ASCP 2016

SCOTTSDALE, ARIZ. – A sublingual formulation of cyclobenzaprine taken at bedtime was significantly better than placebo at reducing symptoms of military-related posttraumatic stress disorder, and study participants taking cyclobenzaprine also reported better sleep, a study showed.

After 12 weeks of nightly use at bedtime, 5.6 mg of sublingual cyclobenzaprine (CBP) resulted in a significant reduction on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), compared with placebo. Under several different analytic and data imputation methods, CAPS-5 values improved by 20.2 to 22.6 points from baseline for the 5.6-mg group, compared with reductions of 17.4 to 20.6 for the placebo group (P value range, 0.038-0.016). Improvement in the CAPS-5 was the study’s primary efficacy outcome measure.

Patients also saw significantly improved global symptoms, as assessed by the Clinician Global Impression – Improvement scale (CGI-I; 63.3% responders cyclobenzaprine versus 44.6% placebo, P = 0.041).

Significant reductions in hyperarousal (P less than 0.05) and exaggerated startle (P =0.015) symptoms also were seen in the 5.6-mg cyclobenzaprine group, and those participants also had significantly less symptom-related disruption in work/school, and in social/leisure activities, as measured by those domains on the Sheehan Disability Scale (for both, P less than 0.050).

Gregory M. Sullivan, MD, chief medical officer of Tonix Pharmaceuticals, presented these findings from AtEase, a randomized, placebo-controlled, double-blind study of sublingual cyclobenzaprine for military PTSD, at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Drug Clinical Evaluation Unit meeting.

The phase II safety, efficacy, and dose-ranging study of 245 patients (231 in the modified intent-to-treat population, and 237 in the safety population) also compared 2.8- and 5.6-mg sublingual doses. At the end of the 12-week study period, those on the lower dose did not experience significantly improved sleep or PTSD symptoms.

The AtEase participants were current or former servicemembers with PTSD. Ninety-three percent of the patients were male and had been deployed an average of 2.3 times. The index trauma occurred a mean of 7 years ago. Demographic distribution was representative of the U.S. military, according to Dr. Sullivan. The mean CAPS-5 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were similar across treatment arms. The mean CAPS-5 score for participants in the study was 39.5 representing “severe” PTSD. “These people are quite ill,” said Seth Lederman, MD, Tonix CEO, in an interview.

Oral symptoms were the most frequent side effects reported in the safety analysis. Of those taking the 2.8-mg cyclobenzaprine dose, 38.7% (36/93) experienced oral hypoesthesia, as did 36% (18/50) of the 5.6-mg dosing group. This compared with 2.1% (2/94) of the placebo group. Somnolence was noted by 11.8% (11/93) of the lower dose group, by 16% (8/50) of the higher dose group, and by 6.4% (6/94) of the placebo group. No participants discontinued the study because of adverse events.

Military traumatic brain injury may be different from most civilian TBI, said Dr. Lederman, because of both the intensity and duration of the events that precipitated the condition. Most military-related trauma stems from combat, and most patients with military-related trauma are men; in the civilian population, PTSD patients are predominantly women. “Especially in today’s military, servicemembers are deploying multiple times,” he noted. “Everyone has their breaking point.”

Effective medical treatments for military PTSD are lacking, said Dr. Sullivan. One multicenter trial found that sertraline not effective for PTSD in military veterans (J Clin Psychiatry. 2007 May;68[5]:711-20), and selective serotonin reuptake inhibitors are associated with sexual dysfunction and insomnia for some patients.

Cyclobenzaprine is thought to interact with several receptors thought to be important for sleep, including 5-HT2A, alpha-1 adrenergic, and H1 histamine receptors.

Problems with sleep for individuals with PTSD may include nightmares, as well as sleep disturbances associated with the hyperarousal that characterizes the disorder. Sleep disruption may contribute to “attenuated extinction consolidation, or a delay in the processing of emotionally charged memories,” Dr. Sullivan said. Sleep disturbances in those with PTSD also are associated with depression, substance use disorders, and suicidal behavior.

“Processing memories is an essential part of learning and extinction,” Dr. Lederman said. “We saw startle improve” in the clinical trial of sublingual cyclobenzaprine, an indication of diminished hyperarousal, he said.

The sublingual formulation, said Dr. Lederman, avoids first-pass metabolism of cyclobenzaprine, which converts large amounts of the dose to norcyclobenzaprine. This metabolite has a much longer half-life than cyclobenzaprine and is responsible, in large part, for the persistent grogginess many patients report when taking the oral formulation of the medication. Previous work showed that the exposure ratio for cyclobenzaprine/norcyclobenzaprine for oral immediate-release cyclobenzaprine was 1.2, compared with 1.9 for sublingual cyclobenzaprine

“With the sublingual formulation, we hope to achieve a true ‘on-off’ effect, really helping sleep quality and improving sleep architecture,” Dr. Lederman said.

