth study, by 19.8 points from a baseline of 30.1 in the high-anxiety group, and by 17.3 points from a baseline of 29.6 in the study of patients who’d switched antidepressants.
These exploratory studies were sponsored by Otsuka Pharmaceutical. Dr. Baker is a company employee.
Brexpiprazole also is FDA-approved for treatment of schizophrenia.
VIENNA – Adjunctive brexpiprazole in patients with an inadequate response to antidepressant monotherapy for major depressive disorder resulted in clinically meaningful improvement in multiple aspects of functional impairment, including cognitive dysfunction, in three open-label exploratory studies, Ross A. Baker, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
Clinician-rated depressive symptoms also showed significant improvement once brexpiprazole (Rexulti) was on board, added Dr. Baker of Otsuka Pharmaceutical in Princeton, N.J.
But fatigue and cognitive impairment are another matter. They are now recognized as core aspects of major depression. Even after patients’ depressive symptoms have gone into remission, lingering cognitive dysfunction often impairs performance at work or school, social life, and family/home life. Antidepressants don’t improve this depression-related cognitive impairment. This was the impetus for the three open-label exploratory studies, which addressed these common problems of functional disability and cognitive impairment in different populations with major depressive disorder. The target dose of brexpiprazole in all three studies was 2 mg per day in addition to whatever antidepressant medication patients were already on.
One 12-week study included 47 young patients working at a job or in school. Their mean baseline score on the Sheehan Disability Scale (SDS) was 6.5; a score of 5 or more on the 0-10 scale indicates significant functional impairment in the three domains covered by the SDS: home responsibilities, social life, and work or school performance.
After 12 weeks of adjunctive brexpiprazole, the patients’ mean SDS score had improved by 3.7 points. The improvement was significant across all three domains in this study, as well as in the other two open-label studies.
Patients also demonstrated significant improvement on the Cognitive and Physical Functioning Questionnaire (CPFQ), a self-rated scale that addresses cognitive impairment and executive function. The CPFQ consists of seven items, each scored 1-6, with a higher score indicating worse function in that domain. After 12 weeks on adjunctive brexpiprazole, the young patients experienced a mean 8.1-point improvement from a baseline CPFQ score of 26.1.
Another study included 37 patients with prominent anxiety as a feature of their major depressive disorder. Over the course of 6 weeks of treatment, their mean SDS score improved by 3.6 points from a baseline of 6.5. Also, their CPFQ score fell by 9.9 points from a baseline of 29.3.
The third study involved 61 patients who had switched antidepressants after an inadequate response. After 6 weeks on adjunctive brexpiprazole, their mean SDS score improved from 6.3 to 3.2, and their CPFQ dropped by 9.9 points from a baseline of 29.3 points.
Increased energy and alertness were commonly reported by participants in all three studies.
MADRS scores improved by a mean of 18.1 points from 28.3 points at baseline in the youth study, by 19.8 points from a baseline of 30.1 in the high-anxiety group, and by 17.3 points from a baseline of 29.6 in the study of patients who’d switched antidepressants.
These exploratory studies were sponsored by Otsuka Pharmaceutical. Dr. Baker is a company employee.
Brexpiprazole also is FDA-approved for treatment of schizophrenia.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Mean scores on the Sheehan Disability Scale improved by 3.1-3.7 points from a baseline of 6.3-6.5 after 6 or 12 weeks of adjunctive brexpiprazole in three studies.
Data source: The three open-label exploratory studies included a total of 145 patients with major depressive disorder.
Disclosures: The studies were sponsored by Otsuka Pharmaceuticals. The presenter is employed by the company.
Aerobic exercise improves depression-related cognitive impairment
VIENNA – An adjunctive aerobic exercise program improved cognitive impairment in patients hospitalized for depression in a Swiss randomized controlled trial, Christian Imboden, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
This study addresses a major unmet need in the treatment of depression: namely, options to improve the cognitive dysfunction that accompanies the mood disorder.
“In my opinion, cognition is a very important target of exercise. Cognition is still an unsolved problem in depression. It lasts for months after remission. It’s a big problem when people go back to work. I think aerobic exercise might be one means for patients to improve their cognition,” said Dr. Imboden, a psychiatrist at Solothurn City Hospital in Switzerland.
He presented a study involving 33 inpatients with a mean baseline score of 21.4 on the 17-item Hamilton Depression Rating Scale. They averaged just under 38 years of age. Fifteen were hospitalized for a first episode of major depressive disorder, 15 had recurrent depression, and 3 had a diagnosis of bipolar depression.
Participants were randomized to the 6-week endurance exercise program or to a standardized stretching and coordination program that met three times per week as a control arm. The exercise group was required to burn 17.5 kcal per kilo of body weight per week on an indoor bicycle at 60%-75% of their maximal age-appropriate heart rate. Cognitive variables were measured at baseline and after 6 weeks using the German-language TAP-test version 2.3.
At the end of 6 weeks, the 16 patients in the exercise group demonstrated significantly greater improvement in working memory reaction time than controls.
“It’s a medium effect size for working memory,” Dr. Imboden said.
The exercisers also showed a trend, albeit not statistically significant, for greater improvement on a measure of alertness, compared with the controls.
The exercise group and controls showed similar improvements in core depressive symptoms over time. After 6 weeks, their mean Hamilton score had improved from 21.7 to 8.6. This result differs from numerous prior studies by other investigators, which have found – typically in outpatients – that exercise significantly reduced depressive symptom severity relative to controls in patients with mild to moderate depression.
Dr. Imboden believes he knows the explanation for the divergent findings. “We have a very effective inpatient treatment program with evidence-based pharmacology, CBT [cognitive-behavioral therapy], and CBT-I for sleep problems. All of our patients were below 10 on the Hamilton score. I think the added value of exercise is very difficult to show under these circumstances, especially with a small sample size,” he said in an interview.
Also, the control arms in exercise research studies often tend to show a large placebo effect. When sedentary patients in the depth of depression are able to overcome their lassitude and sign up for an exercise trial, even simple stretching represents a significant increase in bodily movement, the psychiatrist added.
The biggest need now is to come up with ways to facilitate the transfer of exercise programs from the treatment setting into posttreatment daily life, according to Dr. Imboden.
“Everybody who’s exercising knows it’s helpful, but it can be difficult to create a routine,” he said.
The study was funded by a health research foundation grant, a Swiss health insurance company, and the Canton of Solothurn. Dr. Imboden reported having no financial disclosures.
VIENNA – An adjunctive aerobic exercise program improved cognitive impairment in patients hospitalized for depression in a Swiss randomized controlled trial, Christian Imboden, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
This study addresses a major unmet need in the treatment of depression: namely, options to improve the cognitive dysfunction that accompanies the mood disorder.
“In my opinion, cognition is a very important target of exercise. Cognition is still an unsolved problem in depression. It lasts for months after remission. It’s a big problem when people go back to work. I think aerobic exercise might be one means for patients to improve their cognition,” said Dr. Imboden, a psychiatrist at Solothurn City Hospital in Switzerland.
He presented a study involving 33 inpatients with a mean baseline score of 21.4 on the 17-item Hamilton Depression Rating Scale. They averaged just under 38 years of age. Fifteen were hospitalized for a first episode of major depressive disorder, 15 had recurrent depression, and 3 had a diagnosis of bipolar depression.
Participants were randomized to the 6-week endurance exercise program or to a standardized stretching and coordination program that met three times per week as a control arm. The exercise group was required to burn 17.5 kcal per kilo of body weight per week on an indoor bicycle at 60%-75% of their maximal age-appropriate heart rate. Cognitive variables were measured at baseline and after 6 weeks using the German-language TAP-test version 2.3.
At the end of 6 weeks, the 16 patients in the exercise group demonstrated significantly greater improvement in working memory reaction time than controls.
“It’s a medium effect size for working memory,” Dr. Imboden said.
The exercisers also showed a trend, albeit not statistically significant, for greater improvement on a measure of alertness, compared with the controls.
The exercise group and controls showed similar improvements in core depressive symptoms over time. After 6 weeks, their mean Hamilton score had improved from 21.7 to 8.6. This result differs from numerous prior studies by other investigators, which have found – typically in outpatients – that exercise significantly reduced depressive symptom severity relative to controls in patients with mild to moderate depression.
Dr. Imboden believes he knows the explanation for the divergent findings. “We have a very effective inpatient treatment program with evidence-based pharmacology, CBT [cognitive-behavioral therapy], and CBT-I for sleep problems. All of our patients were below 10 on the Hamilton score. I think the added value of exercise is very difficult to show under these circumstances, especially with a small sample size,” he said in an interview.
Also, the control arms in exercise research studies often tend to show a large placebo effect. When sedentary patients in the depth of depression are able to overcome their lassitude and sign up for an exercise trial, even simple stretching represents a significant increase in bodily movement, the psychiatrist added.
The biggest need now is to come up with ways to facilitate the transfer of exercise programs from the treatment setting into posttreatment daily life, according to Dr. Imboden.
“Everybody who’s exercising knows it’s helpful, but it can be difficult to create a routine,” he said.
The study was funded by a health research foundation grant, a Swiss health insurance company, and the Canton of Solothurn. Dr. Imboden reported having no financial disclosures.
VIENNA – An adjunctive aerobic exercise program improved cognitive impairment in patients hospitalized for depression in a Swiss randomized controlled trial, Christian Imboden, MD, reported at the annual congress of the European College of Neuropsychopharmacology.
This study addresses a major unmet need in the treatment of depression: namely, options to improve the cognitive dysfunction that accompanies the mood disorder.
