Psychostimulants, Ketamine Improve Depression Quickly in Hospice

DENVER – Methylphenidate and oral ketamine show considerable promise as extremely rapid-acting, safe, and cost-effective treatments for depression in the hospice setting.

Moreover, early indications are that ketamine might be even more effective as the treatment of anxiety disorders than as an antidepressant in this population nearing end of life, Dr. Scott A. Irwin said at the conference.

This is off-label therapy. But standard antidepressant medications and guideline-recommended treatment algorithms for depression just don’t cut it in the hospice setting. The reason is quite simple: "We don’t have that kind of time," noted Dr. Irwin, director of psychiatry programs at the Institute for Palliative Medicine at San Diego Hospice.

For example, current American Psychiatric Association guidelines for treatment of moderate to severe depression call for 6-8 weeks of antidepressant medication and psychotherapy before switching agents or adding a second one in the event there hasn’t been at least moderate improvement. Patients are then supposed to be monitored for another 6-8 weeks. Yet, the median time in hospice care in the United States is only about 3 weeks. One-third of patients at San Diego Hospice die within the first week.

In one study of more than 1,000 consecutive patients in a palliative care unit, three-quarters of those who were prescribed an antidepressant got the medication only during their last 2 weeks of life. That’s not enough time to allow relief of symptoms, the psychiatrist said.

The prevalence of major depressive disorder in palliative care patients has been estimated at about 15%. No published randomized controlled trials have examined methylphenidate for treatment of such episodes in palliative care settings. But mechanistically, it is sound, Dr. Irwin said, since the psychostimulant blocks reuptake of dopamine in central adrenergic neurons and inhibits reuptake of serotonin and norepinephrine as well, just like standard antidepressants. There have been encouraging review articles, and Dr. Irwin presented his own highly promising retrospective blinded chart review study.

His study included 64 palliative care patients with psychiatrist-diagnosed depressive disorders treated in various ways, with treatment efficacy and side effects evaluated using the Clinical Global Impressions Scale (CGI).

Twenty of 21 methylphenidate-treated patients (95%) were blindly rated as having a significant clinical response, as were 4 of 9 (44%) treated with selective serotonin reuptake inhibitors (SSRIs), 3 of 13 (23%) who received other antidepressants, and 0 of 21 who received usual care alone. The time to response was 4 days with methylphenidate, 10 days with SSRIs, and about 5 days with other antidepressants. Those response times for standard antidepressants are much shorter than expected and require further study, according to Dr. Irwin.

Methylphenidate was blindly rated as significantly more effective than were the nonstimulant antidepressants. The mean score on the CGI 0-4 efficacy scale, in which lower is better, was 2.33 in methylphenidate-treated patients, compared with 3.06 with nonstimulant antidepressants.

On the other hand, side effects were significantly greater with methylphenidate: a mean score of 1.72, compared with 1.13. However, Dr. Irwin characterized side effects in the 1.0-2.0 range on the CGI as being in the "mild and don’t worry about-it" level.

It’s readily apparent within the first day or two if methylphenidate is going to be effective, he continued.

Somatic symptoms, which are very common in palliative care patients, typically improve markedly in methylphenidate-treated patients as their depression improves. However, anxiety increases in a minority of treated patients as depression wanes, sometimes requiring methylphenidate discontinuation, said Dr. Irwin, who is also a faculty psychiatrist at the University of California, San Diego.

He is now conducting a prospective open-label study of methylphenidate in hospice patients having a current major depressive episode. The study employs a flexible dosing schedule with dosing changes on days 3, 7, and 14, and a maximum dose of 20 mg b.i.d. But he finds it extremely challenging to conduct clinical trials in hospice patients because of their high death rate, its unpredictable timing, and informed consent issues.

Turning to ketamine for depression, Dr. Irwin said exciting preliminary evidence in nonhospice patients suggests that a single intravenous infusion of the anesthetic improves depression literally within minutes and that the effect lasts for weeks.

As it turns out, hospice physicians already have long experience using ketamine, not as an antidepressant but for treatment of pain, including cancer pain. They view ketamine as a familiar and inexpensive analgesic that they’re comfortable giving by the oral, subcutaneous, and transdermal routes.

Dr. Irwin is in the midst of conducting an open label pilot study to evaluate the efficacy and tolerability of oral ketamine for the treatment of major depression in hospice patients. Fourteen of a planned 20 patients have completed the 28-day study. The dosing is 0.5 mg/kg of the intravenous ketamine solution mixed in cherry syrup to hide the universally loathed taste. Treatment is once daily.

The therapeutic efficacy has been impressive, as reflected in a drop in average scores on the Hospital Anxiety and Depression Scale from about 20 to 5.