“Early effects on sleep and hyperarousal are consistent with the mechanistic hypothesis that TNX-102 SL’s primary actions on sleep architecture and autonomic balance underlie the observed PTSD treatment effect,” wrote Dr. Sullivan. The later reduction in exaggerated startle is consistent with the memory consolidation hypothesis, he said.

Sublingual cyclobenzaprine also is being trialed for fibromyalgia, another condition where significant sleep disruption can be a prominent symptom. Next steps for military PTSD include a larger clinical trial that plans to enroll 450 patients, said Dr. Lederman.

Dr. Lederman and Dr. Sullivan are both employed by Tonix Pharmaceuticals, which was the sponsor of the AtEase study.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – A sublingual formulation of cyclobenzaprine taken at bedtime was significantly better than placebo at reducing symptoms of military-related posttraumatic stress disorder, and study participants taking cyclobenzaprine also reported better sleep, a study showed.

After 12 weeks of nightly use at bedtime, 5.6 mg of sublingual cyclobenzaprine (CBP) resulted in a significant reduction on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), compared with placebo. Under several different analytic and data imputation methods, CAPS-5 values improved by 20.2 to 22.6 points from baseline for the 5.6-mg group, compared with reductions of 17.4 to 20.6 for the placebo group (P value range, 0.038-0.016). Improvement in the CAPS-5 was the study’s primary efficacy outcome measure.

Patients also saw significantly improved global symptoms, as assessed by the Clinician Global Impression – Improvement scale (CGI-I; 63.3% responders cyclobenzaprine versus 44.6% placebo, P = 0.041).

Significant reductions in hyperarousal (P less than 0.05) and exaggerated startle (P =0.015) symptoms also were seen in the 5.6-mg cyclobenzaprine group, and those participants also had significantly less symptom-related disruption in work/school, and in social/leisure activities, as measured by those domains on the Sheehan Disability Scale (for both, P less than 0.050).

Gregory M. Sullivan, MD, chief medical officer of Tonix Pharmaceuticals, presented these findings from AtEase, a randomized, placebo-controlled, double-blind study of sublingual cyclobenzaprine for military PTSD, at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Drug Clinical Evaluation Unit meeting.

The phase II safety, efficacy, and dose-ranging study of 245 patients (231 in the modified intent-to-treat population, and 237 in the safety population) also compared 2.8- and 5.6-mg sublingual doses. At the end of the 12-week study period, those on the lower dose did not experience significantly improved sleep or PTSD symptoms.

The AtEase participants were current or former servicemembers with PTSD. Ninety-three percent of the patients were male and had been deployed an average of 2.3 times. The index trauma occurred a mean of 7 years ago. Demographic distribution was representative of the U.S. military, according to Dr. Sullivan. The mean CAPS-5 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were similar across treatment arms. The mean CAPS-5 score for participants in the study was 39.5 representing “severe” PTSD. “These people are quite ill,” said Seth Lederman, MD, Tonix CEO, in an interview.

Oral symptoms were the most frequent side effects reported in the safety analysis. Of those taking the 2.8-mg cyclobenzaprine dose, 38.7% (36/93) experienced oral hypoesthesia, as did 36% (18/50) of the 5.6-mg dosing group. This compared with 2.1% (2/94) of the placebo group. Somnolence was noted by 11.8% (11/93) of the lower dose group, by 16% (8/50) of the higher dose group, and by 6.4% (6/94) of the placebo group. No participants discontinued the study because of adverse events.

Military traumatic brain injury may be different from most civilian TBI, said Dr. Lederman, because of both the intensity and duration of the events that precipitated the condition. Most military-related trauma stems from combat, and most patients with military-related trauma are men; in the civilian population, PTSD patients are predominantly women. “Especially in today’s military, servicemembers are deploying multiple times,” he noted. “Everyone has their breaking point.”

Effective medical treatments for military PTSD are lacking, said Dr. Sullivan. One multicenter trial found that sertraline not effective for PTSD in military veterans (J Clin Psychiatry. 2007 May;68[5]:711-20), and selective serotonin reuptake inhibitors are associated with sexual dysfunction and insomnia for some patients.

Cyclobenzaprine is thought to interact with several receptors thought to be important for sleep, including 5-HT2A, alpha-1 adrenergic, and H1 histamine receptors.

Problems with sleep for individuals with PTSD may include nightmares, as well as sleep disturbances associated with the hyperarousal that characterizes the disorder. Sleep disruption may contribute to “attenuated extinction consolidation, or a delay in the processing of emotionally charged memories,” Dr. Sullivan said. Sleep disturbances in those with PTSD also are associated with depression, substance use disorders, and suicidal behavior.

“Processing memories is an essential part of learning and extinction,” Dr. Lederman said. “We saw startle improve” in the clinical trial of sublingual cyclobenzaprine, an indication of diminished hyperarousal, he said.

