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Depression: Think outside of the box for diagnosis, treatment
In the treatment of depression, clinicians are commonly dealing with a mix of comorbidities that are more complex than just depression, and as such, effective treatment options may likewise require thinking outside of the box – and beyond the definitions of the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision).
“The DSM-5 isn’t handed to us on tablets from Mount Sinai,” said Charles B. Nemeroff, MD, PhD, professor and chair in the department of psychiatry and behavioral sciences at the Mulva Clinic for the Neurosciences at the University of Texas at Austin. He spoke at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“Our patients don’t fall into these very convenient buckets,” Dr. Nemeroff said. “The problem with depression is patients have very high rates of morbidity and comorbidity.”
The array of potential psychiatric comorbidities that are common in depression is somewhat staggering: As many as 70% of patients also have social anxiety disorder; 67% of patients have obsessive-compulsive disorder (OCD); up to 65% of patients have panic disorder; 48% of patients have posttraumatic stress disorder (PTSD); and 42% have generalized anxiety disorder, Dr. Nemeroff said.
And while the DSM-5 may have all those bases covered, in real world clinical practice, cracking the code of each patient’s unique and often more complicated psychiatric profile – and how to best manage it – can be a challenge. But Dr. Nemeroff said important clues can guide the clinician’s path.
A key starting point is making sure to gauge the severity of the patient’s core depression with one of the validated depression scales – whether it’s the self-reported Beck Depression Inventory, the clinician-rated Hamilton Rating Scale for Depression, the clinician-rated Montgomery Asberg Depression Rating Scale, or the Inventory of Depressive Symptoms, clinicians should pick one and track the score with each visit, Dr. Nemeroff advised.
“It doesn’t matter which tool you prefer – most tend to like the Beck Depression Scale, but the bottom line is that you have to get a measure of severity at every visit,” he said.
Among the most important comorbidities to identify as soon as possible is bipolar disorder, due to the potential worsening of the condition that can occur among those patients if treated with antidepressants, Dr. Nemeroff said.
“The question of whether the patient is bipolar should always be in the back of your mind,” he cautioned. “And if patients have been started on antidepressants, the clues may become evident very quickly.”
The most important indicator that the patient has bipolar disorder “is if they tell you that they were prescribed an antidepressant and it resulted in an increase in what we know to be hypomania – they may describe it as agitation or an inability to sleep,” Dr. Nemeroff said.
Of note, the effect is much more common with SNRIs [serotonin norepinephrine reuptake inhibitors] than SSRIs [selective serotonin reuptake inhibitors], he said.
“The effect is particularly notable with venlafaxine,” he said. “But SNRIs all have the propensity to switch people with depression into hypomania, but only patients who have bipolar disorder.”
“If you give a patient 150 mg of venlafaxine and they switch to developing hypomania, you now have the diagnosis of bipolar disorder, and you can treat them appropriately.”
Other important clues of bipolarity in depressed patients include:
- Family history: Most cases are genetically driven.
- Earlier age of onset (younger than age 25): “If the patient tells you they were depressed prepuberty, you should be thinking about the possibility of bipolar disorder, as it often presents as depression in childhood.”
- Psychotic features: As many as 80% of patients with psychotic depression end up being bipolar, Dr. Nemeroff said.
- Atypical depression: For example, depression with hypersomnia, or having an increased appetite instead of decreased, or a high amount of anxiety.
Remission should be the goal of treatment, and Dr. Nemeroff said that in efforts to accomplish that with the help of medications, psychiatrists may need to think “outside of the box” – or beyond the label.
“Many practitioners become slaves to the PDR [Physicians’ Desk Reference],” he said. “It is only a guide to what the clinical trials show, and not a mandate in terms of dosing.”
“There’s often strong data in the literature that supports going to a higher dose, if necessary, and I have [plenty] of patients, for instance, on 450 or 600 mg of venlafaxine who had not responded to 150 or even 300 mg.”
Treatment resistance
When patients continue to fail to respond, regardless of dosing or medication adjustments, Dr. Nemeroff suggested that clinicians should consider the potential important reasons. For instance, in addition to comorbid psychiatric conditions, practitioners should determine if there are medical conditions that they are not aware of.
“Does the patient have an underlying medical condition, such as thyroid dysfunction, early Parkinson’s disease, or even something like cancer?” he said.
There is also the inevitable question of whether the patient is indeed taking the medication. “We know that 30% of our patients do not follow their prescriptions, so of course that’s an important question to ask,” Dr. Nemeroff said.
Finally, while some pharmacogenomic tests are emerging with the suggestion of identifying which patients may or may not respond to certain drugs, Dr. Nemeroff says he’s seen little convincing evidence of their benefits.
“We have a problem in this field in that we don’t have the kinds of markers that they do in oncology, so we’re left with having to generally play trial and error,” he said.
“But when it comes to these pharmacogenomic tests, there’s just no ‘there there’,” he asserted. “From what I’ve seen so far, it’s frankly neuro-mythology.”
Dr. Nemeroff disclosed that he receives grant/research support from the National Institutes of Health and serves as a consultant for and/or on the advisory boards of multiple pharmaceutical companies.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
In the treatment of depression, clinicians are commonly dealing with a mix of comorbidities that are more complex than just depression, and as such, effective treatment options may likewise require thinking outside of the box – and beyond the definitions of the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision).
“The DSM-5 isn’t handed to us on tablets from Mount Sinai,” said Charles B. Nemeroff, MD, PhD, professor and chair in the department of psychiatry and behavioral sciences at the Mulva Clinic for the Neurosciences at the University of Texas at Austin. He spoke at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“Our patients don’t fall into these very convenient buckets,” Dr. Nemeroff said. “The problem with depression is patients have very high rates of morbidity and comorbidity.”
The array of potential psychiatric comorbidities that are common in depression is somewhat staggering: As many as 70% of patients also have social anxiety disorder; 67% of patients have obsessive-compulsive disorder (OCD); up to 65% of patients have panic disorder; 48% of patients have posttraumatic stress disorder (PTSD); and 42% have generalized anxiety disorder, Dr. Nemeroff said.
And while the DSM-5 may have all those bases covered, in real world clinical practice, cracking the code of each patient’s unique and often more complicated psychiatric profile – and how to best manage it – can be a challenge. But Dr. Nemeroff said important clues can guide the clinician’s path.
A key starting point is making sure to gauge the severity of the patient’s core depression with one of the validated depression scales – whether it’s the self-reported Beck Depression Inventory, the clinician-rated Hamilton Rating Scale for Depression, the clinician-rated Montgomery Asberg Depression Rating Scale, or the Inventory of Depressive Symptoms, clinicians should pick one and track the score with each visit, Dr. Nemeroff advised.
“It doesn’t matter which tool you prefer – most tend to like the Beck Depression Scale, but the bottom line is that you have to get a measure of severity at every visit,” he said.
Among the most important comorbidities to identify as soon as possible is bipolar disorder, due to the potential worsening of the condition that can occur among those patients if treated with antidepressants, Dr. Nemeroff said.
“The question of whether the patient is bipolar should always be in the back of your mind,” he cautioned. “And if patients have been started on antidepressants, the clues may become evident very quickly.”
The most important indicator that the patient has bipolar disorder “is if they tell you that they were prescribed an antidepressant and it resulted in an increase in what we know to be hypomania – they may describe it as agitation or an inability to sleep,” Dr. Nemeroff said.
Of note, the effect is much more common with SNRIs [serotonin norepinephrine reuptake inhibitors] than SSRIs [selective serotonin reuptake inhibitors], he said.
“The effect is particularly notable with venlafaxine,” he said. “But SNRIs all have the propensity to switch people with depression into hypomania, but only patients who have bipolar disorder.”
“If you give a patient 150 mg of venlafaxine and they switch to developing hypomania, you now have the diagnosis of bipolar disorder, and you can treat them appropriately.”
Other important clues of bipolarity in depressed patients include:
- Family history: Most cases are genetically driven.
- Earlier age of onset (younger than age 25): “If the patient tells you they were depressed prepuberty, you should be thinking about the possibility of bipolar disorder, as it often presents as depression in childhood.”
- Psychotic features: As many as 80% of patients with psychotic depression end up being bipolar, Dr. Nemeroff said.
- Atypical depression: For example, depression with hypersomnia, or having an increased appetite instead of decreased, or a high amount of anxiety.