“In my opinion, cognition is a very important target of exercise. Cognition is still an unsolved problem in depression. It lasts for months after remission. It’s a big problem when people go back to work. I think aerobic exercise might be one means for patients to improve their cognition,” said Dr. Imboden, a psychiatrist at Solothurn City Hospital in Switzerland.
He presented a study involving 33 inpatients with a mean baseline score of 21.4 on the 17-item Hamilton Depression Rating Scale. They averaged just under 38 years of age. Fifteen were hospitalized for a first episode of major depressive disorder, 15 had recurrent depression, and 3 had a diagnosis of bipolar depression.
Participants were randomized to the 6-week endurance exercise program or to a standardized stretching and coordination program that met three times per week as a control arm. The exercise group was required to burn 17.5 kcal per kilo of body weight per week on an indoor bicycle at 60%-75% of their maximal age-appropriate heart rate. Cognitive variables were measured at baseline and after 6 weeks using the German-language TAP-test version 2.3.
At the end of 6 weeks, the 16 patients in the exercise group demonstrated significantly greater improvement in working memory reaction time than controls.
“It’s a medium effect size for working memory,” Dr. Imboden said.
The exercisers also showed a trend, albeit not statistically significant, for greater improvement on a measure of alertness, compared with the controls.
The exercise group and controls showed similar improvements in core depressive symptoms over time. After 6 weeks, their mean Hamilton score had improved from 21.7 to 8.6. This result differs from numerous prior studies by other investigators, which have found – typically in outpatients – that exercise significantly reduced depressive symptom severity relative to controls in patients with mild to moderate depression.
Dr. Imboden believes he knows the explanation for the divergent findings. “We have a very effective inpatient treatment program with evidence-based pharmacology, CBT [cognitive-behavioral therapy], and CBT-I for sleep problems. All of our patients were below 10 on the Hamilton score. I think the added value of exercise is very difficult to show under these circumstances, especially with a small sample size,” he said in an interview.
Also, the control arms in exercise research studies often tend to show a large placebo effect. When sedentary patients in the depth of depression are able to overcome their lassitude and sign up for an exercise trial, even simple stretching represents a significant increase in bodily movement, the psychiatrist added.
The biggest need now is to come up with ways to facilitate the transfer of exercise programs from the treatment setting into posttreatment daily life, according to Dr. Imboden.
“Everybody who’s exercising knows it’s helpful, but it can be difficult to create a routine,” he said.
The study was funded by a health research foundation grant, a Swiss health insurance company, and the Canton of Solothurn. Dr. Imboden reported having no financial disclosures.
Key clinical point:
Major finding: Cognitive dysfunction – particularly working memory – improved significantly in depressed inpatients who burned calories by peddling an indoor bike at 60%-75% of their maximum heart rate in a structured 6-week aerobic exercise program.
Data source: A randomized controlled prospective clinical trial included 33 inpatients with moderate to severe depression who were assigned to an aerobic exercise program or a stretching regimen control group.
Disclosures: The study was funded by a health research foundation grant, a Swiss health insurance company, and the Canton of Solothurn. The presenter reported having no financial disclosures.
Nutraceutical cocktail protects against postpartum blues
VIENNA – A dietary supplement blend virtually eliminated postpartum blues in a promising proof-of-concept controlled trial, Yekta Dowlati, PhD, reported during the annual congress of the European College of Neuropsychopharmacology.
The nutraceutical cocktail is designed to compensate for the effects of the early postpartum surge in monoamine oxidase A (MAO-A) activity that her research group previously has reported. They found that as estrogen levels plunge by 100-fold in the first 3 days postpartum, brain MAO-A levels rise by 40% in affect-controlling regions, including the prefrontal cortex and anterior cingulate cortex (Arch Gen Psychiatry. 2010 May;67[5]:468-74).
That suggests a potential causal relationship with postpartum blues, since MAO-A is an enzyme whose effects include promotion of oxidative stress, apoptosis, and metabolizing serotonin, norepinephrine, and dopamine, explained Dr. Dowlati of the department of psychiatry at the University of Toronto.
Postpartum blues is a common prodrome for postpartum depression, the most frequent complication of childbearing, which has an estimated incidence of 13%. Severe postpartum blues is a strong predictor of subsequent postpartum depression. Yet, despite the large burden of illness imposed by postpartum depression, there is no proven preventive strategy. The hypothesis being pursued in developing this nutraceutical is that a safe dietary intervention that prevents postpartum blues also may prevent postpartum depression.
The nutraceutical cocktail developed by Dr. Dowlati and her coinvestigators consists of monoamine precursors: 2 g of tryptophan, 10 g of tyrosine, and blueberry juice plus blueberry extract.
She reported on 41 healthy breast-feeding mothers who on day 5 postpartum, when postpartum blues typically peaks, were assigned to drink the dietary supplement or not. Later that day, they underwent a quantified assessment of their severity of postpartum blues based upon change from baseline in depressed mood scores on a 0-100 visual analog scale after undergoing a standardized sad mood induction procedure. This is a simple protocol widely used by psychiatrists and psychologists researching the neurobiology of mood states. Dr. Dowlati and her colleagues used the Velten protocol, in which subjects read depressing sentences while listening to sad music.
Mean scores on the Visual Analog Scale for sadness following the standardized mood induction procedure jumped by 43.8 points in the control group but were unchanged, with a mere 0.5-point increase, in the 21 women in the active treatment arm.
“The results of the present study, albeit in an open-label trial, reflect by far the most robust effects of a dietary supplement ever seen on postpartum blues. Our effect size was 2.9. Previous trials have reported effect sizes of 0.07-0.28,” she noted.
An effect size of 2.9 means that if a postpartum woman did not experience a plunge in mood after the induction protocol, there was statistically a 98%-99% chance that she had consumed the supplement.
“One explanation to account for an active effect is that the supplement is compensating for the effects of monoamine metabolism and increased oxidative stress by elevated postpartum MAO-A levels,” according to Dr. Dowlati. “Given the effect size of 2.9 and minimal effects of tryptophan and tyrosine supplementation on total levels in breast milk, there is excellent reason to pursue this supplement in a randomized, double-blind, placebo-controlled trial to further assess its effects.”
Before conducting this efficacy study, the investigators evaluated the safety of their planned intervention by randomizing 54 healthy breast-feeding women to single larger doses of oral tyrosine or tryptophan than were used in the nutraceutical cocktail or to no supplements. They found no subsequent increase in total tyrosine or total tryptophan levels in the subjects’ breast milk, although dose-dependent increases were found in free tyrosine and free tryptophan in maternal plasma. Free tyrosine was increased in breast milk; however, the level was significantly lower than what the investigators found in laboratory analysis of a dozen popular brands of infant formula.
The safety and open-label efficacy studies were funded by the Canadian Institutes of Health Research, the Ontario Mental Health Foundation, and university research grants. Dr. Dowlati reported having no financial conflicts of interest.
VIENNA – A dietary supplement blend virtually eliminated postpartum blues in a promising proof-of-concept controlled trial, Yekta Dowlati, PhD, reported during the annual congress of the European College of Neuropsychopharmacology.
The nutraceutical cocktail is designed to compensate for the effects of the early postpartum surge in monoamine oxidase A (MAO-A) activity that her research group previously has reported. They found that as estrogen levels plunge by 100-fold in the first 3 days postpartum, brain MAO-A levels rise by 40% in affect-controlling regions, including the prefrontal cortex and anterior cingulate cortex (Arch Gen Psychiatry. 2010 May;67[5]:468-74).
That suggests a potential causal relationship with postpartum blues, since MAO-A is an enzyme whose effects include promotion of oxidative stress, apoptosis, and metabolizing serotonin, norepinephrine, and dopamine, explained Dr. Dowlati of the department of psychiatry at the University of Toronto.
Postpartum blues is a common prodrome for postpartum depression, the most frequent complication of childbearing, which has an estimated incidence of 13%. Severe postpartum blues is a strong predictor of subsequent postpartum depression. Yet, despite the large burden of illness imposed by postpartum depression, there is no proven preventive strategy. The hypothesis being pursued in developing this nutraceutical is that a safe dietary intervention that prevents postpartum blues also may prevent postpartum depression.
The nutraceutical cocktail developed by Dr. Dowlati and her coinvestigators consists of monoamine precursors: 2 g of tryptophan, 10 g of tyrosine, and blueberry juice plus blueberry extract.
She reported on 41 healthy breast-feeding mothers who on day 5 postpartum, when postpartum blues typically peaks, were assigned to drink the dietary supplement or not. Later that day, they underwent a quantified assessment of their severity of postpartum blues based upon change from baseline in depressed mood scores on a 0-100 visual analog scale after undergoing a standardized sad mood induction procedure. This is a simple protocol widely used by psychiatrists and psychologists researching the neurobiology of mood states. Dr. Dowlati and her colleagues used the Velten protocol, in which subjects read depressing sentences while listening to sad music.
Mean scores on the Visual Analog Scale for sadness following the standardized mood induction procedure jumped by 43.8 points in the control group but were unchanged, with a mere 0.5-point increase, in the 21 women in the active treatment arm.
“The results of the present study, albeit in an open-label trial, reflect by far the most robust effects of a dietary supplement ever seen on postpartum blues. Our effect size was 2.9. Previous trials have reported effect sizes of 0.07-0.28,” she noted.
An effect size of 2.9 means that if a postpartum woman did not experience a plunge in mood after the induction protocol, there was statistically a 98%-99% chance that she had consumed the supplement.
“One explanation to account for an active effect is that the supplement is compensating for the effects of monoamine metabolism and increased oxidative stress by elevated postpartum MAO-A levels,” according to Dr. Dowlati. “Given the effect size of 2.9 and minimal effects of tryptophan and tyrosine supplementation on total levels in breast milk, there is excellent reason to pursue this supplement in a randomized, double-blind, placebo-controlled trial to further assess its effects.”