"Interestingly, several patients had diagnosable severe anxiety disorders that went away completely. We’re finding that anxiety may be even more affected by ketamine than depression," Dr. Irwin said.

The high burden of somatic symptoms present in these patients also lightened significantly, with scores on the Adverse Symptom Checklist falling from about 28 to 5. This doesn’t appear to be a result of the drug’s analgesic effect, because some patients didn’t have significant pain, while in others the somatic symptoms improved while pain scores remained unchanged.

Another 30 or so San Diego Hospice patients have received oral ketamine outside of the pilot study, with similar benefits.

"We’ve gone to nightly dosing. And if you see a decrement in benefit, bump up the dose by 20%," Dr. Irwin advised in response to audience questions.

He called depression near the end of life a major yet widely underappreciated public health problem. The consequences of untreated depression in these patients include longer inpatient hospital stays, worsening medical illness, greater difficulty in treating pain and nausea, and interference with making preparations for death. Untreated depression also impedes interactions with caregivers and, most importantly, with loved ones.

Dr. Irwin recalled one of the first hospice patients for whom he prescribed methylphenidate. After 24 hours on treatment, the man no longer met criteria for major depressive disorder. He lived for another week with newly restored enjoyment of nature and his family. Dr. Irwin learned of his death when he ran into the patient’s daughter in the parking lot.

"She said, ‘I want to thank you for giving me my father back. I will now remember him as the great man he always was, and not the miserable man that he’d become for the last 6 months,’ "

Dr. Irwin said. "So we changed her life for decades.

"If anyone asks you, ‘Why bother treating depression in hospice when you’re only changing the last few days?’ tell them it’s a family experience. It’s not just about the patient."

He reported having no financial conflicts.

DENVER – Methylphenidate and oral ketamine show considerable promise as extremely rapid-acting, safe, and cost-effective treatments for depression in the hospice setting.

Moreover, early indications are that ketamine might be even more effective as the treatment of anxiety disorders than as an antidepressant in this population nearing end of life, Dr. Scott A. Irwin said at the conference.

This is off-label therapy. But standard antidepressant medications and guideline-recommended treatment algorithms for depression just don’t cut it in the hospice setting. The reason is quite simple: "We don’t have that kind of time," noted Dr. Irwin, director of psychiatry programs at the Institute for Palliative Medicine at San Diego Hospice.

For example, current American Psychiatric Association guidelines for treatment of moderate to severe depression call for 6-8 weeks of antidepressant medication and psychotherapy before switching agents or adding a second one in the event there hasn’t been at least moderate improvement. Patients are then supposed to be monitored for another 6-8 weeks. Yet, the median time in hospice care in the United States is only about 3 weeks. One-third of patients at San Diego Hospice die within the first week.

In one study of more than 1,000 consecutive patients in a palliative care unit, three-quarters of those who were prescribed an antidepressant got the medication only during their last 2 weeks of life. That’s not enough time to allow relief of symptoms, the psychiatrist said.

The prevalence of major depressive disorder in palliative care patients has been estimated at about 15%. No published randomized controlled trials have examined methylphenidate for treatment of such episodes in palliative care settings. But mechanistically, it is sound, Dr. Irwin said, since the psychostimulant blocks reuptake of dopamine in central adrenergic neurons and inhibits reuptake of serotonin and norepinephrine as well, just like standard antidepressants. There have been encouraging review articles, and Dr. Irwin presented his own highly promising retrospective blinded chart review study.

His study included 64 palliative care patients with psychiatrist-diagnosed depressive disorders treated in various ways, with treatment efficacy and side effects evaluated using the Clinical Global Impressions Scale (CGI).

Twenty of 21 methylphenidate-treated patients (95%) were blindly rated as having a significant clinical response, as were 4 of 9 (44%) treated with selective serotonin reuptake inhibitors (SSRIs), 3 of 13 (23%) who received other antidepressants, and 0 of 21 who received usual care alone. The time to response was 4 days with methylphenidate, 10 days with SSRIs, and about 5 days with other antidepressants. Those response times for standard antidepressants are much shorter than expected and require further study, according to Dr. Irwin.

Methylphenidate was blindly rated as significantly more effective than were the nonstimulant antidepressants. The mean score on the CGI 0-4 efficacy scale, in which lower is better, was 2.33 in methylphenidate-treated patients, compared with 3.06 with nonstimulant antidepressants.

On the other hand, side effects were significantly greater with methylphenidate: a mean score of 1.72, compared with 1.13. However, Dr. Irwin characterized side effects in the 1.0-2.0 range on the CGI as being in the "mild and don’t worry about-it" level.

It’s readily apparent within the first day or two if methylphenidate is going to be effective, he continued.