Remission should be the goal of treatment, and Dr. Nemeroff said that in efforts to accomplish that with the help of medications, psychiatrists may need to think “outside of the box” – or beyond the label.
“Many practitioners become slaves to the PDR [Physicians’ Desk Reference],” he said. “It is only a guide to what the clinical trials show, and not a mandate in terms of dosing.”
“There’s often strong data in the literature that supports going to a higher dose, if necessary, and I have [plenty] of patients, for instance, on 450 or 600 mg of venlafaxine who had not responded to 150 or even 300 mg.”
Treatment resistance
When patients continue to fail to respond, regardless of dosing or medication adjustments, Dr. Nemeroff suggested that clinicians should consider the potential important reasons. For instance, in addition to comorbid psychiatric conditions, practitioners should determine if there are medical conditions that they are not aware of.
“Does the patient have an underlying medical condition, such as thyroid dysfunction, early Parkinson’s disease, or even something like cancer?” he said.
There is also the inevitable question of whether the patient is indeed taking the medication. “We know that 30% of our patients do not follow their prescriptions, so of course that’s an important question to ask,” Dr. Nemeroff said.
Finally, while some pharmacogenomic tests are emerging with the suggestion of identifying which patients may or may not respond to certain drugs, Dr. Nemeroff says he’s seen little convincing evidence of their benefits.
“We have a problem in this field in that we don’t have the kinds of markers that they do in oncology, so we’re left with having to generally play trial and error,” he said.
“But when it comes to these pharmacogenomic tests, there’s just no ‘there there’,” he asserted. “From what I’ve seen so far, it’s frankly neuro-mythology.”
Dr. Nemeroff disclosed that he receives grant/research support from the National Institutes of Health and serves as a consultant for and/or on the advisory boards of multiple pharmaceutical companies.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
In the treatment of depression, clinicians are commonly dealing with a mix of comorbidities that are more complex than just depression, and as such, effective treatment options may likewise require thinking outside of the box – and beyond the definitions of the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision).
“The DSM-5 isn’t handed to us on tablets from Mount Sinai,” said Charles B. Nemeroff, MD, PhD, professor and chair in the department of psychiatry and behavioral sciences at the Mulva Clinic for the Neurosciences at the University of Texas at Austin. He spoke at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
“Our patients don’t fall into these very convenient buckets,” Dr. Nemeroff said. “The problem with depression is patients have very high rates of morbidity and comorbidity.”
The array of potential psychiatric comorbidities that are common in depression is somewhat staggering: As many as 70% of patients also have social anxiety disorder; 67% of patients have obsessive-compulsive disorder (OCD); up to 65% of patients have panic disorder; 48% of patients have posttraumatic stress disorder (PTSD); and 42% have generalized anxiety disorder, Dr. Nemeroff said.
And while the DSM-5 may have all those bases covered, in real world clinical practice, cracking the code of each patient’s unique and often more complicated psychiatric profile – and how to best manage it – can be a challenge. But Dr. Nemeroff said important clues can guide the clinician’s path.
A key starting point is making sure to gauge the severity of the patient’s core depression with one of the validated depression scales – whether it’s the self-reported Beck Depression Inventory, the clinician-rated Hamilton Rating Scale for Depression, the clinician-rated Montgomery Asberg Depression Rating Scale, or the Inventory of Depressive Symptoms, clinicians should pick one and track the score with each visit, Dr. Nemeroff advised.
“It doesn’t matter which tool you prefer – most tend to like the Beck Depression Scale, but the bottom line is that you have to get a measure of severity at every visit,” he said.
Among the most important comorbidities to identify as soon as possible is bipolar disorder, due to the potential worsening of the condition that can occur among those patients if treated with antidepressants, Dr. Nemeroff said.
“The question of whether the patient is bipolar should always be in the back of your mind,” he cautioned. “And if patients have been started on antidepressants, the clues may become evident very quickly.”
The most important indicator that the patient has bipolar disorder “is if they tell you that they were prescribed an antidepressant and it resulted in an increase in what we know to be hypomania – they may describe it as agitation or an inability to sleep,” Dr. Nemeroff said.
Of note, the effect is much more common with SNRIs [serotonin norepinephrine reuptake inhibitors] than SSRIs [selective serotonin reuptake inhibitors], he said.
“The effect is particularly notable with venlafaxine,” he said. “But SNRIs all have the propensity to switch people with depression into hypomania, but only patients who have bipolar disorder.”
“If you give a patient 150 mg of venlafaxine and they switch to developing hypomania, you now have the diagnosis of bipolar disorder, and you can treat them appropriately.”
Other important clues of bipolarity in depressed patients include:
- Family history: Most cases are genetically driven.
- Earlier age of onset (younger than age 25): “If the patient tells you they were depressed prepuberty, you should be thinking about the possibility of bipolar disorder, as it often presents as depression in childhood.”
- Psychotic features: As many as 80% of patients with psychotic depression end up being bipolar, Dr. Nemeroff said.
- Atypical depression: For example, depression with hypersomnia, or having an increased appetite instead of decreased, or a high amount of anxiety.
Remission should be the goal of treatment, and Dr. Nemeroff said that in efforts to accomplish that with the help of medications, psychiatrists may need to think “outside of the box” – or beyond the label.
“Many practitioners become slaves to the PDR [Physicians’ Desk Reference],” he said. “It is only a guide to what the clinical trials show, and not a mandate in terms of dosing.”
“There’s often strong data in the literature that supports going to a higher dose, if necessary, and I have [plenty] of patients, for instance, on 450 or 600 mg of venlafaxine who had not responded to 150 or even 300 mg.”
Treatment resistance
When patients continue to fail to respond, regardless of dosing or medication adjustments, Dr. Nemeroff suggested that clinicians should consider the potential important reasons. For instance, in addition to comorbid psychiatric conditions, practitioners should determine if there are medical conditions that they are not aware of.
“Does the patient have an underlying medical condition, such as thyroid dysfunction, early Parkinson’s disease, or even something like cancer?” he said.
There is also the inevitable question of whether the patient is indeed taking the medication. “We know that 30% of our patients do not follow their prescriptions, so of course that’s an important question to ask,” Dr. Nemeroff said.
Finally, while some pharmacogenomic tests are emerging with the suggestion of identifying which patients may or may not respond to certain drugs, Dr. Nemeroff says he’s seen little convincing evidence of their benefits.
“We have a problem in this field in that we don’t have the kinds of markers that they do in oncology, so we’re left with having to generally play trial and error,” he said.
“But when it comes to these pharmacogenomic tests, there’s just no ‘there there’,” he asserted. “From what I’ve seen so far, it’s frankly neuro-mythology.”
Dr. Nemeroff disclosed that he receives grant/research support from the National Institutes of Health and serves as a consultant for and/or on the advisory boards of multiple pharmaceutical companies.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
FROM PSYCHOPHARMACOLOGY UPDATE
Higher potency of fentanyl affects addiction treatment, screening
As fentanyl-related overdose deaths continue to increase, clinicians should take note of important differences that set the drug apart from the other drugs of misuse – and the troubling reality that fentanyl now contaminates most of them.
“It would be fair to tell patients, if you’re buying any illicit drugs – pills, powder, liquid, whatever it is, you’ve got to assume it’s either contaminated with or replaced by fentanyl,” said Edwin Salsitz, MD, an associate clinical professor at the Icahn School of Medicine at Mount Sinai, New York, during a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
In many if not most cases, he noted, patients become addicted to fentanyl unknowingly. They assume they are ingesting oxycodone, cocaine, or another drug, and have no realization that they are even exposed to fentanyl until they test positive for it – or overdose.
Meanwhile, the high potency of fentanyl can overcome the opioid blockade of addiction treatment therapies – methadone and buprenorphine – that take away the high that users get from less potent drugs such as heroin.
“Fentanyl is overcoming this blockade that methadone and buprenorphine used to provide,” Dr. Salsitz said. “With fentanyl having such a higher potency, patients are saying ‘no, I still feel the fentanyl effects,’ and they continue feeling it even with 200 milligrams of methadone or 24 milligrams of buprenorphine.”
‘Wooden chest syndrome’
Among the lesser-known dangers of fentanyl is the possibility that some overdose deaths may occur as the result of a syndrome previously reported as a rare complication following the medical use of fentanyl in critically ill patients – fentanyl-induced chest-wall rigidity, or “wooden chest syndrome,” Dr. Salsitz explained.