Before conducting this efficacy study, the investigators evaluated the safety of their planned intervention by randomizing 54 healthy breast-feeding women to single larger doses of oral tyrosine or tryptophan than were used in the nutraceutical cocktail or to no supplements. They found no subsequent increase in total tyrosine or total tryptophan levels in the subjects’ breast milk, although dose-dependent increases were found in free tyrosine and free tryptophan in maternal plasma. Free tyrosine was increased in breast milk; however, the level was significantly lower than what the investigators found in laboratory analysis of a dozen popular brands of infant formula.
The safety and open-label efficacy studies were funded by the Canadian Institutes of Health Research, the Ontario Mental Health Foundation, and university research grants. Dr. Dowlati reported having no financial conflicts of interest.
VIENNA – A dietary supplement blend virtually eliminated postpartum blues in a promising proof-of-concept controlled trial, Yekta Dowlati, PhD, reported during the annual congress of the European College of Neuropsychopharmacology.
The nutraceutical cocktail is designed to compensate for the effects of the early postpartum surge in monoamine oxidase A (MAO-A) activity that her research group previously has reported. They found that as estrogen levels plunge by 100-fold in the first 3 days postpartum, brain MAO-A levels rise by 40% in affect-controlling regions, including the prefrontal cortex and anterior cingulate cortex (Arch Gen Psychiatry. 2010 May;67[5]:468-74).
That suggests a potential causal relationship with postpartum blues, since MAO-A is an enzyme whose effects include promotion of oxidative stress, apoptosis, and metabolizing serotonin, norepinephrine, and dopamine, explained Dr. Dowlati of the department of psychiatry at the University of Toronto.
Postpartum blues is a common prodrome for postpartum depression, the most frequent complication of childbearing, which has an estimated incidence of 13%. Severe postpartum blues is a strong predictor of subsequent postpartum depression. Yet, despite the large burden of illness imposed by postpartum depression, there is no proven preventive strategy. The hypothesis being pursued in developing this nutraceutical is that a safe dietary intervention that prevents postpartum blues also may prevent postpartum depression.
The nutraceutical cocktail developed by Dr. Dowlati and her coinvestigators consists of monoamine precursors: 2 g of tryptophan, 10 g of tyrosine, and blueberry juice plus blueberry extract.
She reported on 41 healthy breast-feeding mothers who on day 5 postpartum, when postpartum blues typically peaks, were assigned to drink the dietary supplement or not. Later that day, they underwent a quantified assessment of their severity of postpartum blues based upon change from baseline in depressed mood scores on a 0-100 visual analog scale after undergoing a standardized sad mood induction procedure. This is a simple protocol widely used by psychiatrists and psychologists researching the neurobiology of mood states. Dr. Dowlati and her colleagues used the Velten protocol, in which subjects read depressing sentences while listening to sad music.
Mean scores on the Visual Analog Scale for sadness following the standardized mood induction procedure jumped by 43.8 points in the control group but were unchanged, with a mere 0.5-point increase, in the 21 women in the active treatment arm.
“The results of the present study, albeit in an open-label trial, reflect by far the most robust effects of a dietary supplement ever seen on postpartum blues. Our effect size was 2.9. Previous trials have reported effect sizes of 0.07-0.28,” she noted.
An effect size of 2.9 means that if a postpartum woman did not experience a plunge in mood after the induction protocol, there was statistically a 98%-99% chance that she had consumed the supplement.
“One explanation to account for an active effect is that the supplement is compensating for the effects of monoamine metabolism and increased oxidative stress by elevated postpartum MAO-A levels,” according to Dr. Dowlati. “Given the effect size of 2.9 and minimal effects of tryptophan and tyrosine supplementation on total levels in breast milk, there is excellent reason to pursue this supplement in a randomized, double-blind, placebo-controlled trial to further assess its effects.”
Before conducting this efficacy study, the investigators evaluated the safety of their planned intervention by randomizing 54 healthy breast-feeding women to single larger doses of oral tyrosine or tryptophan than were used in the nutraceutical cocktail or to no supplements. They found no subsequent increase in total tyrosine or total tryptophan levels in the subjects’ breast milk, although dose-dependent increases were found in free tyrosine and free tryptophan in maternal plasma. Free tyrosine was increased in breast milk; however, the level was significantly lower than what the investigators found in laboratory analysis of a dozen popular brands of infant formula.
The safety and open-label efficacy studies were funded by the Canadian Institutes of Health Research, the Ontario Mental Health Foundation, and university research grants. Dr. Dowlati reported having no financial conflicts of interest.
Key clinical point:
Major finding: Postpartum women who consumed a dietary supplement designed to compensate for the effects of a surge in monoamine oxidase A activity did not experience any lowering of mood after completing a standardized sad mood induction protocol, while a control group showed a steep rise in sadness scores.
Data source: An open-label proof-of-concept study in which 41 women undertook a standardized sad mood induction protocol on day 5 postpartum, after 21 of them had consumed a dietary supplement blend designed to ward off postpartum blues.
Disclosures: The safety and open-label efficacy studies were funded by the Canadian Institutes of Health Research, the Ontario Mental Health Foundation, and university research grants. Dr. Dowlati reported having no financial conflicts of interest.
Recognizing anti-NMDA receptor encephalitis psychosis on the psych ward
VIENNA – Prominent psychiatric symptoms are common in patients with anti-N-methyl-D-asparate receptor (NMDAR) encephalitis and often occur prior to onset of obvious neurologic symptoms, Maarten J. Titulaer, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Moreover, occasionally the psychiatric symptoms occur in isolation without neurologic involvement, as was the case in 4% of a series of 501 patients with confirmed anti-NMDAR encephalitis reported by Dr. Titulaer and coinvestigators. The most prominent symptoms included delusional thinking, aggression, and mood disturbances, which were usually manic (JAMA Neurol. 2013 Sep 1;70[9]:1133-9).
The clinical implication is that it’s important to consider the possibility of anti-NMDAR encephalitis in all patients presenting with new-onset psychosis or mania, and to be cognizant of the red flags that warrant definitive diagnostic testing. This serious disease responds well to aggressive immunotherapy, especially if started early, which is impressive given that three-quarters of affected patients will need to spend a month or two in the ICU during the course of their illness, explained Dr. Titulaer, a neurologist at Erasmus University in Rotterdam, the Netherlands.
Anti-NMDAR encephalitis is an autoimmune disorder in which autoantibodies directed at NMDA receptors on neuronal plasma membranes induce severe neurologic and often psychiatric symptoms.
Red flags that raise the chance that a patient on the psychiatric ward with new-onset psychosis or mania might have primary anti-NMDAR encephalitis and should undergo diagnostic testing include autonomic disturbances such as tachycardia, fever, or hypertension, mild neurologic symptoms such as facial twitching, as well as catatonia, seizures, mutism, or development of extrapyramidal symptoms when placed on an antipsychotic agent. Anti-NMDAR encephalitis can have a relapsing course, so any behavioral change in a patient with a history of the disorder might signal relapse.
Certain cancers are strongly associated with anti-NMDAR encephalitis. New-onset psychotic or manic patients with a history of ovarian teratoma, small cell lung cancer, breast cancer, or thymoma should be tested for anti-NMDAR encephalitis. And conversely, screening for those tumors in occult form is warranted in patients with confirmed anti-NMDAR encephalitis, according to Dr. Titulaer.
Systematic screening for anti-NMDAR encephalitis should also be considered in women with severe acute psychosis during the postpartum period, particularly in the setting of extrapyramidal side effects of antipsychotic agents. Two of 96 consecutive women with acute-onset postpartum psychosis in a series reported by Dr. Titulaer and colleagues were antibody-positive for the disorder, and neither had an ovarian teratoma (Am J Psychiatry. 2015 Sep 1;172[9]:901-8).
If a patient hasn’t developed neurologic symptoms within 4 weeks after onset of psychiatric symptoms, anti-NMDAR psychosis becomes far less likely.
Some neurologists have suggested the presence of other autoimmune disorders in psychiatric patients is associated with increased likelihood that the psychiatric symptoms are secondary to anti-NMDAR encephalitis, but Dr. Titulaer doesn’t find the evidence to date persuasive.
The diagnosis of anti-NMDAR encephalitis hinges on the finding of IgG antibodies against the NR1 subunit of the NMDAR. But Dr. Titulaer and coinvestigators have shown there are testing pitfalls: The first-line commercially available cell-based serum assays have a sensitivity of roughly 75% along with 97%-99% specificity, so by relying solely on the cell-based assays a physician might miss one in four cases of anti-NMDAR encephalitis and wrongly diagnose the disease in 0.4%-3% of healthy individuals (Lancet Neurol. 2014 Feb;13[2]:167-77).
For this reason, a positive serum test should be confirmed by a cell-based assay of a cerebrospinal fluid (CSF) sample, which has 100% sensitivity and specificity. And if the serum assay is negative but anti-NMDAR is suspected based on clinical grounds or history, go ahead and test the CSF, the neurologist advised.
Other tools that can be helpful in making the diagnosis include the EEG, which is abnormal in 89% of patients with anti-NMDAR encephalitis. Thirty percent of affected patients will display a highly specific EEG abnormality called extreme delta brushes (Neurology. 2012 Sep 11;79[11]:1094-100).
Dr. Titulaer said that this extreme delta brushes pattern is not seen on the regular psychiatry ward, but only in the ICU, when the patient is severely ill. He has yet to see the first convincing extreme delta brushes pattern in a patient outside the ICU.
Brain MRI has proved “very disappointing,” as it’s abnormal in only one-third of patients with anti-NMDAR encephalitis, he continued.