Somatic symptoms, which are very common in palliative care patients, typically improve markedly in methylphenidate-treated patients as their depression improves. However, anxiety increases in a minority of treated patients as depression wanes, sometimes requiring methylphenidate discontinuation, said Dr. Irwin, who is also a faculty psychiatrist at the University of California, San Diego.

He is now conducting a prospective open-label study of methylphenidate in hospice patients having a current major depressive episode. The study employs a flexible dosing schedule with dosing changes on days 3, 7, and 14, and a maximum dose of 20 mg b.i.d. But he finds it extremely challenging to conduct clinical trials in hospice patients because of their high death rate, its unpredictable timing, and informed consent issues.

Turning to ketamine for depression, Dr. Irwin said exciting preliminary evidence in nonhospice patients suggests that a single intravenous infusion of the anesthetic improves depression literally within minutes and that the effect lasts for weeks.

As it turns out, hospice physicians already have long experience using ketamine, not as an antidepressant but for treatment of pain, including cancer pain. They view ketamine as a familiar and inexpensive analgesic that they’re comfortable giving by the oral, subcutaneous, and transdermal routes.

Dr. Irwin is in the midst of conducting an open label pilot study to evaluate the efficacy and tolerability of oral ketamine for the treatment of major depression in hospice patients. Fourteen of a planned 20 patients have completed the 28-day study. The dosing is 0.5 mg/kg of the intravenous ketamine solution mixed in cherry syrup to hide the universally loathed taste. Treatment is once daily.

The therapeutic efficacy has been impressive, as reflected in a drop in average scores on the Hospital Anxiety and Depression Scale from about 20 to 5.

"Interestingly, several patients had diagnosable severe anxiety disorders that went away completely. We’re finding that anxiety may be even more affected by ketamine than depression," Dr. Irwin said.

The high burden of somatic symptoms present in these patients also lightened significantly, with scores on the Adverse Symptom Checklist falling from about 28 to 5. This doesn’t appear to be a result of the drug’s analgesic effect, because some patients didn’t have significant pain, while in others the somatic symptoms improved while pain scores remained unchanged.

Another 30 or so San Diego Hospice patients have received oral ketamine outside of the pilot study, with similar benefits.

"We’ve gone to nightly dosing. And if you see a decrement in benefit, bump up the dose by 20%," Dr. Irwin advised in response to audience questions.

He called depression near the end of life a major yet widely underappreciated public health problem. The consequences of untreated depression in these patients include longer inpatient hospital stays, worsening medical illness, greater difficulty in treating pain and nausea, and interference with making preparations for death. Untreated depression also impedes interactions with caregivers and, most importantly, with loved ones.

Dr. Irwin recalled one of the first hospice patients for whom he prescribed methylphenidate. After 24 hours on treatment, the man no longer met criteria for major depressive disorder. He lived for another week with newly restored enjoyment of nature and his family. Dr. Irwin learned of his death when he ran into the patient’s daughter in the parking lot.

"She said, ‘I want to thank you for giving me my father back. I will now remember him as the great man he always was, and not the miserable man that he’d become for the last 6 months,’ "

Dr. Irwin said. "So we changed her life for decades.

"If anyone asks you, ‘Why bother treating depression in hospice when you’re only changing the last few days?’ tell them it’s a family experience. It’s not just about the patient."

He reported having no financial conflicts.

DENVER – Methylphenidate and oral ketamine show considerable promise as extremely rapid-acting, safe, and cost-effective treatments for depression in the hospice setting.

Moreover, early indications are that ketamine might be even more effective as the treatment of anxiety disorders than as an antidepressant in this population nearing end of life, Dr. Scott A. Irwin said at the conference.

This is off-label therapy. But standard antidepressant medications and guideline-recommended treatment algorithms for depression just don’t cut it in the hospice setting. The reason is quite simple: "We don’t have that kind of time," noted Dr. Irwin, director of psychiatry programs at the Institute for Palliative Medicine at San Diego Hospice.

For example, current American Psychiatric Association guidelines for treatment of moderate to severe depression call for 6-8 weeks of antidepressant medication and psychotherapy before switching agents or adding a second one in the event there hasn’t been at least moderate improvement. Patients are then supposed to be monitored for another 6-8 weeks. Yet, the median time in hospice care in the United States is only about 3 weeks. One-third of patients at San Diego Hospice die within the first week.

In one study of more than 1,000 consecutive patients in a palliative care unit, three-quarters of those who were prescribed an antidepressant got the medication only during their last 2 weeks of life. That’s not enough time to allow relief of symptoms, the psychiatrist said.

The prevalence of major depressive disorder in palliative care patients has been estimated at about 15%. No published randomized controlled trials have examined methylphenidate for treatment of such episodes in palliative care settings. But mechanistically, it is sound, Dr. Irwin said, since the psychostimulant blocks reuptake of dopamine in central adrenergic neurons and inhibits reuptake of serotonin and norepinephrine as well, just like standard antidepressants. There have been encouraging review articles, and Dr. Irwin presented his own highly promising retrospective blinded chart review study.