The sublingual formulation, said Dr. Lederman, avoids first-pass metabolism of cyclobenzaprine, which converts large amounts of the dose to norcyclobenzaprine. This metabolite has a much longer half-life than cyclobenzaprine and is responsible, in large part, for the persistent grogginess many patients report when taking the oral formulation of the medication. Previous work showed that the exposure ratio for cyclobenzaprine/norcyclobenzaprine for oral immediate-release cyclobenzaprine was 1.2, compared with 1.9 for sublingual cyclobenzaprine

“With the sublingual formulation, we hope to achieve a true ‘on-off’ effect, really helping sleep quality and improving sleep architecture,” Dr. Lederman said.

“Early effects on sleep and hyperarousal are consistent with the mechanistic hypothesis that TNX-102 SL’s primary actions on sleep architecture and autonomic balance underlie the observed PTSD treatment effect,” wrote Dr. Sullivan. The later reduction in exaggerated startle is consistent with the memory consolidation hypothesis, he said.

Sublingual cyclobenzaprine also is being trialed for fibromyalgia, another condition where significant sleep disruption can be a prominent symptom. Next steps for military PTSD include a larger clinical trial that plans to enroll 450 patients, said Dr. Lederman.

Dr. Lederman and Dr. Sullivan are both employed by Tonix Pharmaceuticals, which was the sponsor of the AtEase study.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – A sublingual formulation of cyclobenzaprine taken at bedtime was significantly better than placebo at reducing symptoms of military-related posttraumatic stress disorder, and study participants taking cyclobenzaprine also reported better sleep, a study showed.

After 12 weeks of nightly use at bedtime, 5.6 mg of sublingual cyclobenzaprine (CBP) resulted in a significant reduction on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), compared with placebo. Under several different analytic and data imputation methods, CAPS-5 values improved by 20.2 to 22.6 points from baseline for the 5.6-mg group, compared with reductions of 17.4 to 20.6 for the placebo group (P value range, 0.038-0.016). Improvement in the CAPS-5 was the study’s primary efficacy outcome measure.

Patients also saw significantly improved global symptoms, as assessed by the Clinician Global Impression – Improvement scale (CGI-I; 63.3% responders cyclobenzaprine versus 44.6% placebo, P = 0.041).

Significant reductions in hyperarousal (P less than 0.05) and exaggerated startle (P =0.015) symptoms also were seen in the 5.6-mg cyclobenzaprine group, and those participants also had significantly less symptom-related disruption in work/school, and in social/leisure activities, as measured by those domains on the Sheehan Disability Scale (for both, P less than 0.050).

Gregory M. Sullivan, MD, chief medical officer of Tonix Pharmaceuticals, presented these findings from AtEase, a randomized, placebo-controlled, double-blind study of sublingual cyclobenzaprine for military PTSD, at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Drug Clinical Evaluation Unit meeting.

The phase II safety, efficacy, and dose-ranging study of 245 patients (231 in the modified intent-to-treat population, and 237 in the safety population) also compared 2.8- and 5.6-mg sublingual doses. At the end of the 12-week study period, those on the lower dose did not experience significantly improved sleep or PTSD symptoms.

The AtEase participants were current or former servicemembers with PTSD. Ninety-three percent of the patients were male and had been deployed an average of 2.3 times. The index trauma occurred a mean of 7 years ago. Demographic distribution was representative of the U.S. military, according to Dr. Sullivan. The mean CAPS-5 and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were similar across treatment arms. The mean CAPS-5 score for participants in the study was 39.5 representing “severe” PTSD. “These people are quite ill,” said Seth Lederman, MD, Tonix CEO, in an interview.

Oral symptoms were the most frequent side effects reported in the safety analysis. Of those taking the 2.8-mg cyclobenzaprine dose, 38.7% (36/93) experienced oral hypoesthesia, as did 36% (18/50) of the 5.6-mg dosing group. This compared with 2.1% (2/94) of the placebo group. Somnolence was noted by 11.8% (11/93) of the lower dose group, by 16% (8/50) of the higher dose group, and by 6.4% (6/94) of the placebo group. No participants discontinued the study because of adverse events.

Military traumatic brain injury may be different from most civilian TBI, said Dr. Lederman, because of both the intensity and duration of the events that precipitated the condition. Most military-related trauma stems from combat, and most patients with military-related trauma are men; in the civilian population, PTSD patients are predominantly women. “Especially in today’s military, servicemembers are deploying multiple times,” he noted. “Everyone has their breaking point.”

Effective medical treatments for military PTSD are lacking, said Dr. Sullivan. One multicenter trial found that sertraline not effective for PTSD in military veterans (J Clin Psychiatry. 2007 May;68[5]:711-20), and selective serotonin reuptake inhibitors are associated with sexual dysfunction and insomnia for some patients.

Cyclobenzaprine is thought to interact with several receptors thought to be important for sleep, including 5-HT2A, alpha-1 adrenergic, and H1 histamine receptors.

Problems with sleep for individuals with PTSD may include nightmares, as well as sleep disturbances associated with the hyperarousal that characterizes the disorder. Sleep disruption may contribute to “attenuated extinction consolidation, or a delay in the processing of emotionally charged memories,” Dr. Sullivan said. Sleep disturbances in those with PTSD also are associated with depression, substance use disorders, and suicidal behavior.