First-line immunotherapy is corticosteroids, plasmapheresis, and/or intravenous immunoglobulin. In a series of 501 patients who received first-line immunotherapy or tumor removal, 53% improved within 4 weeks. Fifty-seven percent of those who didn’t then got second-line immunotherapy with rituximab (Rituxan) or cyclophosphamide. Outcomes continued to improve for up to 18 months following symptom onset. At 24 months of follow-up, just over 80% of patients in this observational study had a good outcome as defined by a modified Rankin scale score of 0-2, meaning they were living independently with no or minimal disability.
“Not bad, especially considering that the patients who didn’t improve on first-line therapy were in the ICU for a median of 6 weeks,” the neurologist observed.
“It’s important to diagnose patients with anti-NMDAR encephalitis,” he stressed. “Treatment might be difficult. You might need to be very aggressive. But in the end there are very good outcomes. It’s very rewarding to treat these patients.”
In multivariate analysis, Dr. Titulaer and coworkers identified earlier treatment and milder illness as reflected in no ICU admission as significant predictors of good outcome in the study population. Also, the use of second-line immunotherapy in nonresponders to first-line therapy was independently associated with a 2.69-fold increased likelihood of good outcome (Lancet Neurol. 2013 Feb;12[2]:157-65).
Twelve percent of patients experienced one or more relapses within 2 years.
In a separate study of 661 patients with anti-NMDAR encephalitis, only 31 were aged 45 years or older. They had less severe disease than the younger adults but a paradoxically worse outcome, possibly because their median time to diagnosis was twice as long. At 2 years, 60% of the patients aged 45 and up had full or substantial recovery (Neurology. 2013 Sep 17;81[12]:1058-63).
He stressed that treatment of anti-NMDAR encephalitis ought to be an interdisciplinary effort. Psychiatrists will typically not be the ones who administer the potent immunotherapy. But most patients will have behavioral problems in the very early and late phases that warrant psychiatric therapy. Dr. Titulaer suggested psychiatrists steer clear of haloperidol in these patients because it can exacerbate motor symptoms.
Asked if there are any specific patterns of movement disorders linked to anti-NMDAR encephalitis that might raise a psychiatrist’s index of suspicion, the neurologist replied no. Almost all the movement disorders have been seen in psychiatric patients with anti-NMDAR encephalitis. The one specific movement disorder that strongly suggests anti-NMDAR encephalitis is post–herpes simplex virus (HSV) encephalitis choreoathetosis. It appears that HSV encephalitis can trigger formation of NMDAR autoantibodies, resulting in onset of choreoathetosis 3-6 weeks after the HSV encephalopathy.
Dr. Titulaer reported having no financial conflicts of interest in regard to his presentation.
*This story was updated 1/26/2017.
VIENNA – Prominent psychiatric symptoms are common in patients with anti-N-methyl-D-asparate receptor (NMDAR) encephalitis and often occur prior to onset of obvious neurologic symptoms, Maarten J. Titulaer, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Moreover, occasionally the psychiatric symptoms occur in isolation without neurologic involvement, as was the case in 4% of a series of 501 patients with confirmed anti-NMDAR encephalitis reported by Dr. Titulaer and coinvestigators. The most prominent symptoms included delusional thinking, aggression, and mood disturbances, which were usually manic (JAMA Neurol. 2013 Sep 1;70[9]:1133-9).
The clinical implication is that it’s important to consider the possibility of anti-NMDAR encephalitis in all patients presenting with new-onset psychosis or mania, and to be cognizant of the red flags that warrant definitive diagnostic testing. This serious disease responds well to aggressive immunotherapy, especially if started early, which is impressive given that three-quarters of affected patients will need to spend a month or two in the ICU during the course of their illness, explained Dr. Titulaer, a neurologist at Erasmus University in Rotterdam, the Netherlands.
Anti-NMDAR encephalitis is an autoimmune disorder in which autoantibodies directed at NMDA receptors on neuronal plasma membranes induce severe neurologic and often psychiatric symptoms.
Red flags that raise the chance that a patient on the psychiatric ward with new-onset psychosis or mania might have primary anti-NMDAR encephalitis and should undergo diagnostic testing include autonomic disturbances such as tachycardia, fever, or hypertension, mild neurologic symptoms such as facial twitching, as well as catatonia, seizures, mutism, or development of extrapyramidal symptoms when placed on an antipsychotic agent. Anti-NMDAR encephalitis can have a relapsing course, so any behavioral change in a patient with a history of the disorder might signal relapse.
Certain cancers are strongly associated with anti-NMDAR encephalitis. New-onset psychotic or manic patients with a history of ovarian teratoma, small cell lung cancer, breast cancer, or thymoma should be tested for anti-NMDAR encephalitis. And conversely, screening for those tumors in occult form is warranted in patients with confirmed anti-NMDAR encephalitis, according to Dr. Titulaer.
Systematic screening for anti-NMDAR encephalitis should also be considered in women with severe acute psychosis during the postpartum period, particularly in the setting of extrapyramidal side effects of antipsychotic agents. Two of 96 consecutive women with acute-onset postpartum psychosis in a series reported by Dr. Titulaer and colleagues were antibody-positive for the disorder, and neither had an ovarian teratoma (Am J Psychiatry. 2015 Sep 1;172[9]:901-8).
If a patient hasn’t developed neurologic symptoms within 4 weeks after onset of psychiatric symptoms, anti-NMDAR psychosis becomes far less likely.
Some neurologists have suggested the presence of other autoimmune disorders in psychiatric patients is associated with increased likelihood that the psychiatric symptoms are secondary to anti-NMDAR encephalitis, but Dr. Titulaer doesn’t find the evidence to date persuasive.
The diagnosis of anti-NMDAR encephalitis hinges on the finding of IgG antibodies against the NR1 subunit of the NMDAR. But Dr. Titulaer and coinvestigators have shown there are testing pitfalls: The first-line commercially available cell-based serum assays have a sensitivity of roughly 75% along with 97%-99% specificity, so by relying solely on the cell-based assays a physician might miss one in four cases of anti-NMDAR encephalitis and wrongly diagnose the disease in 0.4%-3% of healthy individuals (Lancet Neurol. 2014 Feb;13[2]:167-77).
For this reason, a positive serum test should be confirmed by a cell-based assay of a cerebrospinal fluid (CSF) sample, which has 100% sensitivity and specificity. And if the serum assay is negative but anti-NMDAR is suspected based on clinical grounds or history, go ahead and test the CSF, the neurologist advised.
Other tools that can be helpful in making the diagnosis include the EEG, which is abnormal in 89% of patients with anti-NMDAR encephalitis. Thirty percent of affected patients will display a highly specific EEG abnormality called extreme delta brushes (Neurology. 2012 Sep 11;79[11]:1094-100).
Dr. Titulaer said that this extreme delta brushes pattern is not seen on the regular psychiatry ward, but only in the ICU, when the patient is severely ill. He has yet to see the first convincing extreme delta brushes pattern in a patient outside the ICU.
Brain MRI has proved “very disappointing,” as it’s abnormal in only one-third of patients with anti-NMDAR encephalitis, he continued.
First-line immunotherapy is corticosteroids, plasmapheresis, and/or intravenous immunoglobulin. In a series of 501 patients who received first-line immunotherapy or tumor removal, 53% improved within 4 weeks. Fifty-seven percent of those who didn’t then got second-line immunotherapy with rituximab (Rituxan) or cyclophosphamide. Outcomes continued to improve for up to 18 months following symptom onset. At 24 months of follow-up, just over 80% of patients in this observational study had a good outcome as defined by a modified Rankin scale score of 0-2, meaning they were living independently with no or minimal disability.
“Not bad, especially considering that the patients who didn’t improve on first-line therapy were in the ICU for a median of 6 weeks,” the neurologist observed.
“It’s important to diagnose patients with anti-NMDAR encephalitis,” he stressed. “Treatment might be difficult. You might need to be very aggressive. But in the end there are very good outcomes. It’s very rewarding to treat these patients.”
In multivariate analysis, Dr. Titulaer and coworkers identified earlier treatment and milder illness as reflected in no ICU admission as significant predictors of good outcome in the study population. Also, the use of second-line immunotherapy in nonresponders to first-line therapy was independently associated with a 2.69-fold increased likelihood of good outcome (Lancet Neurol. 2013 Feb;12[2]:157-65).
Twelve percent of patients experienced one or more relapses within 2 years.
In a separate study of 661 patients with anti-NMDAR encephalitis, only 31 were aged 45 years or older. They had less severe disease than the younger adults but a paradoxically worse outcome, possibly because their median time to diagnosis was twice as long. At 2 years, 60% of the patients aged 45 and up had full or substantial recovery (Neurology. 2013 Sep 17;81[12]:1058-63).
He stressed that treatment of anti-NMDAR encephalitis ought to be an interdisciplinary effort. Psychiatrists will typically not be the ones who administer the potent immunotherapy. But most patients will have behavioral problems in the very early and late phases that warrant psychiatric therapy. Dr. Titulaer suggested psychiatrists steer clear of haloperidol in these patients because it can exacerbate motor symptoms.
Asked if there are any specific patterns of movement disorders linked to anti-NMDAR encephalitis that might raise a psychiatrist’s index of suspicion, the neurologist replied no. Almost all the movement disorders have been seen in psychiatric patients with anti-NMDAR encephalitis. The one specific movement disorder that strongly suggests anti-NMDAR encephalitis is post–herpes simplex virus (HSV) encephalitis choreoathetosis. It appears that HSV encephalitis can trigger formation of NMDAR autoantibodies, resulting in onset of choreoathetosis 3-6 weeks after the HSV encephalopathy.
Dr. Titulaer reported having no financial conflicts of interest in regard to his presentation.
*This story was updated 1/26/2017.