In such cases, the muscles of respiration become rigid and paralyzed, causing suffocation within a matter of minutes – too soon to benefit from the overdose rescue medication naloxone.
In one recent study published in Clinical Toxicology , nearly half of fentanyl overdose deaths were found to have occurred even before the body had a chance to produce norfentanyl, a metabolite of fentanyl that takes only about 2-3 minutes to appear in the system, suggesting the deaths occurred rapidly.
In the study of 48 fentanyl deaths, no appreciable concentrations of norfentanyl could be detected in 20 of the 48 overdose deaths (42%), and concentrations were less than 1 ng/mL in 25 cases (52%).
“The lack of any measurable norfentanyl in half of our cases suggests a very rapid death, consistent with acute chest rigidity,” the authors reported.
“In several cases fentanyl concentrations were strikingly high (22 ng/mL and 20 ng/mL) with no norfentanyl detected,” they said.
Dr. Salsitz noted that the syndrome is not well known among the addiction treatment community.
“This is different than the usual respiratory opioid overdose where there’s a gradual decrease in the breathing rate and a gradual decrease in how much air is going in and out of the lungs,” Dr. Salsitz explained.
“With those cases, some may survive for an hour or longer, allowing time for someone to administer naloxone or to get the patient to the emergency room,” he said. “But with this, breathing stops and people can die within minutes.
“I think that this is one of the reasons that fentanyl deaths keep going up despite more and more naloxone availability out there,” he said.
Clearance may take longer
In toxicology testing for fentanyl, clinicians should also note the important difference between fentanyl and other opioids – that fentanyl, because of its high lipophilicity, may be detected in urine toxicology testing up to 3 weeks after last use. This is much longer than the 2- to 4-day clearance observed with other opioids, possibly causing patients to continue to test positive for the drug weeks after cessation.
This effect was observed in one recent study of 12 opioid use disorder patients in a residential treatment program who had previously been exposed to daily fentanyl.
The study showed the mean amount of time of fentanyl clearance was 2 weeks, with a range of 4-26 days after last use.
The authors pointed out that the findings “might explain recent reports of difficulty in buprenorphine inductions for persons who use fentanyl, and point to a need to better understand the pharmacokinetics of fentanyl in the context of opioid withdrawal in persons who regularly use fentanyl.”
Though the study was small, Dr. Salsitz said “that’s not a stumbling block to the important finding that, with regular use of fentanyl, the drug may stay in the urine for a long time.”
Dr. Salsitz noted that similar observations have been made at his center, with clinicians logically assuming that patients were still somehow getting fentanyl.
“When we initially found this in patients, we thought that they were using on the unit, perhaps that they brought in the fentanyl, because otherwise how could it stay in the urine that long,” he noted. “But fentanyl appears to be more lipophilic and gets into the fat; it’s then excreted very slowly and then stays in the urine.”
Dr. Salsitz said most practitioners think of fentanyl as a short-acting drug, so “it’s important to realize that people may continue to test positive and it should be thought of as a long-acting opioid.”
Opiate screening tests don’t work
Dr. Salsitz warned of another misconception in fentanyl testing – the common mistake of assuming that fentanyl should show up in a test for opiates – when in fact fentanyl is not, technically, an opiate.
“The word opiate only refers to morphine, codeine, heroin and sometimes hydrocodone,” he explained. “Other opioids are classified as semisynthetic, such as oxycodone, or synthetics, such as fentanyl and methadone, buprenorphine.”
“In order to detect the synthetics, you must have a separate strip for each one of those drugs. They will not show up positive on a screen for opiates,” he noted.
The belief that fentanyl and other synthetic and semisynthetic opioids will show positive on an opiate screen is a common misconception, he said. “The misunderstanding in toxicology interpretation is a problem for many practitioners, [but] it’s essential to understand because otherwise false assumptions about the patient will be considered.”
Another important testing misreading can occur with the antidepressant drug trazodone, which Dr. Salsitz cautioned may falsely test as positive for fentanyl on immunoassays.
“Trazodone is very commonly used in addiction treatment centers, but it can give a false positive on the fentanyl immunoassay and we’ve had a number of those cases,” he said.
Dr. Salsitz had no disclosures to report.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
As fentanyl-related overdose deaths continue to increase, clinicians should take note of important differences that set the drug apart from the other drugs of misuse – and the troubling reality that fentanyl now contaminates most of them.
“It would be fair to tell patients, if you’re buying any illicit drugs – pills, powder, liquid, whatever it is, you’ve got to assume it’s either contaminated with or replaced by fentanyl,” said Edwin Salsitz, MD, an associate clinical professor at the Icahn School of Medicine at Mount Sinai, New York, during a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
In many if not most cases, he noted, patients become addicted to fentanyl unknowingly. They assume they are ingesting oxycodone, cocaine, or another drug, and have no realization that they are even exposed to fentanyl until they test positive for it – or overdose.
Meanwhile, the high potency of fentanyl can overcome the opioid blockade of addiction treatment therapies – methadone and buprenorphine – that take away the high that users get from less potent drugs such as heroin.
“Fentanyl is overcoming this blockade that methadone and buprenorphine used to provide,” Dr. Salsitz said. “With fentanyl having such a higher potency, patients are saying ‘no, I still feel the fentanyl effects,’ and they continue feeling it even with 200 milligrams of methadone or 24 milligrams of buprenorphine.”
‘Wooden chest syndrome’
Among the lesser-known dangers of fentanyl is the possibility that some overdose deaths may occur as the result of a syndrome previously reported as a rare complication following the medical use of fentanyl in critically ill patients – fentanyl-induced chest-wall rigidity, or “wooden chest syndrome,” Dr. Salsitz explained.
In such cases, the muscles of respiration become rigid and paralyzed, causing suffocation within a matter of minutes – too soon to benefit from the overdose rescue medication naloxone.
In one recent study published in Clinical Toxicology , nearly half of fentanyl overdose deaths were found to have occurred even before the body had a chance to produce norfentanyl, a metabolite of fentanyl that takes only about 2-3 minutes to appear in the system, suggesting the deaths occurred rapidly.
In the study of 48 fentanyl deaths, no appreciable concentrations of norfentanyl could be detected in 20 of the 48 overdose deaths (42%), and concentrations were less than 1 ng/mL in 25 cases (52%).
“The lack of any measurable norfentanyl in half of our cases suggests a very rapid death, consistent with acute chest rigidity,” the authors reported.
“In several cases fentanyl concentrations were strikingly high (22 ng/mL and 20 ng/mL) with no norfentanyl detected,” they said.
Dr. Salsitz noted that the syndrome is not well known among the addiction treatment community.
“This is different than the usual respiratory opioid overdose where there’s a gradual decrease in the breathing rate and a gradual decrease in how much air is going in and out of the lungs,” Dr. Salsitz explained.
“With those cases, some may survive for an hour or longer, allowing time for someone to administer naloxone or to get the patient to the emergency room,” he said. “But with this, breathing stops and people can die within minutes.
“I think that this is one of the reasons that fentanyl deaths keep going up despite more and more naloxone availability out there,” he said.
Clearance may take longer
In toxicology testing for fentanyl, clinicians should also note the important difference between fentanyl and other opioids – that fentanyl, because of its high lipophilicity, may be detected in urine toxicology testing up to 3 weeks after last use. This is much longer than the 2- to 4-day clearance observed with other opioids, possibly causing patients to continue to test positive for the drug weeks after cessation.
This effect was observed in one recent study of 12 opioid use disorder patients in a residential treatment program who had previously been exposed to daily fentanyl.
The study showed the mean amount of time of fentanyl clearance was 2 weeks, with a range of 4-26 days after last use.
The authors pointed out that the findings “might explain recent reports of difficulty in buprenorphine inductions for persons who use fentanyl, and point to a need to better understand the pharmacokinetics of fentanyl in the context of opioid withdrawal in persons who regularly use fentanyl.”
Though the study was small, Dr. Salsitz said “that’s not a stumbling block to the important finding that, with regular use of fentanyl, the drug may stay in the urine for a long time.”
Dr. Salsitz noted that similar observations have been made at his center, with clinicians logically assuming that patients were still somehow getting fentanyl.