“Processing memories is an essential part of learning and extinction,” Dr. Lederman said. “We saw startle improve” in the clinical trial of sublingual cyclobenzaprine, an indication of diminished hyperarousal, he said.

The sublingual formulation, said Dr. Lederman, avoids first-pass metabolism of cyclobenzaprine, which converts large amounts of the dose to norcyclobenzaprine. This metabolite has a much longer half-life than cyclobenzaprine and is responsible, in large part, for the persistent grogginess many patients report when taking the oral formulation of the medication. Previous work showed that the exposure ratio for cyclobenzaprine/norcyclobenzaprine for oral immediate-release cyclobenzaprine was 1.2, compared with 1.9 for sublingual cyclobenzaprine

“With the sublingual formulation, we hope to achieve a true ‘on-off’ effect, really helping sleep quality and improving sleep architecture,” Dr. Lederman said.

“Early effects on sleep and hyperarousal are consistent with the mechanistic hypothesis that TNX-102 SL’s primary actions on sleep architecture and autonomic balance underlie the observed PTSD treatment effect,” wrote Dr. Sullivan. The later reduction in exaggerated startle is consistent with the memory consolidation hypothesis, he said.

Sublingual cyclobenzaprine also is being trialed for fibromyalgia, another condition where significant sleep disruption can be a prominent symptom. Next steps for military PTSD include a larger clinical trial that plans to enroll 450 patients, said Dr. Lederman.

Dr. Lederman and Dr. Sullivan are both employed by Tonix Pharmaceuticals, which was the sponsor of the AtEase study.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – Simple, effective, nonpharmacologic therapies can significantly augment pharmacotherapy for patients with treatment-resistant depression, according to Dr. Mark Hyman Rapaport.

More complex complementary approaches are being explored and may hold promise as part of the future of precision medicine, but well-tested strategies can still help many patients, he said.

Speaking at a session focused on treatment-resistant depression at a meeting of the American Society of Clinical Psychopharmacology, Dr. Rapaport, chairman of the department of psychiatry and behavioral sciences and Reunette W. Harris Professor at Emory University, Atlanta, began with the basics.

Citing a recent meta-analysis examining the way in which exercise works as a treatment for depression, Dr. Rapaport said, “looking at the world’s literature in a very thoughtful way, [the meta-analysis] did demonstrate a significant effect for aerobic exercise in decreasing signs and symptoms of depression.” The meta-analysis, he said, found that exercise provided the equivalent of a 5.07-point improvement on the Hamilton Rating Scale for Depression (HAM-D) (P = .0007). “I think it is something we should encourage our patients to use,” he said.

Similarly, though the treatments “have fallen out of favor,” Dr. Rapaport said “meta-analyses clearly demonstrate” a significant effect of bright white light (BL) therapy in seasonal affective disorder, both as monotherapy and in combination with antidepressants. The light should be dosed at 5000 lux or more for 1 hour daily.

Further, said Dr. Rapaport, BL as monotherapy or used in combination with antidepressants, or with sleep deprivation can be moderately effective in treating major depressive disorder. “It’s something to consider. We do not use it; we should use it,” Dr. Rapaport said. For patients with bipolar disorder, BL therapy can effectively augment medication use as well.

Focused, intensive treatment with light and sleep adjustments can be effective in both bipolar depression and treatment-resistant depression, Dr. Rapaport said. This approach, termed “adjunctive triple chronotherapy,” begins with total sleep deprivation for a period of 33-36 hours. Then, the patient receives BL therapy at 5,000 lux for at least 1 hour for 3 consecutive nights. Finally, patients are asked to advance their sleep phase for 3 days so that they sleep from 6 p.m. to 1 a.m. the 1st night, 8 p.m. to 3 a.m. the 2nd night, and 10 p.m. to 5 a.m. the 3rd night.

The triple chronotherapy approach, said Dr. Rapaport, results in a “rapid and sustained response, both in unipolar and bipolar depression, in the studies that have been done to date.”

Massage can effectively improve mood for individuals with depression as well. In a study of HIV-positive individuals with major depressive disorder and on stable medication, those who received weekly massage had a 33% decrease in HAM-D scores, compared with a 12% increase for those receiving light touch, and a 9% decrease for those on a wait list who received neither touch nor massage (P less than .05). The response rate of 40% for those receiving massage also was significantly higher than the 6.3% for those receiving light touch and the 14% for those on the wait list (P less than .05).

Recently completed unpublished work by Dr. Rapaport and his colleagues involving patients with generalized anxiety disorder also showed significantly greater improvement on a self-rating scale for anxiety for those receiving twice-weekly Swedish massage therapy, compared with those receiving light touch.