VIENNA – Prominent psychiatric symptoms are common in patients with anti-N-methyl-D-asparate receptor (NMDAR) encephalitis and often occur prior to onset of obvious neurologic symptoms, Maarten J. Titulaer, MD, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
Moreover, occasionally the psychiatric symptoms occur in isolation without neurologic involvement, as was the case in 4% of a series of 501 patients with confirmed anti-NMDAR encephalitis reported by Dr. Titulaer and coinvestigators. The most prominent symptoms included delusional thinking, aggression, and mood disturbances, which were usually manic (JAMA Neurol. 2013 Sep 1;70[9]:1133-9).
The clinical implication is that it’s important to consider the possibility of anti-NMDAR encephalitis in all patients presenting with new-onset psychosis or mania, and to be cognizant of the red flags that warrant definitive diagnostic testing. This serious disease responds well to aggressive immunotherapy, especially if started early, which is impressive given that three-quarters of affected patients will need to spend a month or two in the ICU during the course of their illness, explained Dr. Titulaer, a neurologist at Erasmus University in Rotterdam, the Netherlands.
Anti-NMDAR encephalitis is an autoimmune disorder in which autoantibodies directed at NMDA receptors on neuronal plasma membranes induce severe neurologic and often psychiatric symptoms.
Red flags that raise the chance that a patient on the psychiatric ward with new-onset psychosis or mania might have primary anti-NMDAR encephalitis and should undergo diagnostic testing include autonomic disturbances such as tachycardia, fever, or hypertension, mild neurologic symptoms such as facial twitching, as well as catatonia, seizures, mutism, or development of extrapyramidal symptoms when placed on an antipsychotic agent. Anti-NMDAR encephalitis can have a relapsing course, so any behavioral change in a patient with a history of the disorder might signal relapse.
Certain cancers are strongly associated with anti-NMDAR encephalitis. New-onset psychotic or manic patients with a history of ovarian teratoma, small cell lung cancer, breast cancer, or thymoma should be tested for anti-NMDAR encephalitis. And conversely, screening for those tumors in occult form is warranted in patients with confirmed anti-NMDAR encephalitis, according to Dr. Titulaer.
Systematic screening for anti-NMDAR encephalitis should also be considered in women with severe acute psychosis during the postpartum period, particularly in the setting of extrapyramidal side effects of antipsychotic agents. Two of 96 consecutive women with acute-onset postpartum psychosis in a series reported by Dr. Titulaer and colleagues were antibody-positive for the disorder, and neither had an ovarian teratoma (Am J Psychiatry. 2015 Sep 1;172[9]:901-8).
If a patient hasn’t developed neurologic symptoms within 4 weeks after onset of psychiatric symptoms, anti-NMDAR psychosis becomes far less likely.
Some neurologists have suggested the presence of other autoimmune disorders in psychiatric patients is associated with increased likelihood that the psychiatric symptoms are secondary to anti-NMDAR encephalitis, but Dr. Titulaer doesn’t find the evidence to date persuasive.
The diagnosis of anti-NMDAR encephalitis hinges on the finding of IgG antibodies against the NR1 subunit of the NMDAR. But Dr. Titulaer and coinvestigators have shown there are testing pitfalls: The first-line commercially available cell-based serum assays have a sensitivity of roughly 75% along with 97%-99% specificity, so by relying solely on the cell-based assays a physician might miss one in four cases of anti-NMDAR encephalitis and wrongly diagnose the disease in 0.4%-3% of healthy individuals (Lancet Neurol. 2014 Feb;13[2]:167-77).
For this reason, a positive serum test should be confirmed by a cell-based assay of a cerebrospinal fluid (CSF) sample, which has 100% sensitivity and specificity. And if the serum assay is negative but anti-NMDAR is suspected based on clinical grounds or history, go ahead and test the CSF, the neurologist advised.
Other tools that can be helpful in making the diagnosis include the EEG, which is abnormal in 89% of patients with anti-NMDAR encephalitis. Thirty percent of affected patients will display a highly specific EEG abnormality called extreme delta brushes (Neurology. 2012 Sep 11;79[11]:1094-100).
Dr. Titulaer said that this extreme delta brushes pattern is not seen on the regular psychiatry ward, but only in the ICU, when the patient is severely ill. He has yet to see the first convincing extreme delta brushes pattern in a patient outside the ICU.
Brain MRI has proved “very disappointing,” as it’s abnormal in only one-third of patients with anti-NMDAR encephalitis, he continued.
First-line immunotherapy is corticosteroids, plasmapheresis, and/or intravenous immunoglobulin. In a series of 501 patients who received first-line immunotherapy or tumor removal, 53% improved within 4 weeks. Fifty-seven percent of those who didn’t then got second-line immunotherapy with rituximab (Rituxan) or cyclophosphamide. Outcomes continued to improve for up to 18 months following symptom onset. At 24 months of follow-up, just over 80% of patients in this observational study had a good outcome as defined by a modified Rankin scale score of 0-2, meaning they were living independently with no or minimal disability.
“Not bad, especially considering that the patients who didn’t improve on first-line therapy were in the ICU for a median of 6 weeks,” the neurologist observed.
“It’s important to diagnose patients with anti-NMDAR encephalitis,” he stressed. “Treatment might be difficult. You might need to be very aggressive. But in the end there are very good outcomes. It’s very rewarding to treat these patients.”
In multivariate analysis, Dr. Titulaer and coworkers identified earlier treatment and milder illness as reflected in no ICU admission as significant predictors of good outcome in the study population. Also, the use of second-line immunotherapy in nonresponders to first-line therapy was independently associated with a 2.69-fold increased likelihood of good outcome (Lancet Neurol. 2013 Feb;12[2]:157-65).
Twelve percent of patients experienced one or more relapses within 2 years.
In a separate study of 661 patients with anti-NMDAR encephalitis, only 31 were aged 45 years or older. They had less severe disease than the younger adults but a paradoxically worse outcome, possibly because their median time to diagnosis was twice as long. At 2 years, 60% of the patients aged 45 and up had full or substantial recovery (Neurology. 2013 Sep 17;81[12]:1058-63).
He stressed that treatment of anti-NMDAR encephalitis ought to be an interdisciplinary effort. Psychiatrists will typically not be the ones who administer the potent immunotherapy. But most patients will have behavioral problems in the very early and late phases that warrant psychiatric therapy. Dr. Titulaer suggested psychiatrists steer clear of haloperidol in these patients because it can exacerbate motor symptoms.
Asked if there are any specific patterns of movement disorders linked to anti-NMDAR encephalitis that might raise a psychiatrist’s index of suspicion, the neurologist replied no. Almost all the movement disorders have been seen in psychiatric patients with anti-NMDAR encephalitis. The one specific movement disorder that strongly suggests anti-NMDAR encephalitis is post–herpes simplex virus (HSV) encephalitis choreoathetosis. It appears that HSV encephalitis can trigger formation of NMDAR autoantibodies, resulting in onset of choreoathetosis 3-6 weeks after the HSV encephalopathy.
Dr. Titulaer reported having no financial conflicts of interest in regard to his presentation.
*This story was updated 1/26/2017.
Bias rampant in major depression treatment literature
VIENNA – Janneke A. Bastiaansen, PhD, has some advice for clinicians and researchers as they peruse the published literature on clinical trials of medication or psychotherapy for major depressive disorder: Don’t believe everything you read.
“Be critical. Use your critical mind,” she urged at the annual congress of the European College of Neuropsychopharmacology.
The results of her analysis of 105 clinical trials of antidepressant drugs and 142 studies of psychotherapy indicated that the literature is rife with four types of bias: publication, outcome reporting, spin, and citation bias.
“The quality of the evidence base is vital. We base our clinical decisions on what’s out there in the literature. And I think it’s really important to know that there are various biases that can color the literature,” said Dr. Bastiaansen, a psychologist at the University of Groningen, the Netherlands.
She took a closer look at 105 clinical trials of antidepressant drugs registered with the U.S. National Institutes of Health at clinicaltrials.gov. Fifty-three reported positive findings, and 52 were negative. Fifty-two of the 53 positive trials were ultimately published, as were only 25 of the 52 negative studies. That’s a sterling example of publication bias.
Upon careful scrutiny of the 25 negative trials that were published, 10 were misleadingly reported as positive studies. The investigators either switched out the prespecified primary outcome previously filed with NIH and promoted a positive secondary outcome to primary outcome status because the original primary outcome was negative, or they omitted the negative outcomes altogether. That’s outcome-reporting bias.
Of the 15 published negative drug trials that were free of outcome-reporting bias, the authors of 10 of the studies employed “spin,” using phrases such as “the treatment was numerically superior.”
Thus, only 5 of the 25 published negative clinical trials unambiguously reported that the studied treatment was not effective.
“Here the message is that, when you read a paper, look at the results, come up with your own conclusion, and then compare it with the conclusion of the authors, because sometimes they’ve colored it in a more positive way,” Dr. Bastiaansen said in an interview.
Citation bias is the phenomenon whereby positive clinical trials are cited more frequently than published negative trials.
“As a clinician, if you look at the literature and print out every paper that’s out there on a given antidepressant drug for major depression, and you look at that pile, you’ll think: ‘Ah, the literature is really strong about this treatment effect,’ because positive papers selectively cite other positive papers,” she continued.
The pharmaceutical industry takes a lot of heat for selectively burying company-sponsored negative trials, but the literature on psychotherapy for major depression is actually more opaque.
“A lot of people aim their arrows at the pharmaceutical industry and say: ‘Everything’s bad about pharma,’ but actually, you see bias in every field. You see it in the trials of psychotherapy. It’s very important to know that it’s ubiquitous. The positive side of the antidepressant drug trials is that there’s this standard database [clinicaltrials.gov], and you can use it to check out what trial is published and what’s not. It’s not the case for psychotherapy trials. I think we need a mandatory registry for clinical trials of psychotherapy as well,” Dr. Bastiaansen said.