His study included 64 palliative care patients with psychiatrist-diagnosed depressive disorders treated in various ways, with treatment efficacy and side effects evaluated using the Clinical Global Impressions Scale (CGI).

Twenty of 21 methylphenidate-treated patients (95%) were blindly rated as having a significant clinical response, as were 4 of 9 (44%) treated with selective serotonin reuptake inhibitors (SSRIs), 3 of 13 (23%) who received other antidepressants, and 0 of 21 who received usual care alone. The time to response was 4 days with methylphenidate, 10 days with SSRIs, and about 5 days with other antidepressants. Those response times for standard antidepressants are much shorter than expected and require further study, according to Dr. Irwin.

Methylphenidate was blindly rated as significantly more effective than were the nonstimulant antidepressants. The mean score on the CGI 0-4 efficacy scale, in which lower is better, was 2.33 in methylphenidate-treated patients, compared with 3.06 with nonstimulant antidepressants.

On the other hand, side effects were significantly greater with methylphenidate: a mean score of 1.72, compared with 1.13. However, Dr. Irwin characterized side effects in the 1.0-2.0 range on the CGI as being in the "mild and don’t worry about-it" level.

It’s readily apparent within the first day or two if methylphenidate is going to be effective, he continued.

Somatic symptoms, which are very common in palliative care patients, typically improve markedly in methylphenidate-treated patients as their depression improves. However, anxiety increases in a minority of treated patients as depression wanes, sometimes requiring methylphenidate discontinuation, said Dr. Irwin, who is also a faculty psychiatrist at the University of California, San Diego.

He is now conducting a prospective open-label study of methylphenidate in hospice patients having a current major depressive episode. The study employs a flexible dosing schedule with dosing changes on days 3, 7, and 14, and a maximum dose of 20 mg b.i.d. But he finds it extremely challenging to conduct clinical trials in hospice patients because of their high death rate, its unpredictable timing, and informed consent issues.

Turning to ketamine for depression, Dr. Irwin said exciting preliminary evidence in nonhospice patients suggests that a single intravenous infusion of the anesthetic improves depression literally within minutes and that the effect lasts for weeks.

As it turns out, hospice physicians already have long experience using ketamine, not as an antidepressant but for treatment of pain, including cancer pain. They view ketamine as a familiar and inexpensive analgesic that they’re comfortable giving by the oral, subcutaneous, and transdermal routes.

Dr. Irwin is in the midst of conducting an open label pilot study to evaluate the efficacy and tolerability of oral ketamine for the treatment of major depression in hospice patients. Fourteen of a planned 20 patients have completed the 28-day study. The dosing is 0.5 mg/kg of the intravenous ketamine solution mixed in cherry syrup to hide the universally loathed taste. Treatment is once daily.

The therapeutic efficacy has been impressive, as reflected in a drop in average scores on the Hospital Anxiety and Depression Scale from about 20 to 5.

"Interestingly, several patients had diagnosable severe anxiety disorders that went away completely. We’re finding that anxiety may be even more affected by ketamine than depression," Dr. Irwin said.

The high burden of somatic symptoms present in these patients also lightened significantly, with scores on the Adverse Symptom Checklist falling from about 28 to 5. This doesn’t appear to be a result of the drug’s analgesic effect, because some patients didn’t have significant pain, while in others the somatic symptoms improved while pain scores remained unchanged.

Another 30 or so San Diego Hospice patients have received oral ketamine outside of the pilot study, with similar benefits.

"We’ve gone to nightly dosing. And if you see a decrement in benefit, bump up the dose by 20%," Dr. Irwin advised in response to audience questions.

He called depression near the end of life a major yet widely underappreciated public health problem. The consequences of untreated depression in these patients include longer inpatient hospital stays, worsening medical illness, greater difficulty in treating pain and nausea, and interference with making preparations for death. Untreated depression also impedes interactions with caregivers and, most importantly, with loved ones.

Dr. Irwin recalled one of the first hospice patients for whom he prescribed methylphenidate. After 24 hours on treatment, the man no longer met criteria for major depressive disorder. He lived for another week with newly restored enjoyment of nature and his family. Dr. Irwin learned of his death when he ran into the patient’s daughter in the parking lot.

"She said, ‘I want to thank you for giving me my father back. I will now remember him as the great man he always was, and not the miserable man that he’d become for the last 6 months,’ "

Dr. Irwin said. "So we changed her life for decades.

"If anyone asks you, ‘Why bother treating depression in hospice when you’re only changing the last few days?’ tell them it’s a family experience. It’s not just about the patient."

He reported having no financial conflicts.