“When we initially found this in patients, we thought that they were using on the unit, perhaps that they brought in the fentanyl, because otherwise how could it stay in the urine that long,” he noted. “But fentanyl appears to be more lipophilic and gets into the fat; it’s then excreted very slowly and then stays in the urine.”
Dr. Salsitz said most practitioners think of fentanyl as a short-acting drug, so “it’s important to realize that people may continue to test positive and it should be thought of as a long-acting opioid.”
Opiate screening tests don’t work
Dr. Salsitz warned of another misconception in fentanyl testing – the common mistake of assuming that fentanyl should show up in a test for opiates – when in fact fentanyl is not, technically, an opiate.
“The word opiate only refers to morphine, codeine, heroin and sometimes hydrocodone,” he explained. “Other opioids are classified as semisynthetic, such as oxycodone, or synthetics, such as fentanyl and methadone, buprenorphine.”
“In order to detect the synthetics, you must have a separate strip for each one of those drugs. They will not show up positive on a screen for opiates,” he noted.
The belief that fentanyl and other synthetic and semisynthetic opioids will show positive on an opiate screen is a common misconception, he said. “The misunderstanding in toxicology interpretation is a problem for many practitioners, [but] it’s essential to understand because otherwise false assumptions about the patient will be considered.”
Another important testing misreading can occur with the antidepressant drug trazodone, which Dr. Salsitz cautioned may falsely test as positive for fentanyl on immunoassays.
“Trazodone is very commonly used in addiction treatment centers, but it can give a false positive on the fentanyl immunoassay and we’ve had a number of those cases,” he said.
Dr. Salsitz had no disclosures to report.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
As fentanyl-related overdose deaths continue to increase, clinicians should take note of important differences that set the drug apart from the other drugs of misuse – and the troubling reality that fentanyl now contaminates most of them.
“It would be fair to tell patients, if you’re buying any illicit drugs – pills, powder, liquid, whatever it is, you’ve got to assume it’s either contaminated with or replaced by fentanyl,” said Edwin Salsitz, MD, an associate clinical professor at the Icahn School of Medicine at Mount Sinai, New York, during a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists.
In many if not most cases, he noted, patients become addicted to fentanyl unknowingly. They assume they are ingesting oxycodone, cocaine, or another drug, and have no realization that they are even exposed to fentanyl until they test positive for it – or overdose.
Meanwhile, the high potency of fentanyl can overcome the opioid blockade of addiction treatment therapies – methadone and buprenorphine – that take away the high that users get from less potent drugs such as heroin.
“Fentanyl is overcoming this blockade that methadone and buprenorphine used to provide,” Dr. Salsitz said. “With fentanyl having such a higher potency, patients are saying ‘no, I still feel the fentanyl effects,’ and they continue feeling it even with 200 milligrams of methadone or 24 milligrams of buprenorphine.”
‘Wooden chest syndrome’
Among the lesser-known dangers of fentanyl is the possibility that some overdose deaths may occur as the result of a syndrome previously reported as a rare complication following the medical use of fentanyl in critically ill patients – fentanyl-induced chest-wall rigidity, or “wooden chest syndrome,” Dr. Salsitz explained.
In such cases, the muscles of respiration become rigid and paralyzed, causing suffocation within a matter of minutes – too soon to benefit from the overdose rescue medication naloxone.
In one recent study published in Clinical Toxicology , nearly half of fentanyl overdose deaths were found to have occurred even before the body had a chance to produce norfentanyl, a metabolite of fentanyl that takes only about 2-3 minutes to appear in the system, suggesting the deaths occurred rapidly.
In the study of 48 fentanyl deaths, no appreciable concentrations of norfentanyl could be detected in 20 of the 48 overdose deaths (42%), and concentrations were less than 1 ng/mL in 25 cases (52%).
“The lack of any measurable norfentanyl in half of our cases suggests a very rapid death, consistent with acute chest rigidity,” the authors reported.
“In several cases fentanyl concentrations were strikingly high (22 ng/mL and 20 ng/mL) with no norfentanyl detected,” they said.
Dr. Salsitz noted that the syndrome is not well known among the addiction treatment community.
“This is different than the usual respiratory opioid overdose where there’s a gradual decrease in the breathing rate and a gradual decrease in how much air is going in and out of the lungs,” Dr. Salsitz explained.
“With those cases, some may survive for an hour or longer, allowing time for someone to administer naloxone or to get the patient to the emergency room,” he said. “But with this, breathing stops and people can die within minutes.
“I think that this is one of the reasons that fentanyl deaths keep going up despite more and more naloxone availability out there,” he said.
Clearance may take longer
In toxicology testing for fentanyl, clinicians should also note the important difference between fentanyl and other opioids – that fentanyl, because of its high lipophilicity, may be detected in urine toxicology testing up to 3 weeks after last use. This is much longer than the 2- to 4-day clearance observed with other opioids, possibly causing patients to continue to test positive for the drug weeks after cessation.
This effect was observed in one recent study of 12 opioid use disorder patients in a residential treatment program who had previously been exposed to daily fentanyl.
The study showed the mean amount of time of fentanyl clearance was 2 weeks, with a range of 4-26 days after last use.
The authors pointed out that the findings “might explain recent reports of difficulty in buprenorphine inductions for persons who use fentanyl, and point to a need to better understand the pharmacokinetics of fentanyl in the context of opioid withdrawal in persons who regularly use fentanyl.”
Though the study was small, Dr. Salsitz said “that’s not a stumbling block to the important finding that, with regular use of fentanyl, the drug may stay in the urine for a long time.”
Dr. Salsitz noted that similar observations have been made at his center, with clinicians logically assuming that patients were still somehow getting fentanyl.
“When we initially found this in patients, we thought that they were using on the unit, perhaps that they brought in the fentanyl, because otherwise how could it stay in the urine that long,” he noted. “But fentanyl appears to be more lipophilic and gets into the fat; it’s then excreted very slowly and then stays in the urine.”
Dr. Salsitz said most practitioners think of fentanyl as a short-acting drug, so “it’s important to realize that people may continue to test positive and it should be thought of as a long-acting opioid.”
Opiate screening tests don’t work
Dr. Salsitz warned of another misconception in fentanyl testing – the common mistake of assuming that fentanyl should show up in a test for opiates – when in fact fentanyl is not, technically, an opiate.
“The word opiate only refers to morphine, codeine, heroin and sometimes hydrocodone,” he explained. “Other opioids are classified as semisynthetic, such as oxycodone, or synthetics, such as fentanyl and methadone, buprenorphine.”
“In order to detect the synthetics, you must have a separate strip for each one of those drugs. They will not show up positive on a screen for opiates,” he noted.
The belief that fentanyl and other synthetic and semisynthetic opioids will show positive on an opiate screen is a common misconception, he said. “The misunderstanding in toxicology interpretation is a problem for many practitioners, [but] it’s essential to understand because otherwise false assumptions about the patient will be considered.”
Another important testing misreading can occur with the antidepressant drug trazodone, which Dr. Salsitz cautioned may falsely test as positive for fentanyl on immunoassays.
“Trazodone is very commonly used in addiction treatment centers, but it can give a false positive on the fentanyl immunoassay and we’ve had a number of those cases,” he said.
Dr. Salsitz had no disclosures to report.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
FROM PSYCHOPHARMACOLOGY UPDATE
Telepsychiatry tips: Etiquette and ethics
From providing virtual therapy sessions to patients in the front seats of their cars, to sessions with patients who turn out to be in another state,
But key practice tips are emerging for the optimization of virtual sessions, said Sanjay Gupta, MD, chief medical officer of the BryLin Behavioral Health System in Buffalo, N.Y., during a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.
Dr. Gupta noted that while “many pitfalls [may] occur,” an overriding rule that should be emphasized with telepsychiatry is that “[virtual visits] are held to the same standard of care as an in-person visit.” This “rule” needs to be followed diligently, he said, as the key difference in virtual visits is a reduced sense of the formality of a psychotherapy session.
With virtual sessions, the therapeutic experience “can feel kind of trivialized,” said Dr. Gupta, who is also a clinical professor in the department of psychiatry, State University of New York at Buffalo. He noted that it is crucial that “the sacredness of a private setting should not be diluted.”
Challenges in finding that privacy for some, however, lead to the issue of the “patients in cars” scenario, Dr. Gupta said. Still, he added, while psychiatric sessions should never be conducted when a patient is driving, the front seat of a parked car may, for some, be the most private setting available.