“Our patients – their symptoms aren’t just what we see on the monitors – they deal with quality of life, they deal with functioning,” said Dr. Rapaport, “so there are many things that we as clinicians need to look at,” he said at the meeting. “The key is this: There’s a slowly increasing but limited data set for [treatment-resistant depression]. We need to find the right treatments for the right subjects. “

The ASCP meeting was formerly known as the New Clinical Drug Evaluation Unit meeting. Dr. Rapaport reported no relevant financial conflicts.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – Simple, effective, nonpharmacologic therapies can significantly augment pharmacotherapy for patients with treatment-resistant depression, according to Dr. Mark Hyman Rapaport.

More complex complementary approaches are being explored and may hold promise as part of the future of precision medicine, but well-tested strategies can still help many patients, he said.

Speaking at a session focused on treatment-resistant depression at a meeting of the American Society of Clinical Psychopharmacology, Dr. Rapaport, chairman of the department of psychiatry and behavioral sciences and Reunette W. Harris Professor at Emory University, Atlanta, began with the basics.

Citing a recent meta-analysis examining the way in which exercise works as a treatment for depression, Dr. Rapaport said, “looking at the world’s literature in a very thoughtful way, [the meta-analysis] did demonstrate a significant effect for aerobic exercise in decreasing signs and symptoms of depression.” The meta-analysis, he said, found that exercise provided the equivalent of a 5.07-point improvement on the Hamilton Rating Scale for Depression (HAM-D) (P = .0007). “I think it is something we should encourage our patients to use,” he said.

Similarly, though the treatments “have fallen out of favor,” Dr. Rapaport said “meta-analyses clearly demonstrate” a significant effect of bright white light (BL) therapy in seasonal affective disorder, both as monotherapy and in combination with antidepressants. The light should be dosed at 5000 lux or more for 1 hour daily.

Further, said Dr. Rapaport, BL as monotherapy or used in combination with antidepressants, or with sleep deprivation can be moderately effective in treating major depressive disorder. “It’s something to consider. We do not use it; we should use it,” Dr. Rapaport said. For patients with bipolar disorder, BL therapy can effectively augment medication use as well.

Focused, intensive treatment with light and sleep adjustments can be effective in both bipolar depression and treatment-resistant depression, Dr. Rapaport said. This approach, termed “adjunctive triple chronotherapy,” begins with total sleep deprivation for a period of 33-36 hours. Then, the patient receives BL therapy at 5,000 lux for at least 1 hour for 3 consecutive nights. Finally, patients are asked to advance their sleep phase for 3 days so that they sleep from 6 p.m. to 1 a.m. the 1st night, 8 p.m. to 3 a.m. the 2nd night, and 10 p.m. to 5 a.m. the 3rd night.

The triple chronotherapy approach, said Dr. Rapaport, results in a “rapid and sustained response, both in unipolar and bipolar depression, in the studies that have been done to date.”

Massage can effectively improve mood for individuals with depression as well. In a study of HIV-positive individuals with major depressive disorder and on stable medication, those who received weekly massage had a 33% decrease in HAM-D scores, compared with a 12% increase for those receiving light touch, and a 9% decrease for those on a wait list who received neither touch nor massage (P less than .05). The response rate of 40% for those receiving massage also was significantly higher than the 6.3% for those receiving light touch and the 14% for those on the wait list (P less than .05).

Recently completed unpublished work by Dr. Rapaport and his colleagues involving patients with generalized anxiety disorder also showed significantly greater improvement on a self-rating scale for anxiety for those receiving twice-weekly Swedish massage therapy, compared with those receiving light touch.

“Our patients – their symptoms aren’t just what we see on the monitors – they deal with quality of life, they deal with functioning,” said Dr. Rapaport, “so there are many things that we as clinicians need to look at,” he said at the meeting. “The key is this: There’s a slowly increasing but limited data set for [treatment-resistant depression]. We need to find the right treatments for the right subjects. “

The ASCP meeting was formerly known as the New Clinical Drug Evaluation Unit meeting. Dr. Rapaport reported no relevant financial conflicts.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – Simple, effective, nonpharmacologic therapies can significantly augment pharmacotherapy for patients with treatment-resistant depression, according to Dr. Mark Hyman Rapaport.

More complex complementary approaches are being explored and may hold promise as part of the future of precision medicine, but well-tested strategies can still help many patients, he said.

Speaking at a session focused on treatment-resistant depression at a meeting of the American Society of Clinical Psychopharmacology, Dr. Rapaport, chairman of the department of psychiatry and behavioral sciences and Reunette W. Harris Professor at Emory University, Atlanta, began with the basics.

Citing a recent meta-analysis examining the way in which exercise works as a treatment for depression, Dr. Rapaport said, “looking at the world’s literature in a very thoughtful way, [the meta-analysis] did demonstrate a significant effect for aerobic exercise in decreasing signs and symptoms of depression.” The meta-analysis, he said, found that exercise provided the equivalent of a 5.07-point improvement on the Hamilton Rating Scale for Depression (HAM-D) (P = .0007). “I think it is something we should encourage our patients to use,” he said.