Of the 142 psychotherapy studies, 49 were negative, but the abstracts of only 12 of those 49 concluded that psychotherapy was not more effective than a control.
Dr. Bastiaansen declared having no financial conflicts regarding her university-funded study.
VIENNA – Janneke A. Bastiaansen, PhD, has some advice for clinicians and researchers as they peruse the published literature on clinical trials of medication or psychotherapy for major depressive disorder: Don’t believe everything you read.
“Be critical. Use your critical mind,” she urged at the annual congress of the European College of Neuropsychopharmacology.
The results of her analysis of 105 clinical trials of antidepressant drugs and 142 studies of psychotherapy indicated that the literature is rife with four types of bias: publication, outcome reporting, spin, and citation bias.
“The quality of the evidence base is vital. We base our clinical decisions on what’s out there in the literature. And I think it’s really important to know that there are various biases that can color the literature,” said Dr. Bastiaansen, a psychologist at the University of Groningen, the Netherlands.
She took a closer look at 105 clinical trials of antidepressant drugs registered with the U.S. National Institutes of Health at clinicaltrials.gov. Fifty-three reported positive findings, and 52 were negative. Fifty-two of the 53 positive trials were ultimately published, as were only 25 of the 52 negative studies. That’s a sterling example of publication bias.
Upon careful scrutiny of the 25 negative trials that were published, 10 were misleadingly reported as positive studies. The investigators either switched out the prespecified primary outcome previously filed with NIH and promoted a positive secondary outcome to primary outcome status because the original primary outcome was negative, or they omitted the negative outcomes altogether. That’s outcome-reporting bias.
Of the 15 published negative drug trials that were free of outcome-reporting bias, the authors of 10 of the studies employed “spin,” using phrases such as “the treatment was numerically superior.”
Thus, only 5 of the 25 published negative clinical trials unambiguously reported that the studied treatment was not effective.
“Here the message is that, when you read a paper, look at the results, come up with your own conclusion, and then compare it with the conclusion of the authors, because sometimes they’ve colored it in a more positive way,” Dr. Bastiaansen said in an interview.
Citation bias is the phenomenon whereby positive clinical trials are cited more frequently than published negative trials.
“As a clinician, if you look at the literature and print out every paper that’s out there on a given antidepressant drug for major depression, and you look at that pile, you’ll think: ‘Ah, the literature is really strong about this treatment effect,’ because positive papers selectively cite other positive papers,” she continued.
The pharmaceutical industry takes a lot of heat for selectively burying company-sponsored negative trials, but the literature on psychotherapy for major depression is actually more opaque.
“A lot of people aim their arrows at the pharmaceutical industry and say: ‘Everything’s bad about pharma,’ but actually, you see bias in every field. You see it in the trials of psychotherapy. It’s very important to know that it’s ubiquitous. The positive side of the antidepressant drug trials is that there’s this standard database [clinicaltrials.gov], and you can use it to check out what trial is published and what’s not. It’s not the case for psychotherapy trials. I think we need a mandatory registry for clinical trials of psychotherapy as well,” Dr. Bastiaansen said.
Of the 142 psychotherapy studies, 49 were negative, but the abstracts of only 12 of those 49 concluded that psychotherapy was not more effective than a control.
Dr. Bastiaansen declared having no financial conflicts regarding her university-funded study.
VIENNA – Janneke A. Bastiaansen, PhD, has some advice for clinicians and researchers as they peruse the published literature on clinical trials of medication or psychotherapy for major depressive disorder: Don’t believe everything you read.
“Be critical. Use your critical mind,” she urged at the annual congress of the European College of Neuropsychopharmacology.
The results of her analysis of 105 clinical trials of antidepressant drugs and 142 studies of psychotherapy indicated that the literature is rife with four types of bias: publication, outcome reporting, spin, and citation bias.
“The quality of the evidence base is vital. We base our clinical decisions on what’s out there in the literature. And I think it’s really important to know that there are various biases that can color the literature,” said Dr. Bastiaansen, a psychologist at the University of Groningen, the Netherlands.
She took a closer look at 105 clinical trials of antidepressant drugs registered with the U.S. National Institutes of Health at clinicaltrials.gov. Fifty-three reported positive findings, and 52 were negative. Fifty-two of the 53 positive trials were ultimately published, as were only 25 of the 52 negative studies. That’s a sterling example of publication bias.
Upon careful scrutiny of the 25 negative trials that were published, 10 were misleadingly reported as positive studies. The investigators either switched out the prespecified primary outcome previously filed with NIH and promoted a positive secondary outcome to primary outcome status because the original primary outcome was negative, or they omitted the negative outcomes altogether. That’s outcome-reporting bias.
Of the 15 published negative drug trials that were free of outcome-reporting bias, the authors of 10 of the studies employed “spin,” using phrases such as “the treatment was numerically superior.”
Thus, only 5 of the 25 published negative clinical trials unambiguously reported that the studied treatment was not effective.
“Here the message is that, when you read a paper, look at the results, come up with your own conclusion, and then compare it with the conclusion of the authors, because sometimes they’ve colored it in a more positive way,” Dr. Bastiaansen said in an interview.
Citation bias is the phenomenon whereby positive clinical trials are cited more frequently than published negative trials.
“As a clinician, if you look at the literature and print out every paper that’s out there on a given antidepressant drug for major depression, and you look at that pile, you’ll think: ‘Ah, the literature is really strong about this treatment effect,’ because positive papers selectively cite other positive papers,” she continued.
The pharmaceutical industry takes a lot of heat for selectively burying company-sponsored negative trials, but the literature on psychotherapy for major depression is actually more opaque.
“A lot of people aim their arrows at the pharmaceutical industry and say: ‘Everything’s bad about pharma,’ but actually, you see bias in every field. You see it in the trials of psychotherapy. It’s very important to know that it’s ubiquitous. The positive side of the antidepressant drug trials is that there’s this standard database [clinicaltrials.gov], and you can use it to check out what trial is published and what’s not. It’s not the case for psychotherapy trials. I think we need a mandatory registry for clinical trials of psychotherapy as well,” Dr. Bastiaansen said.
Of the 142 psychotherapy studies, 49 were negative, but the abstracts of only 12 of those 49 concluded that psychotherapy was not more effective than a control.
Dr. Bastiaansen declared having no financial conflicts regarding her university-funded study.
Key clinical point:
Major finding: Only 5 of 25 published negative clinical trials of antidepressant drug therapy unambiguously reported that the studied treatment was not effective.
Data source: For this study, 105 clinical trials of antidepressant drugs and 142 on psychotherapy for major depressive disorder were examined systematically for evidence of four types of bias that damage the quality of the evidence base.
Disclosures: The presenter reported having no financial conflicts of interest regarding her university-funded study.
Finger length ratio identifies women at increased risk for depression and anxiety
VIENNA – They say that in hula dancing, it’s the expressive hands, not the quaking hips, that tell the story.
And in Dutch women, a relatively short index finger on the left hand bespeaks an increased risk for depression and stress.
That’s right: The ratio of the length of the index finger to the ring finger, or 2D:4D digit ratio, of the left hand shows potential as a quick and dirty biomarker that could be used to screen patients for increased risk for depression. But only in women, Deborah De Kruijff reported at the annual congress of the European College of Neuropsychopharmacology.
She and her coinvestigators measured the lengths of the index and ring fingers on both hands of 124 male and 146 female Dutch college students using Vernier calipers accurate to within 0.01 mm. Participants completed the 21-item version of the Depression, Anxiety, and Stress Scale (DASS-21) and correlated the 2D:4D digit ratios with the DASS-21 total scores as well as the scores on the depression, anxiety, and stress subscales.
The 2D:4D digit ratio didn’t correlate with DASS-21 scores in men. But in women, the lower the 2D:4D ratio on the left hand, the higher their overall DASS-21 score as well as their scores on the depression and stress subscales. Each of these associations was highly statistically significant at the P = .002 to .005 level, according to Ms. De Kruijff, a PhD candidate in neuroscience at Utrecht (the Netherlands) University.
Finding correlates between the 2D:4D digit ratio and predispositions to various diseases, personality traits, and other human characteristics was a popular scientific pastime in the 1800s. After a long dry spell, it rebounded as a research area several decades ago. The 2D:4D ratio is a sexually dimorphic trait. It is thought to depend upon prenatal exposure to sex hormones. A low 2D:4D ratio is associated with in utero exposure to relatively higher levels of fetal testosterone than fetal estrogen. Thus, a greater proportion of men than women have index fingers that are shorter than the ring finger.
Other investigators have linked a low 2D:4D ratio to increased risks of prostate cancer, attention-deficit/hyperactivity disorder, and autism spectrum disorder in men, and to greater assertiveness and increased risk of anorexia nervosa in women.
Ms. De Kruijff said more research is needed to understand why only the finger length on the left hand of the women was predictive of increased risk of depression and stress.
She reported having no financial conflicts of interest regarding this university-funded study.
VIENNA – They say that in hula dancing, it’s the expressive hands, not the quaking hips, that tell the story.
And in Dutch women, a relatively short index finger on the left hand bespeaks an increased risk for depression and stress.
That’s right: The ratio of the length of the index finger to the ring finger, or 2D:4D digit ratio, of the left hand shows potential as a quick and dirty biomarker that could be used to screen patients for increased risk for depression. But only in women, Deborah De Kruijff reported at the annual congress of the European College of Neuropsychopharmacology.