“For many patients, their car may be the only private place from which they can take a video call,” Dr. Gupta noted. “Perhaps they are at work and the only way they could fit in the appointment is by going out to their car on their break. Or patients may even be at home, but they’re not alone and need to go out to their car for privacy.”
If the car isn’t being driven, sitting inside it should be fine for virtual therapy, but even there, clinicians should retain a focus on the consistency of care regardless of the setting.
Meanwhile, psychiatrists can take key measures to keep things professional, at least on their end of the session.
Before starting, for instance, keep in mind the patient’s viewing experience, Dr. Gupta suggested. Tips he offered include:
- Keep the background of your video image subtle, with no distractions, such as windows looking out to an ocean or other distracting background elements.
- The camera should be above eye level to suggest a face-to-face conversation more effectively.
- Try not to have other browser windows open and look directly into the camera lens so that the patient knows they have your full attention.
- Try not to take notes or document in the electronic health record during the session, which also can give the impression of being distracted and not listening to the patient.
Psychiatrists should remember that older patients – who may be uncomfortable with email, much less video conferencing – may still struggle with video-calling technology. In such cases, consider:
- Sending the patient instructions in advance of the appointment.
- Have your office hold a “tech check” prior to the appointment to ensure the patient is ready.
- Be prepared to provide troubleshooting.
Whether the patient is tech savvy or not, make sure communication is clear:
- Speak in short sentences on teleconferencing sessions.
- Speak slowly and use a lower frequency.
- Recognize that non-native English speakers may struggle with comprehension, and explore interpreter options.
Dr. Gupta noted that the first minute of the virtual therapy session is crucial in setting the tone.
“The patient wants to hear a professional, confident tone on the other end at the beginning of the session,” he said. “Be warm and respectful throughout the visit, and make sure to explain to the patient how the session will be reconnected if the call is interrupted.”
Clinicians should also make sure to identify the patient’s physical location during the session in case of an emergency, such as the patient becoming suicidal.
Impending ‘telehealth cliff’
Many laws and licensing requirements for telehealth are still relatively loose, falling under the COVID-19 public health emergency (PHE) policies. These policies allow practitioners who are eligible to bill Medicare for telehealth services regardless of where the patient or provider is located, and providers can also deliver telehealth services across state lines, depending on state and federal rules.
However, Dr. Gupta warns that practitioners should be prepared for the potential “telehealth cliff” that is anticipated when those PHE policies are lifted, as barriers in licensing, billing, and other factors, such as HIPAA, are reinstated.
“HIPAA is [flexible] now as long as the public emergency policies exist,” Dr. Gupta said. “However, in noncrisis times, technology will be required to be HIPAA compliant. If you are a solo provider, for instance, you really need to choose a telepsychiatry platform that is HIPAA compliant before that happens.”
While the timing of the “telehealth cliff” is still uncertain, providers have been promised a 60-day advance notice of the PHE end, and at that time, there will be an additional 151-day grace period before the waivers lift.
A key federal measure that could protect more favorable telemedicine policies across state lines, the Temporary Reciprocity to Ensure Access to Treatment Act, currently remains stalled in Congress.
Regardless of those developments, Dr. Gupta underscored that “telepsychiatry is here to stay because the patients and their families like it, and they will be the driving factors.”
He noted that “the future is likely going to be a hybrid model of in-person and virtual visits,” to accommodate the various scenarios in which in-person visits may be preferred or necessary, but many will still likely choose the convenience and greater flexibility of virtual sessions.
Dr. Gupta serves or has served as a speaker or member of a speaker’s bureau for AbbVie, Acadia, Alkermes, Intra-Cellular Therapies, Janssen, Neurocrine, and Otsuka, and serves as a consultant/on an advisory board for Intra-Cellular Therapies.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
From providing virtual therapy sessions to patients in the front seats of their cars, to sessions with patients who turn out to be in another state,
But key practice tips are emerging for the optimization of virtual sessions, said Sanjay Gupta, MD, chief medical officer of the BryLin Behavioral Health System in Buffalo, N.Y., during a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.
Dr. Gupta noted that while “many pitfalls [may] occur,” an overriding rule that should be emphasized with telepsychiatry is that “[virtual visits] are held to the same standard of care as an in-person visit.” This “rule” needs to be followed diligently, he said, as the key difference in virtual visits is a reduced sense of the formality of a psychotherapy session.
With virtual sessions, the therapeutic experience “can feel kind of trivialized,” said Dr. Gupta, who is also a clinical professor in the department of psychiatry, State University of New York at Buffalo. He noted that it is crucial that “the sacredness of a private setting should not be diluted.”
Challenges in finding that privacy for some, however, lead to the issue of the “patients in cars” scenario, Dr. Gupta said. Still, he added, while psychiatric sessions should never be conducted when a patient is driving, the front seat of a parked car may, for some, be the most private setting available.
“For many patients, their car may be the only private place from which they can take a video call,” Dr. Gupta noted. “Perhaps they are at work and the only way they could fit in the appointment is by going out to their car on their break. Or patients may even be at home, but they’re not alone and need to go out to their car for privacy.”
If the car isn’t being driven, sitting inside it should be fine for virtual therapy, but even there, clinicians should retain a focus on the consistency of care regardless of the setting.
Meanwhile, psychiatrists can take key measures to keep things professional, at least on their end of the session.
Before starting, for instance, keep in mind the patient’s viewing experience, Dr. Gupta suggested. Tips he offered include:
- Keep the background of your video image subtle, with no distractions, such as windows looking out to an ocean or other distracting background elements.
- The camera should be above eye level to suggest a face-to-face conversation more effectively.
- Try not to have other browser windows open and look directly into the camera lens so that the patient knows they have your full attention.
- Try not to take notes or document in the electronic health record during the session, which also can give the impression of being distracted and not listening to the patient.
Psychiatrists should remember that older patients – who may be uncomfortable with email, much less video conferencing – may still struggle with video-calling technology. In such cases, consider:
- Sending the patient instructions in advance of the appointment.
- Have your office hold a “tech check” prior to the appointment to ensure the patient is ready.
- Be prepared to provide troubleshooting.
Whether the patient is tech savvy or not, make sure communication is clear:
- Speak in short sentences on teleconferencing sessions.
- Speak slowly and use a lower frequency.
- Recognize that non-native English speakers may struggle with comprehension, and explore interpreter options.
Dr. Gupta noted that the first minute of the virtual therapy session is crucial in setting the tone.
“The patient wants to hear a professional, confident tone on the other end at the beginning of the session,” he said. “Be warm and respectful throughout the visit, and make sure to explain to the patient how the session will be reconnected if the call is interrupted.”
Clinicians should also make sure to identify the patient’s physical location during the session in case of an emergency, such as the patient becoming suicidal.
Impending ‘telehealth cliff’
Many laws and licensing requirements for telehealth are still relatively loose, falling under the COVID-19 public health emergency (PHE) policies. These policies allow practitioners who are eligible to bill Medicare for telehealth services regardless of where the patient or provider is located, and providers can also deliver telehealth services across state lines, depending on state and federal rules.
However, Dr. Gupta warns that practitioners should be prepared for the potential “telehealth cliff” that is anticipated when those PHE policies are lifted, as barriers in licensing, billing, and other factors, such as HIPAA, are reinstated.
“HIPAA is [flexible] now as long as the public emergency policies exist,” Dr. Gupta said. “However, in noncrisis times, technology will be required to be HIPAA compliant. If you are a solo provider, for instance, you really need to choose a telepsychiatry platform that is HIPAA compliant before that happens.”
While the timing of the “telehealth cliff” is still uncertain, providers have been promised a 60-day advance notice of the PHE end, and at that time, there will be an additional 151-day grace period before the waivers lift.
A key federal measure that could protect more favorable telemedicine policies across state lines, the Temporary Reciprocity to Ensure Access to Treatment Act, currently remains stalled in Congress.
Regardless of those developments, Dr. Gupta underscored that “telepsychiatry is here to stay because the patients and their families like it, and they will be the driving factors.”
He noted that “the future is likely going to be a hybrid model of in-person and virtual visits,” to accommodate the various scenarios in which in-person visits may be preferred or necessary, but many will still likely choose the convenience and greater flexibility of virtual sessions.