Similarly, though the treatments “have fallen out of favor,” Dr. Rapaport said “meta-analyses clearly demonstrate” a significant effect of bright white light (BL) therapy in seasonal affective disorder, both as monotherapy and in combination with antidepressants. The light should be dosed at 5000 lux or more for 1 hour daily.

Further, said Dr. Rapaport, BL as monotherapy or used in combination with antidepressants, or with sleep deprivation can be moderately effective in treating major depressive disorder. “It’s something to consider. We do not use it; we should use it,” Dr. Rapaport said. For patients with bipolar disorder, BL therapy can effectively augment medication use as well.

Focused, intensive treatment with light and sleep adjustments can be effective in both bipolar depression and treatment-resistant depression, Dr. Rapaport said. This approach, termed “adjunctive triple chronotherapy,” begins with total sleep deprivation for a period of 33-36 hours. Then, the patient receives BL therapy at 5,000 lux for at least 1 hour for 3 consecutive nights. Finally, patients are asked to advance their sleep phase for 3 days so that they sleep from 6 p.m. to 1 a.m. the 1st night, 8 p.m. to 3 a.m. the 2nd night, and 10 p.m. to 5 a.m. the 3rd night.

The triple chronotherapy approach, said Dr. Rapaport, results in a “rapid and sustained response, both in unipolar and bipolar depression, in the studies that have been done to date.”

Massage can effectively improve mood for individuals with depression as well. In a study of HIV-positive individuals with major depressive disorder and on stable medication, those who received weekly massage had a 33% decrease in HAM-D scores, compared with a 12% increase for those receiving light touch, and a 9% decrease for those on a wait list who received neither touch nor massage (P less than .05). The response rate of 40% for those receiving massage also was significantly higher than the 6.3% for those receiving light touch and the 14% for those on the wait list (P less than .05).

Recently completed unpublished work by Dr. Rapaport and his colleagues involving patients with generalized anxiety disorder also showed significantly greater improvement on a self-rating scale for anxiety for those receiving twice-weekly Swedish massage therapy, compared with those receiving light touch.

“Our patients – their symptoms aren’t just what we see on the monitors – they deal with quality of life, they deal with functioning,” said Dr. Rapaport, “so there are many things that we as clinicians need to look at,” he said at the meeting. “The key is this: There’s a slowly increasing but limited data set for [treatment-resistant depression]. We need to find the right treatments for the right subjects. “

The ASCP meeting was formerly known as the New Clinical Drug Evaluation Unit meeting. Dr. Rapaport reported no relevant financial conflicts.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – A small proof-of-concept study of low-field magnetic stimulation to augment medical treatment for 85 individuals with treatment-resistant major depressive disorder failed to meet its primary endpoint of significant improvement in core depression symptoms at 48 hours after treatment, though some nonsignificant improvement in mood was seen, compared with sham treatment.

The study’s design did succeed, however, in reducing the substantial placebo response that plagues many clinical trials of treatments for psychiatric illness.

During a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting, Dr. Maurizio Fava shared the results of a double-blind, proof-of-concept trial of low-field magnetic stimulation (LFMS) augmentation of antidepressant therapy for patients with treatment-resistant depression.

Overall, patients receiving LFMS saw no significant improvement on an abbreviated 6-item Hamilton Rating Scale for Depression (HAMD-6), compared with those receiving sham treatment (P = .61). Since the study looked at changes in depression scores just 24 hours after treatment, Dr. Fava said, “We used the HAMD-6, because it’s a more sensitive measure for rapid changes than the HAMD-17.

“Unfortunately, the LFMS did not separate out after 48 hours,” he said.

Nonsignificant differences also were seen for two other rating scales, the Montgomery-Åsberg Depression Scale (MADRS) and the Strengths and Difficulties Questionnaire (SDQ). The use of a visual analog scale to detect mood changes 120 minutes after treatment did not yield significant differences between those receiving LFMS and those receiving sham.

Many avenues in addition to medication are being explored to provide rapid relief for individuals with treatment-resistant depression (TRD), said Dr. Fava, the study’s lead investigator, associate dean for clinical and translational research, and Slater Family Professor of Psychiatry at Harvard Medical School, Boston.

The six-site Rapidly-Acting Treatments for Treatment-Resistant Depression trial was sham controlled and used a prerandomized sequential parallel comparison design (SPCD). The intervention of LFMS or sham was delivered for 20 minutes daily on 2 consecutive days, and then again for 2 more days after an interim assessment.

“In the second stage of the study, only the patients who had not responded to sham are included,” Dr. Fava said. This is the aspect of an SPCD study that can help to reduce the negative effect on results that can be seen with high placebo response rates, a common phenomenon in psychiatric clinical trials.

“This was a complicated study, involving all kind of methodologic approaches,” said Dr. Fava, noting that each enrollee had the diagnosis of moderate to severe depression (MADRS score equal to or greater than 20) confirmed by two interviewers, including one remote interviewer who was not involved in the study.