She and her coinvestigators measured the lengths of the index and ring fingers on both hands of 124 male and 146 female Dutch college students using Vernier calipers accurate to within 0.01 mm. Participants completed the 21-item version of the Depression, Anxiety, and Stress Scale (DASS-21) and correlated the 2D:4D digit ratios with the DASS-21 total scores as well as the scores on the depression, anxiety, and stress subscales.
The 2D:4D digit ratio didn’t correlate with DASS-21 scores in men. But in women, the lower the 2D:4D ratio on the left hand, the higher their overall DASS-21 score as well as their scores on the depression and stress subscales. Each of these associations was highly statistically significant at the P = .002 to .005 level, according to Ms. De Kruijff, a PhD candidate in neuroscience at Utrecht (the Netherlands) University.
Finding correlates between the 2D:4D digit ratio and predispositions to various diseases, personality traits, and other human characteristics was a popular scientific pastime in the 1800s. After a long dry spell, it rebounded as a research area several decades ago. The 2D:4D ratio is a sexually dimorphic trait. It is thought to depend upon prenatal exposure to sex hormones. A low 2D:4D ratio is associated with in utero exposure to relatively higher levels of fetal testosterone than fetal estrogen. Thus, a greater proportion of men than women have index fingers that are shorter than the ring finger.
Other investigators have linked a low 2D:4D ratio to increased risks of prostate cancer, attention-deficit/hyperactivity disorder, and autism spectrum disorder in men, and to greater assertiveness and increased risk of anorexia nervosa in women.
Ms. De Kruijff said more research is needed to understand why only the finger length on the left hand of the women was predictive of increased risk of depression and stress.
She reported having no financial conflicts of interest regarding this university-funded study.
VIENNA – They say that in hula dancing, it’s the expressive hands, not the quaking hips, that tell the story.
And in Dutch women, a relatively short index finger on the left hand bespeaks an increased risk for depression and stress.
That’s right: The ratio of the length of the index finger to the ring finger, or 2D:4D digit ratio, of the left hand shows potential as a quick and dirty biomarker that could be used to screen patients for increased risk for depression. But only in women, Deborah De Kruijff reported at the annual congress of the European College of Neuropsychopharmacology.
She and her coinvestigators measured the lengths of the index and ring fingers on both hands of 124 male and 146 female Dutch college students using Vernier calipers accurate to within 0.01 mm. Participants completed the 21-item version of the Depression, Anxiety, and Stress Scale (DASS-21) and correlated the 2D:4D digit ratios with the DASS-21 total scores as well as the scores on the depression, anxiety, and stress subscales.
The 2D:4D digit ratio didn’t correlate with DASS-21 scores in men. But in women, the lower the 2D:4D ratio on the left hand, the higher their overall DASS-21 score as well as their scores on the depression and stress subscales. Each of these associations was highly statistically significant at the P = .002 to .005 level, according to Ms. De Kruijff, a PhD candidate in neuroscience at Utrecht (the Netherlands) University.
Finding correlates between the 2D:4D digit ratio and predispositions to various diseases, personality traits, and other human characteristics was a popular scientific pastime in the 1800s. After a long dry spell, it rebounded as a research area several decades ago. The 2D:4D ratio is a sexually dimorphic trait. It is thought to depend upon prenatal exposure to sex hormones. A low 2D:4D ratio is associated with in utero exposure to relatively higher levels of fetal testosterone than fetal estrogen. Thus, a greater proportion of men than women have index fingers that are shorter than the ring finger.
Other investigators have linked a low 2D:4D ratio to increased risks of prostate cancer, attention-deficit/hyperactivity disorder, and autism spectrum disorder in men, and to greater assertiveness and increased risk of anorexia nervosa in women.
Ms. De Kruijff said more research is needed to understand why only the finger length on the left hand of the women was predictive of increased risk of depression and stress.
She reported having no financial conflicts of interest regarding this university-funded study.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: The lower the ratio of the length of the index finger to the ring finger on the left hand in women, the higher they scored on a validated measure of depression and stress.
Data source: A cross-sectional study involving 124 male and 146 female university students who completed the 21-item version of the Depression, Anxiety, and Stress Scale and were measured for the lengths of their index and ring fingers on both hands.
Disclosures: The presenter reported having no financial conflicts of interest regarding this university-funded study.
Early change in emotional processing predicts antidepressant response
VIENNA – A novel method of individualizing antidepressant drug therapy while drastically shortening the time required to figure out whether a given agent will be effective in a depressed patient is undergoing its definitive evaluation in five European countries.
“I think this study will provide a critical test of whether we can use these kinds of correlations with emotional processing of information to actually improve the treatment of depression,” Catherine J. Harmer, DPhil, said at the annual congress of the European College of Neuropsychopharmacology.
The clinical trial, known as PReDicT (Predicting Response to Depression Treatment), has been funded with a 4 million Euro grant from the European Commission through its Horizon 2020 public health improvement program. PReDicT represents the culmination of years of original work by Dr. Harmer, who is credited with developing and validating an influential cognitive neuropsychological theory of antidepressant drug action.
As early as 2009, she and her coinvestigators demonstrated that depression is associated with a measurable negative bias in the processing of emotional information. Depressed patients selectively pay more attention to and better remember negative information. For example, when depressed patients taking the Facial Expression Recognition Test are quickly shown a photo of a smiling face, they are more likely to describe it as “sad.” Similarly, in a word recall test that includes “positive” adjectives such as cheerful, poised, original, and optimistic and “negative” words such as mean, hostile, domineering, and untidy, they recall fewer positive words than nondepressed people.
This negative emotional bias is a key factor in maintenance of depression. Many weeks before patients report feeling improvement in their mood and clinical symptoms of depression in response to effective antidepressant medication, the drug produces a favorable effect on their cognitive biases in emotional processing, explained Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).
Dr. Harmer hypothesized that antidepressants don’t necessarily act as direct mood enhancers, but instead change the balance away from negative to more positive emotional processing, resulting in neural modulation in limbic and prefrontal circuitry. These neural changes take time to reach the subjective conscious mind, which is why improvement in clinical symptoms of depression doesn’t manifest until 2-3 weeks into therapy, with the drug’s full effects not seen until 6-7 weeks (Br J Psychiatry. 2009 Aug;195[2]:102-8).
“Antidepressants can target cognitive biases surprisingly early on in treatment, before patients report any change in their clinical symptoms. This could explain the delay in antidepressant effect. You need life events, stressors, and environmental stimuli before a change in bias would be expected to result in a change in clinical state,” she said.
Together with her colleagues, she employed functional MRI to study changes in the brain associated with the improvement in negative biases in emotional processing that occur when depressed patients go on antidepressant medication. Forty-two unmedicated depressed patients were randomized to 10 mg of escitalopram (Lexapro) daily for 7 days or placebo. At baseline, all subjects demonstrated amygdala hyperactivity in response to fearful facial expressions, a response that didn’t occur in healthy controls. After 7 days of escitalopram – weeks before any improvement in depressed mood – amygdala activity was normalized in the active treatment group but not in placebo-treated controls (Psychol Med. 2012 Dec;42[12]:2609-17).
Dr. Harmer and a colleague expanded on her theory of depression in a review article aptly titled, “It’s the way that you look at it” (Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368[1615]:20120407).
A measurable improvement in emotional processing can be seen within a few hours after a depressed patient takes the first dose of an effective antidepressant. Thus, early change in negative emotional processing is predictive of subsequent clinical outcome. Lack of an early shift to positive emotional processing has been associated in multiple studies by Dr. Harmer and others with a high likelihood that an antidepressant won’t provide significant improvement in depressive symptoms at week 6.
The predictive accuracy of tests of emotional processing is higher when testing is done after a patient has been on an antidepressant medication for a few days rather than after the very first dose. Based upon Dr. Harmer’s work, pharmaceutical companies are now using tests of change in emotional processing at 1 week to help screen and select novel treatments for depression and anxiety.
In PReDicT, depressed patients being treated in primary care clinics across Europe will undergo emotional processing testing at baseline. In the active intervention arm, participants will be retested after 1 week on antidepressant therapy in order to identify those who are unlikely to have a favorable clinical response to that drug, enabling physicians to accelerate decision making about the appropriate next treatment. Treatment decisions in the control group will be made without the emotional processing results, mirroring current everyday practice.
Instead of waiting 4-6 weeks before concluding that a switch to another antidepressant with a different mechanism of action is warranted, as is now routine, participating PReDicT physicians whose patients are in the active intervention arm can make an informed change after just 1 week. The study hypothesis is that participants randomized to this study arm will take less time to respond to antidepressant therapy, because their physicians will be able to find the right drug faster than in the control group. The primary study endpoint will be the percentage of patients in the two study arms showing at least a 50% reduction in their Quick Inventory of Depressive Symptomatology (QIDS SR-16) score at 8 weeks. Secondary endpoints will focus on cumulative health care costs at weeks 24 and 48.
The PReDicT study is being run by P1vital Products Ltd., an Oxfordshire health care company that will use its proprietary Internet-based eHealth Emotional Test Battery to assess early changes in emotional processing. The test battery, which is classified as a medical device, is based upon Dr. Harmer’s earlier work. She is an investigator in PReDicT.
Her research funding comes from the U.K. Medical Research Council, Eli Lilly, and the EU’s Horizon 2020 program.
VIENNA – A novel method of individualizing antidepressant drug therapy while drastically shortening the time required to figure out whether a given agent will be effective in a depressed patient is undergoing its definitive evaluation in five European countries.
“I think this study will provide a critical test of whether we can use these kinds of correlations with emotional processing of information to actually improve the treatment of depression,” Catherine J. Harmer, DPhil, said at the annual congress of the European College of Neuropsychopharmacology.