Dr. Gupta serves or has served as a speaker or member of a speaker’s bureau for AbbVie, Acadia, Alkermes, Intra-Cellular Therapies, Janssen, Neurocrine, and Otsuka, and serves as a consultant/on an advisory board for Intra-Cellular Therapies.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
From providing virtual therapy sessions to patients in the front seats of their cars, to sessions with patients who turn out to be in another state,
But key practice tips are emerging for the optimization of virtual sessions, said Sanjay Gupta, MD, chief medical officer of the BryLin Behavioral Health System in Buffalo, N.Y., during a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.
Dr. Gupta noted that while “many pitfalls [may] occur,” an overriding rule that should be emphasized with telepsychiatry is that “[virtual visits] are held to the same standard of care as an in-person visit.” This “rule” needs to be followed diligently, he said, as the key difference in virtual visits is a reduced sense of the formality of a psychotherapy session.
With virtual sessions, the therapeutic experience “can feel kind of trivialized,” said Dr. Gupta, who is also a clinical professor in the department of psychiatry, State University of New York at Buffalo. He noted that it is crucial that “the sacredness of a private setting should not be diluted.”
Challenges in finding that privacy for some, however, lead to the issue of the “patients in cars” scenario, Dr. Gupta said. Still, he added, while psychiatric sessions should never be conducted when a patient is driving, the front seat of a parked car may, for some, be the most private setting available.
“For many patients, their car may be the only private place from which they can take a video call,” Dr. Gupta noted. “Perhaps they are at work and the only way they could fit in the appointment is by going out to their car on their break. Or patients may even be at home, but they’re not alone and need to go out to their car for privacy.”
If the car isn’t being driven, sitting inside it should be fine for virtual therapy, but even there, clinicians should retain a focus on the consistency of care regardless of the setting.
Meanwhile, psychiatrists can take key measures to keep things professional, at least on their end of the session.
Before starting, for instance, keep in mind the patient’s viewing experience, Dr. Gupta suggested. Tips he offered include:
- Keep the background of your video image subtle, with no distractions, such as windows looking out to an ocean or other distracting background elements.
- The camera should be above eye level to suggest a face-to-face conversation more effectively.
- Try not to have other browser windows open and look directly into the camera lens so that the patient knows they have your full attention.
- Try not to take notes or document in the electronic health record during the session, which also can give the impression of being distracted and not listening to the patient.
Psychiatrists should remember that older patients – who may be uncomfortable with email, much less video conferencing – may still struggle with video-calling technology. In such cases, consider:
- Sending the patient instructions in advance of the appointment.
- Have your office hold a “tech check” prior to the appointment to ensure the patient is ready.
- Be prepared to provide troubleshooting.
Whether the patient is tech savvy or not, make sure communication is clear:
- Speak in short sentences on teleconferencing sessions.
- Speak slowly and use a lower frequency.
- Recognize that non-native English speakers may struggle with comprehension, and explore interpreter options.
Dr. Gupta noted that the first minute of the virtual therapy session is crucial in setting the tone.
“The patient wants to hear a professional, confident tone on the other end at the beginning of the session,” he said. “Be warm and respectful throughout the visit, and make sure to explain to the patient how the session will be reconnected if the call is interrupted.”
Clinicians should also make sure to identify the patient’s physical location during the session in case of an emergency, such as the patient becoming suicidal.
Impending ‘telehealth cliff’
Many laws and licensing requirements for telehealth are still relatively loose, falling under the COVID-19 public health emergency (PHE) policies. These policies allow practitioners who are eligible to bill Medicare for telehealth services regardless of where the patient or provider is located, and providers can also deliver telehealth services across state lines, depending on state and federal rules.
However, Dr. Gupta warns that practitioners should be prepared for the potential “telehealth cliff” that is anticipated when those PHE policies are lifted, as barriers in licensing, billing, and other factors, such as HIPAA, are reinstated.
“HIPAA is [flexible] now as long as the public emergency policies exist,” Dr. Gupta said. “However, in noncrisis times, technology will be required to be HIPAA compliant. If you are a solo provider, for instance, you really need to choose a telepsychiatry platform that is HIPAA compliant before that happens.”
While the timing of the “telehealth cliff” is still uncertain, providers have been promised a 60-day advance notice of the PHE end, and at that time, there will be an additional 151-day grace period before the waivers lift.
A key federal measure that could protect more favorable telemedicine policies across state lines, the Temporary Reciprocity to Ensure Access to Treatment Act, currently remains stalled in Congress.
Regardless of those developments, Dr. Gupta underscored that “telepsychiatry is here to stay because the patients and their families like it, and they will be the driving factors.”
He noted that “the future is likely going to be a hybrid model of in-person and virtual visits,” to accommodate the various scenarios in which in-person visits may be preferred or necessary, but many will still likely choose the convenience and greater flexibility of virtual sessions.
Dr. Gupta serves or has served as a speaker or member of a speaker’s bureau for AbbVie, Acadia, Alkermes, Intra-Cellular Therapies, Janssen, Neurocrine, and Otsuka, and serves as a consultant/on an advisory board for Intra-Cellular Therapies.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
FROM PSYCHOPHARMACOLOGY UPDATE
Clozapine underutilized in treatment-resistant schizophrenia
, and when it is used, the drug is often delayed by several crucial years, reducing chances of efficacy.
“Despite being the only pharmacological therapy approved for treatment-resistant schizophrenia, clozapine is underutilized globally, even in developed countries, where only about 30% of patients who would benefit from the drug receive it,” said John M. Kane, MD, of the department of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., in a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.
Clozapine, a tricyclic dibenzodiazepine available in branded and various generic versions, is approved by the U.S. Food and Drug Administration as a third-line therapy for severe, treatment-resistant schizophrenia, with studies showing benefits exceeding those of any other antipsychotics for the indication.
But while recommendations suggest use after a trial of two or more antipsychotics, with at least one being an atypical antipsychotic, one recent review finds delays in clozapine commencement ranging from 19.3 weeks to 5.5 years, and the duration of illness prior to clozapine use ranging from 1.1 to 9.7 years.
Blood monitoring, side effects
The key deterrents preventing many clinicians and patients from trying clozapine sooner are the drug’s safety and tolerability profiles, and notably the requirement of regular blood testing due to an increased risk of agranulocytosis.
Specifically, the blood testing is required every week for 6 months, then every other week for the next 6 months, and then once a month after that; however, “many of us think that that’s excessive at this point in time,” Dr. Kane noted.
Various other potential side effects are also of concern, including myocarditis, seizures, constipation, arrhythmia, hypersalivation, pneumonia, and metabolic symptoms including diabetes.
In terms of the common strategies that clinicians turn to when patients fail to respond to their current antipsychotic, including increasing doses, combining agents, or treatment switching, “none of the strategies likely rival clozapine in terms of efficacy,” Dr. Kane said.
Regarding higher dosing: “There is very little data suggesting that higher doses of antipsychotic drugs will work when the moderate or recommended dose has not worked,” he said.
Combination therapy strategies may provide benefits, but “they’re not a substitute for clozapine,” Dr. Kane added, noting that the combinations that do appear to be the most effective involve clozapine.
And regarding drug switching, studies suggest the likelihood of response in switching from one drug to another is “actually very low,” Dr. Kane added.
Clozapine also doesn’t work for all – the response rate runs between about 30% and 60%, Dr. Kane said, but when it is effective, the benefits can be profound.
“There are some patients who have a very pronounced response to clozapine – some patients describe it as life-changing,” he said.
Treatment delays reduce efficacy
Importantly, the delays before receiving clozapine are not inconsequential – data show that each outpatient antipsychotic trial prior to clozapine reduces the likelihood of response by 8%-11%, and each hospital admission further reduces the likelihood of response by 4%-8%, underscoring the need to identify treatment resistance as early as possible, Dr. Kane said.
“It’s critically important to try to identify treatment resistance earlier than we usually do because if we can get it under control sooner, we have a better chance of improving the patient’s outcome, and this has been shown in a number of studies,” he said.
“The longer you wait, the less likely you are to see a good response even to clozapine.”
Despite the concerns about clozapine, Dr. Kane notes that even the blood monitoring does not appear to be a big complaint for patients, especially they are improving.
“In our experience, the patients who benefit from clozapine don’t really have a problem with the monitoring,” he said.