Patients who were on a stable dose of antidepressant were included “if they failed to achieve a treatment response after no more than one, but not more than three, treatment courses of antidepressant therapy of at least 8 weeks’ duration,” Dr. Fava said. “We wanted to avoid ‘super-resistance,’ which can reduce the ability to detect a signal” for efficacy, he said.

Dr. Fava also made the point that this study was of very short design, compared with other SPCD trials. “People were skeptical that you would see a reduction in placebo with only 4 days of treatment in two stages,” he said. However, “The design worked,” he said, since the reduction in depression scores was the equivalent of just 1.6 points on the HAMD-17 in the second stage of the study after the placebo responders had been eliminated. “That’s a very low placebo rate,” Dr. Fava said.

Many experimental building blocks support the use of LFMS to treat depression. Investigations began after a serendipitous 2004 discovery that patients with bipolar disorder who underwent diagnostic echo-planar magnetic resonance spectroscopic imaging (EP-MRSI) experienced relief from depressive symptoms after the scan (Am J Psychiatry. 2004 Jan;161[1]:93-8). Since then, LFMS has been shown to reduce helpless behavior in mice during a forced swim test.

In humans, FDG-PET imaging studies also have shown perceptible physiological changes when individuals with depression receive LFMS, consistent with those seen in reduced depression. Patients in two earlier proof-of-concept studies who had either bipolar or unipolar depression and who received LFMS experienced significantly greater symptom relief than did those receiving sham treatment.

Study design limitations included the relatively small sample size and potential recruitment biases for those seeking this form of augmentation for depression treatment. The study included only patients with unipolar depression, although “two previous positive studies included 81 bipolar patients and 22 unipolar patients,” Dr. Fava said.

Potential technical limitations included the low dosing of LFMS, with just 20 minutes of exposure two times; however, Dr. Fava said, the duration was chosen to parallel the previous studies done in patients with bipolar disorder. Also, seeing a detectable change in depression scoring at 48-72 hours after LFMS might not be an entirely realistic expectation.

The National Institutes of Health and the Department of Health and Human Services funded the study. Dr. Fava reported having a patent for Sequential Parallel Comparison Design (SPCD), which is licensed by Massachusetts General Hospital to RCT Logic, LLC. He also reported multiple financial relationships with pharmaceutical and medical device companies.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – A small proof-of-concept study of low-field magnetic stimulation to augment medical treatment for 85 individuals with treatment-resistant major depressive disorder failed to meet its primary endpoint of significant improvement in core depression symptoms at 48 hours after treatment, though some nonsignificant improvement in mood was seen, compared with sham treatment.

The study’s design did succeed, however, in reducing the substantial placebo response that plagues many clinical trials of treatments for psychiatric illness.

During a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting, Dr. Maurizio Fava shared the results of a double-blind, proof-of-concept trial of low-field magnetic stimulation (LFMS) augmentation of antidepressant therapy for patients with treatment-resistant depression.

Overall, patients receiving LFMS saw no significant improvement on an abbreviated 6-item Hamilton Rating Scale for Depression (HAMD-6), compared with those receiving sham treatment (P = .61). Since the study looked at changes in depression scores just 24 hours after treatment, Dr. Fava said, “We used the HAMD-6, because it’s a more sensitive measure for rapid changes than the HAMD-17.

“Unfortunately, the LFMS did not separate out after 48 hours,” he said.

Nonsignificant differences also were seen for two other rating scales, the Montgomery-Åsberg Depression Scale (MADRS) and the Strengths and Difficulties Questionnaire (SDQ). The use of a visual analog scale to detect mood changes 120 minutes after treatment did not yield significant differences between those receiving LFMS and those receiving sham.

Many avenues in addition to medication are being explored to provide rapid relief for individuals with treatment-resistant depression (TRD), said Dr. Fava, the study’s lead investigator, associate dean for clinical and translational research, and Slater Family Professor of Psychiatry at Harvard Medical School, Boston.

The six-site Rapidly-Acting Treatments for Treatment-Resistant Depression trial was sham controlled and used a prerandomized sequential parallel comparison design (SPCD). The intervention of LFMS or sham was delivered for 20 minutes daily on 2 consecutive days, and then again for 2 more days after an interim assessment.

“In the second stage of the study, only the patients who had not responded to sham are included,” Dr. Fava said. This is the aspect of an SPCD study that can help to reduce the negative effect on results that can be seen with high placebo response rates, a common phenomenon in psychiatric clinical trials.

“This was a complicated study, involving all kind of methodologic approaches,” said Dr. Fava, noting that each enrollee had the diagnosis of moderate to severe depression (MADRS score equal to or greater than 20) confirmed by two interviewers, including one remote interviewer who was not involved in the study.

Patients who were on a stable dose of antidepressant were included “if they failed to achieve a treatment response after no more than one, but not more than three, treatment courses of antidepressant therapy of at least 8 weeks’ duration,” Dr. Fava said. “We wanted to avoid ‘super-resistance,’ which can reduce the ability to detect a signal” for efficacy, he said.