The clinical trial, known as PReDicT (Predicting Response to Depression Treatment), has been funded with a 4 million Euro grant from the European Commission through its Horizon 2020 public health improvement program. PReDicT represents the culmination of years of original work by Dr. Harmer, who is credited with developing and validating an influential cognitive neuropsychological theory of antidepressant drug action.
As early as 2009, she and her coinvestigators demonstrated that depression is associated with a measurable negative bias in the processing of emotional information. Depressed patients selectively pay more attention to and better remember negative information. For example, when depressed patients taking the Facial Expression Recognition Test are quickly shown a photo of a smiling face, they are more likely to describe it as “sad.” Similarly, in a word recall test that includes “positive” adjectives such as cheerful, poised, original, and optimistic and “negative” words such as mean, hostile, domineering, and untidy, they recall fewer positive words than nondepressed people.
This negative emotional bias is a key factor in maintenance of depression. Many weeks before patients report feeling improvement in their mood and clinical symptoms of depression in response to effective antidepressant medication, the drug produces a favorable effect on their cognitive biases in emotional processing, explained Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).
Dr. Harmer hypothesized that antidepressants don’t necessarily act as direct mood enhancers, but instead change the balance away from negative to more positive emotional processing, resulting in neural modulation in limbic and prefrontal circuitry. These neural changes take time to reach the subjective conscious mind, which is why improvement in clinical symptoms of depression doesn’t manifest until 2-3 weeks into therapy, with the drug’s full effects not seen until 6-7 weeks (Br J Psychiatry. 2009 Aug;195[2]:102-8).
“Antidepressants can target cognitive biases surprisingly early on in treatment, before patients report any change in their clinical symptoms. This could explain the delay in antidepressant effect. You need life events, stressors, and environmental stimuli before a change in bias would be expected to result in a change in clinical state,” she said.
Together with her colleagues, she employed functional MRI to study changes in the brain associated with the improvement in negative biases in emotional processing that occur when depressed patients go on antidepressant medication. Forty-two unmedicated depressed patients were randomized to 10 mg of escitalopram (Lexapro) daily for 7 days or placebo. At baseline, all subjects demonstrated amygdala hyperactivity in response to fearful facial expressions, a response that didn’t occur in healthy controls. After 7 days of escitalopram – weeks before any improvement in depressed mood – amygdala activity was normalized in the active treatment group but not in placebo-treated controls (Psychol Med. 2012 Dec;42[12]:2609-17).
Dr. Harmer and a colleague expanded on her theory of depression in a review article aptly titled, “It’s the way that you look at it” (Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368[1615]:20120407).
A measurable improvement in emotional processing can be seen within a few hours after a depressed patient takes the first dose of an effective antidepressant. Thus, early change in negative emotional processing is predictive of subsequent clinical outcome. Lack of an early shift to positive emotional processing has been associated in multiple studies by Dr. Harmer and others with a high likelihood that an antidepressant won’t provide significant improvement in depressive symptoms at week 6.
The predictive accuracy of tests of emotional processing is higher when testing is done after a patient has been on an antidepressant medication for a few days rather than after the very first dose. Based upon Dr. Harmer’s work, pharmaceutical companies are now using tests of change in emotional processing at 1 week to help screen and select novel treatments for depression and anxiety.
In PReDicT, depressed patients being treated in primary care clinics across Europe will undergo emotional processing testing at baseline. In the active intervention arm, participants will be retested after 1 week on antidepressant therapy in order to identify those who are unlikely to have a favorable clinical response to that drug, enabling physicians to accelerate decision making about the appropriate next treatment. Treatment decisions in the control group will be made without the emotional processing results, mirroring current everyday practice.
Instead of waiting 4-6 weeks before concluding that a switch to another antidepressant with a different mechanism of action is warranted, as is now routine, participating PReDicT physicians whose patients are in the active intervention arm can make an informed change after just 1 week. The study hypothesis is that participants randomized to this study arm will take less time to respond to antidepressant therapy, because their physicians will be able to find the right drug faster than in the control group. The primary study endpoint will be the percentage of patients in the two study arms showing at least a 50% reduction in their Quick Inventory of Depressive Symptomatology (QIDS SR-16) score at 8 weeks. Secondary endpoints will focus on cumulative health care costs at weeks 24 and 48.
The PReDicT study is being run by P1vital Products Ltd., an Oxfordshire health care company that will use its proprietary Internet-based eHealth Emotional Test Battery to assess early changes in emotional processing. The test battery, which is classified as a medical device, is based upon Dr. Harmer’s earlier work. She is an investigator in PReDicT.
Her research funding comes from the U.K. Medical Research Council, Eli Lilly, and the EU’s Horizon 2020 program.
VIENNA – A novel method of individualizing antidepressant drug therapy while drastically shortening the time required to figure out whether a given agent will be effective in a depressed patient is undergoing its definitive evaluation in five European countries.
“I think this study will provide a critical test of whether we can use these kinds of correlations with emotional processing of information to actually improve the treatment of depression,” Catherine J. Harmer, DPhil, said at the annual congress of the European College of Neuropsychopharmacology.
The clinical trial, known as PReDicT (Predicting Response to Depression Treatment), has been funded with a 4 million Euro grant from the European Commission through its Horizon 2020 public health improvement program. PReDicT represents the culmination of years of original work by Dr. Harmer, who is credited with developing and validating an influential cognitive neuropsychological theory of antidepressant drug action.
As early as 2009, she and her coinvestigators demonstrated that depression is associated with a measurable negative bias in the processing of emotional information. Depressed patients selectively pay more attention to and better remember negative information. For example, when depressed patients taking the Facial Expression Recognition Test are quickly shown a photo of a smiling face, they are more likely to describe it as “sad.” Similarly, in a word recall test that includes “positive” adjectives such as cheerful, poised, original, and optimistic and “negative” words such as mean, hostile, domineering, and untidy, they recall fewer positive words than nondepressed people.
This negative emotional bias is a key factor in maintenance of depression. Many weeks before patients report feeling improvement in their mood and clinical symptoms of depression in response to effective antidepressant medication, the drug produces a favorable effect on their cognitive biases in emotional processing, explained Dr. Harmer, professor of cognitive neuroscience and director of the Psychopharmacology and Emotional Research Lab at the University of Oxford (England).
Dr. Harmer hypothesized that antidepressants don’t necessarily act as direct mood enhancers, but instead change the balance away from negative to more positive emotional processing, resulting in neural modulation in limbic and prefrontal circuitry. These neural changes take time to reach the subjective conscious mind, which is why improvement in clinical symptoms of depression doesn’t manifest until 2-3 weeks into therapy, with the drug’s full effects not seen until 6-7 weeks (Br J Psychiatry. 2009 Aug;195[2]:102-8).
“Antidepressants can target cognitive biases surprisingly early on in treatment, before patients report any change in their clinical symptoms. This could explain the delay in antidepressant effect. You need life events, stressors, and environmental stimuli before a change in bias would be expected to result in a change in clinical state,” she said.
Together with her colleagues, she employed functional MRI to study changes in the brain associated with the improvement in negative biases in emotional processing that occur when depressed patients go on antidepressant medication. Forty-two unmedicated depressed patients were randomized to 10 mg of escitalopram (Lexapro) daily for 7 days or placebo. At baseline, all subjects demonstrated amygdala hyperactivity in response to fearful facial expressions, a response that didn’t occur in healthy controls. After 7 days of escitalopram – weeks before any improvement in depressed mood – amygdala activity was normalized in the active treatment group but not in placebo-treated controls (Psychol Med. 2012 Dec;42[12]:2609-17).
Dr. Harmer and a colleague expanded on her theory of depression in a review article aptly titled, “It’s the way that you look at it” (Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368[1615]:20120407).
A measurable improvement in emotional processing can be seen within a few hours after a depressed patient takes the first dose of an effective antidepressant. Thus, early change in negative emotional processing is predictive of subsequent clinical outcome. Lack of an early shift to positive emotional processing has been associated in multiple studies by Dr. Harmer and others with a high likelihood that an antidepressant won’t provide significant improvement in depressive symptoms at week 6.
The predictive accuracy of tests of emotional processing is higher when testing is done after a patient has been on an antidepressant medication for a few days rather than after the very first dose. Based upon Dr. Harmer’s work, pharmaceutical companies are now using tests of change in emotional processing at 1 week to help screen and select novel treatments for depression and anxiety.
In PReDicT, depressed patients being treated in primary care clinics across Europe will undergo emotional processing testing at baseline. In the active intervention arm, participants will be retested after 1 week on antidepressant therapy in order to identify those who are unlikely to have a favorable clinical response to that drug, enabling physicians to accelerate decision making about the appropriate next treatment. Treatment decisions in the control group will be made without the emotional processing results, mirroring current everyday practice.
Instead of waiting 4-6 weeks before concluding that a switch to another antidepressant with a different mechanism of action is warranted, as is now routine, participating PReDicT physicians whose patients are in the active intervention arm can make an informed change after just 1 week. The study hypothesis is that participants randomized to this study arm will take less time to respond to antidepressant therapy, because their physicians will be able to find the right drug faster than in the control group. The primary study endpoint will be the percentage of patients in the two study arms showing at least a 50% reduction in their Quick Inventory of Depressive Symptomatology (QIDS SR-16) score at 8 weeks. Secondary endpoints will focus on cumulative health care costs at weeks 24 and 48.
The PReDicT study is being run by P1vital Products Ltd., an Oxfordshire health care company that will use its proprietary Internet-based eHealth Emotional Test Battery to assess early changes in emotional processing. The test battery, which is classified as a medical device, is based upon Dr. Harmer’s earlier work. She is an investigator in PReDicT.
Her research funding comes from the U.K. Medical Research Council, Eli Lilly, and the EU’s Horizon 2020 program.