“In fact, patients who benefit from clozapine are much more adherent to the medication than other patients that we see, which is understandable, because if you feel you’re really getting a benefit from medicine, you’re going to be much more motivated to take it even if it has side effects.”
A recent systematic review of 13 studies and 1,487 patients backs that up, concluding that “patients generally have a favorable experience when being treated with clozapine,” with the caveat that “conclusions are limited by the risk of bias, particularly survivorship bias.”
Preference for clozapine over other antipsychotic medications was reported by 54%-86% of patients in the review, with specific improvements in mood (11%-78%) and cognition (5%-68%).
Clinicians the biggest ‘obstacle’
Dr. Kane notes that an important factor in underutilization could indeed be the manner in which clinicians discuss clozapine with their patients – often opening the discussion by focusing on the negative aspects that, without the context of the potential benefits, can be deal-breakers for patient from the start.
“The clinicians in my opinion are really the obstacle,” Dr. Kane said. “What we always hear from clinicians is ‘I can’t do it because the patient refuses, or the patient doesn’t like the side effects’.”
Dr. Kane notes that most side effects can indeed be managed – regarding the risk for metabolic syndrome, for instance, he recommends that patients should be given metformin from the beginning when they’re started on clozapine.
He adds that in most cases, a 3-month trial is enough to answer the question of whether clozapine is working or not.
“Three months is a good trial, but it may not even tell you the total response to clozapine because that may actually accrue over time,” he said. “We’ve seen patients who actually get better and better beyond 3 months.”
Not offering the drug to patients, however, is doing them a serious disservice, Dr. Kane added.
“What I tell patients and families is that it would be a shame to miss this opportunity for a potential treatment that could be life-changing,” he said. “Does it have potential side effects? Yes. Do you have to get blood tests? Yes. And I can’t tell by evaluating a patient’s history or examining that patient whether or not they’re going to be a good responder. But would you really want to miss an opportunity to find that out?”
“To me the argument is – let’s try this drug for 3 months and see what effect it has, and at that point you’ll be in a much better position to make a decision about the benefits versus risk,” Dr. Kane said.
The only FDA-approved drug for treatment-resistant schizophrenia
Remarkably, clozapine isn’t just the only drug to currently have approval from the FDA for treatment-resistant schizophrenia – it has been for the last 3 decades.
“There have been attempts to develop medications with similar efficacy, but they have not succeeded,” Dr. Kane said in an interview. “We are still uncertain as to what accounts for clozapine’s unique qualities.”
Yet, with treatment-resistant schizophrenia patients representing some of the most dire mental illness cases clinicians may face, the need for better treatment decisions – and additional options – is pressing, Dr. Kane said.
“[The lack of any other drugs] is a big embarrassment to our field, in my opinion,” he said. “I’m a big proponent of clozapine, but we should have found another substance by now that could substitute for clozapine, which obviously has a lot of side effects and is not the easiest drug to use.”
Dr. Kane reported relationships either as a speaker or consultant/advisory board member and/or receives research grant support from Alkermes, Allergan, Click Therapeutics, Dainippon Sumitomo, H. Lundbeck, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Neumora Therapeutics, Novartis Pharmaceuticals, Otsuka, Reviva, Roche, Saladax, Sunovion, Takeda, and Teva. Dr. Kane receives non-mutual funds stock ownership/stock options from LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics, and receives patent holder/royalties paid by UpToDate.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
, and when it is used, the drug is often delayed by several crucial years, reducing chances of efficacy.
“Despite being the only pharmacological therapy approved for treatment-resistant schizophrenia, clozapine is underutilized globally, even in developed countries, where only about 30% of patients who would benefit from the drug receive it,” said John M. Kane, MD, of the department of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., in a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.
Clozapine, a tricyclic dibenzodiazepine available in branded and various generic versions, is approved by the U.S. Food and Drug Administration as a third-line therapy for severe, treatment-resistant schizophrenia, with studies showing benefits exceeding those of any other antipsychotics for the indication.
But while recommendations suggest use after a trial of two or more antipsychotics, with at least one being an atypical antipsychotic, one recent review finds delays in clozapine commencement ranging from 19.3 weeks to 5.5 years, and the duration of illness prior to clozapine use ranging from 1.1 to 9.7 years.
Blood monitoring, side effects
The key deterrents preventing many clinicians and patients from trying clozapine sooner are the drug’s safety and tolerability profiles, and notably the requirement of regular blood testing due to an increased risk of agranulocytosis.
Specifically, the blood testing is required every week for 6 months, then every other week for the next 6 months, and then once a month after that; however, “many of us think that that’s excessive at this point in time,” Dr. Kane noted.
Various other potential side effects are also of concern, including myocarditis, seizures, constipation, arrhythmia, hypersalivation, pneumonia, and metabolic symptoms including diabetes.
In terms of the common strategies that clinicians turn to when patients fail to respond to their current antipsychotic, including increasing doses, combining agents, or treatment switching, “none of the strategies likely rival clozapine in terms of efficacy,” Dr. Kane said.
Regarding higher dosing: “There is very little data suggesting that higher doses of antipsychotic drugs will work when the moderate or recommended dose has not worked,” he said.
Combination therapy strategies may provide benefits, but “they’re not a substitute for clozapine,” Dr. Kane added, noting that the combinations that do appear to be the most effective involve clozapine.
And regarding drug switching, studies suggest the likelihood of response in switching from one drug to another is “actually very low,” Dr. Kane added.
Clozapine also doesn’t work for all – the response rate runs between about 30% and 60%, Dr. Kane said, but when it is effective, the benefits can be profound.
“There are some patients who have a very pronounced response to clozapine – some patients describe it as life-changing,” he said.
Treatment delays reduce efficacy
Importantly, the delays before receiving clozapine are not inconsequential – data show that each outpatient antipsychotic trial prior to clozapine reduces the likelihood of response by 8%-11%, and each hospital admission further reduces the likelihood of response by 4%-8%, underscoring the need to identify treatment resistance as early as possible, Dr. Kane said.
“It’s critically important to try to identify treatment resistance earlier than we usually do because if we can get it under control sooner, we have a better chance of improving the patient’s outcome, and this has been shown in a number of studies,” he said.
“The longer you wait, the less likely you are to see a good response even to clozapine.”
Despite the concerns about clozapine, Dr. Kane notes that even the blood monitoring does not appear to be a big complaint for patients, especially they are improving.
“In our experience, the patients who benefit from clozapine don’t really have a problem with the monitoring,” he said.
“In fact, patients who benefit from clozapine are much more adherent to the medication than other patients that we see, which is understandable, because if you feel you’re really getting a benefit from medicine, you’re going to be much more motivated to take it even if it has side effects.”
A recent systematic review of 13 studies and 1,487 patients backs that up, concluding that “patients generally have a favorable experience when being treated with clozapine,” with the caveat that “conclusions are limited by the risk of bias, particularly survivorship bias.”
Preference for clozapine over other antipsychotic medications was reported by 54%-86% of patients in the review, with specific improvements in mood (11%-78%) and cognition (5%-68%).
Clinicians the biggest ‘obstacle’
Dr. Kane notes that an important factor in underutilization could indeed be the manner in which clinicians discuss clozapine with their patients – often opening the discussion by focusing on the negative aspects that, without the context of the potential benefits, can be deal-breakers for patient from the start.
“The clinicians in my opinion are really the obstacle,” Dr. Kane said. “What we always hear from clinicians is ‘I can’t do it because the patient refuses, or the patient doesn’t like the side effects’.”
Dr. Kane notes that most side effects can indeed be managed – regarding the risk for metabolic syndrome, for instance, he recommends that patients should be given metformin from the beginning when they’re started on clozapine.
He adds that in most cases, a 3-month trial is enough to answer the question of whether clozapine is working or not.
“Three months is a good trial, but it may not even tell you the total response to clozapine because that may actually accrue over time,” he said. “We’ve seen patients who actually get better and better beyond 3 months.”
Not offering the drug to patients, however, is doing them a serious disservice, Dr. Kane added.
“What I tell patients and families is that it would be a shame to miss this opportunity for a potential treatment that could be life-changing,” he said. “Does it have potential side effects? Yes. Do you have to get blood tests? Yes. And I can’t tell by evaluating a patient’s history or examining that patient whether or not they’re going to be a good responder. But would you really want to miss an opportunity to find that out?”
“To me the argument is – let’s try this drug for 3 months and see what effect it has, and at that point you’ll be in a much better position to make a decision about the benefits versus risk,” Dr. Kane said.
The only FDA-approved drug for treatment-resistant schizophrenia
Remarkably, clozapine isn’t just the only drug to currently have approval from the FDA for treatment-resistant schizophrenia – it has been for the last 3 decades.
“There have been attempts to develop medications with similar efficacy, but they have not succeeded,” Dr. Kane said in an interview. “We are still uncertain as to what accounts for clozapine’s unique qualities.”
Yet, with treatment-resistant schizophrenia patients representing some of the most dire mental illness cases clinicians may face, the need for better treatment decisions – and additional options – is pressing, Dr. Kane said.
“[The lack of any other drugs] is a big embarrassment to our field, in my opinion,” he said. “I’m a big proponent of clozapine, but we should have found another substance by now that could substitute for clozapine, which obviously has a lot of side effects and is not the easiest drug to use.”
Dr. Kane reported relationships either as a speaker or consultant/advisory board member and/or receives research grant support from Alkermes, Allergan, Click Therapeutics, Dainippon Sumitomo, H. Lundbeck, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Neumora Therapeutics, Novartis Pharmaceuticals, Otsuka, Reviva, Roche, Saladax, Sunovion, Takeda, and Teva. Dr. Kane receives non-mutual funds stock ownership/stock options from LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics, and receives patent holder/royalties paid by UpToDate.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
, and when it is used, the drug is often delayed by several crucial years, reducing chances of efficacy.
“Despite being the only pharmacological therapy approved for treatment-resistant schizophrenia, clozapine is underutilized globally, even in developed countries, where only about 30% of patients who would benefit from the drug receive it,” said John M. Kane, MD, of the department of psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, N.Y., in a presentation on the subject at the 21st Annual Psychopharmacology Update presented by Current Psychiatry and the American Academy of Clinical Psychiatrists in Cincinnati, Ohio.
Clozapine, a tricyclic dibenzodiazepine available in branded and various generic versions, is approved by the U.S. Food and Drug Administration as a third-line therapy for severe, treatment-resistant schizophrenia, with studies showing benefits exceeding those of any other antipsychotics for the indication.
But while recommendations suggest use after a trial of two or more antipsychotics, with at least one being an atypical antipsychotic, one recent review finds delays in clozapine commencement ranging from 19.3 weeks to 5.5 years, and the duration of illness prior to clozapine use ranging from 1.1 to 9.7 years.
Blood monitoring, side effects
The key deterrents preventing many clinicians and patients from trying clozapine sooner are the drug’s safety and tolerability profiles, and notably the requirement of regular blood testing due to an increased risk of agranulocytosis.
Specifically, the blood testing is required every week for 6 months, then every other week for the next 6 months, and then once a month after that; however, “many of us think that that’s excessive at this point in time,” Dr. Kane noted.
Various other potential side effects are also of concern, including myocarditis, seizures, constipation, arrhythmia, hypersalivation, pneumonia, and metabolic symptoms including diabetes.
In terms of the common strategies that clinicians turn to when patients fail to respond to their current antipsychotic, including increasing doses, combining agents, or treatment switching, “none of the strategies likely rival clozapine in terms of efficacy,” Dr. Kane said.
Regarding higher dosing: “There is very little data suggesting that higher doses of antipsychotic drugs will work when the moderate or recommended dose has not worked,” he said.
Combination therapy strategies may provide benefits, but “they’re not a substitute for clozapine,” Dr. Kane added, noting that the combinations that do appear to be the most effective involve clozapine.
And regarding drug switching, studies suggest the likelihood of response in switching from one drug to another is “actually very low,” Dr. Kane added.
Clozapine also doesn’t work for all – the response rate runs between about 30% and 60%, Dr. Kane said, but when it is effective, the benefits can be profound.
“There are some patients who have a very pronounced response to clozapine – some patients describe it as life-changing,” he said.
Treatment delays reduce efficacy
Importantly, the delays before receiving clozapine are not inconsequential – data show that each outpatient antipsychotic trial prior to clozapine reduces the likelihood of response by 8%-11%, and each hospital admission further reduces the likelihood of response by 4%-8%, underscoring the need to identify treatment resistance as early as possible, Dr. Kane said.
“It’s critically important to try to identify treatment resistance earlier than we usually do because if we can get it under control sooner, we have a better chance of improving the patient’s outcome, and this has been shown in a number of studies,” he said.
“The longer you wait, the less likely you are to see a good response even to clozapine.”
Despite the concerns about clozapine, Dr. Kane notes that even the blood monitoring does not appear to be a big complaint for patients, especially they are improving.
“In our experience, the patients who benefit from clozapine don’t really have a problem with the monitoring,” he said.
“In fact, patients who benefit from clozapine are much more adherent to the medication than other patients that we see, which is understandable, because if you feel you’re really getting a benefit from medicine, you’re going to be much more motivated to take it even if it has side effects.”
A recent systematic review of 13 studies and 1,487 patients backs that up, concluding that “patients generally have a favorable experience when being treated with clozapine,” with the caveat that “conclusions are limited by the risk of bias, particularly survivorship bias.”
Preference for clozapine over other antipsychotic medications was reported by 54%-86% of patients in the review, with specific improvements in mood (11%-78%) and cognition (5%-68%).
Clinicians the biggest ‘obstacle’
Dr. Kane notes that an important factor in underutilization could indeed be the manner in which clinicians discuss clozapine with their patients – often opening the discussion by focusing on the negative aspects that, without the context of the potential benefits, can be deal-breakers for patient from the start.
“The clinicians in my opinion are really the obstacle,” Dr. Kane said. “What we always hear from clinicians is ‘I can’t do it because the patient refuses, or the patient doesn’t like the side effects’.”
Dr. Kane notes that most side effects can indeed be managed – regarding the risk for metabolic syndrome, for instance, he recommends that patients should be given metformin from the beginning when they’re started on clozapine.
He adds that in most cases, a 3-month trial is enough to answer the question of whether clozapine is working or not.
“Three months is a good trial, but it may not even tell you the total response to clozapine because that may actually accrue over time,” he said. “We’ve seen patients who actually get better and better beyond 3 months.”
Not offering the drug to patients, however, is doing them a serious disservice, Dr. Kane added.
“What I tell patients and families is that it would be a shame to miss this opportunity for a potential treatment that could be life-changing,” he said. “Does it have potential side effects? Yes. Do you have to get blood tests? Yes. And I can’t tell by evaluating a patient’s history or examining that patient whether or not they’re going to be a good responder. But would you really want to miss an opportunity to find that out?”
“To me the argument is – let’s try this drug for 3 months and see what effect it has, and at that point you’ll be in a much better position to make a decision about the benefits versus risk,” Dr. Kane said.
The only FDA-approved drug for treatment-resistant schizophrenia
Remarkably, clozapine isn’t just the only drug to currently have approval from the FDA for treatment-resistant schizophrenia – it has been for the last 3 decades.
“There have been attempts to develop medications with similar efficacy, but they have not succeeded,” Dr. Kane said in an interview. “We are still uncertain as to what accounts for clozapine’s unique qualities.”
Yet, with treatment-resistant schizophrenia patients representing some of the most dire mental illness cases clinicians may face, the need for better treatment decisions – and additional options – is pressing, Dr. Kane said.
“[The lack of any other drugs] is a big embarrassment to our field, in my opinion,” he said. “I’m a big proponent of clozapine, but we should have found another substance by now that could substitute for clozapine, which obviously has a lot of side effects and is not the easiest drug to use.”
Dr. Kane reported relationships either as a speaker or consultant/advisory board member and/or receives research grant support from Alkermes, Allergan, Click Therapeutics, Dainippon Sumitomo, H. Lundbeck, HLS Therapeutics, Indivior, Intra-Cellular Therapies, Janssen Pharmaceutical, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Neumora Therapeutics, Novartis Pharmaceuticals, Otsuka, Reviva, Roche, Saladax, Sunovion, Takeda, and Teva. Dr. Kane receives non-mutual funds stock ownership/stock options from LB Pharmaceuticals, Vanguard Research Group, and North Shore Therapeutics, and receives patent holder/royalties paid by UpToDate.
The Psychopharmacology Update was sponsored by Medscape Live. Medscape Live and this news organization are owned by the same parent company.
FROM PSYCHOPHARMACOLOGY UPDATE