Dr. Fava also made the point that this study was of very short design, compared with other SPCD trials. “People were skeptical that you would see a reduction in placebo with only 4 days of treatment in two stages,” he said. However, “The design worked,” he said, since the reduction in depression scores was the equivalent of just 1.6 points on the HAMD-17 in the second stage of the study after the placebo responders had been eliminated. “That’s a very low placebo rate,” Dr. Fava said.

Many experimental building blocks support the use of LFMS to treat depression. Investigations began after a serendipitous 2004 discovery that patients with bipolar disorder who underwent diagnostic echo-planar magnetic resonance spectroscopic imaging (EP-MRSI) experienced relief from depressive symptoms after the scan (Am J Psychiatry. 2004 Jan;161[1]:93-8). Since then, LFMS has been shown to reduce helpless behavior in mice during a forced swim test.

In humans, FDG-PET imaging studies also have shown perceptible physiological changes when individuals with depression receive LFMS, consistent with those seen in reduced depression. Patients in two earlier proof-of-concept studies who had either bipolar or unipolar depression and who received LFMS experienced significantly greater symptom relief than did those receiving sham treatment.

Study design limitations included the relatively small sample size and potential recruitment biases for those seeking this form of augmentation for depression treatment. The study included only patients with unipolar depression, although “two previous positive studies included 81 bipolar patients and 22 unipolar patients,” Dr. Fava said.

Potential technical limitations included the low dosing of LFMS, with just 20 minutes of exposure two times; however, Dr. Fava said, the duration was chosen to parallel the previous studies done in patients with bipolar disorder. Also, seeing a detectable change in depression scoring at 48-72 hours after LFMS might not be an entirely realistic expectation.

The National Institutes of Health and the Department of Health and Human Services funded the study. Dr. Fava reported having a patent for Sequential Parallel Comparison Design (SPCD), which is licensed by Massachusetts General Hospital to RCT Logic, LLC. He also reported multiple financial relationships with pharmaceutical and medical device companies.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – A small proof-of-concept study of low-field magnetic stimulation to augment medical treatment for 85 individuals with treatment-resistant major depressive disorder failed to meet its primary endpoint of significant improvement in core depression symptoms at 48 hours after treatment, though some nonsignificant improvement in mood was seen, compared with sham treatment.

The study’s design did succeed, however, in reducing the substantial placebo response that plagues many clinical trials of treatments for psychiatric illness.

During a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting, Dr. Maurizio Fava shared the results of a double-blind, proof-of-concept trial of low-field magnetic stimulation (LFMS) augmentation of antidepressant therapy for patients with treatment-resistant depression.

Overall, patients receiving LFMS saw no significant improvement on an abbreviated 6-item Hamilton Rating Scale for Depression (HAMD-6), compared with those receiving sham treatment (P = .61). Since the study looked at changes in depression scores just 24 hours after treatment, Dr. Fava said, “We used the HAMD-6, because it’s a more sensitive measure for rapid changes than the HAMD-17.

“Unfortunately, the LFMS did not separate out after 48 hours,” he said.

Nonsignificant differences also were seen for two other rating scales, the Montgomery-Åsberg Depression Scale (MADRS) and the Strengths and Difficulties Questionnaire (SDQ). The use of a visual analog scale to detect mood changes 120 minutes after treatment did not yield significant differences between those receiving LFMS and those receiving sham.

Many avenues in addition to medication are being explored to provide rapid relief for individuals with treatment-resistant depression (TRD), said Dr. Fava, the study’s lead investigator, associate dean for clinical and translational research, and Slater Family Professor of Psychiatry at Harvard Medical School, Boston.

The six-site Rapidly-Acting Treatments for Treatment-Resistant Depression trial was sham controlled and used a prerandomized sequential parallel comparison design (SPCD). The intervention of LFMS or sham was delivered for 20 minutes daily on 2 consecutive days, and then again for 2 more days after an interim assessment.

“In the second stage of the study, only the patients who had not responded to sham are included,” Dr. Fava said. This is the aspect of an SPCD study that can help to reduce the negative effect on results that can be seen with high placebo response rates, a common phenomenon in psychiatric clinical trials.

“This was a complicated study, involving all kind of methodologic approaches,” said Dr. Fava, noting that each enrollee had the diagnosis of moderate to severe depression (MADRS score equal to or greater than 20) confirmed by two interviewers, including one remote interviewer who was not involved in the study.

Patients who were on a stable dose of antidepressant were included “if they failed to achieve a treatment response after no more than one, but not more than three, treatment courses of antidepressant therapy of at least 8 weeks’ duration,” Dr. Fava said. “We wanted to avoid ‘super-resistance,’ which can reduce the ability to detect a signal” for efficacy, he said.

Dr. Fava also made the point that this study was of very short design, compared with other SPCD trials. “People were skeptical that you would see a reduction in placebo with only 4 days of treatment in two stages,” he said. However, “The design worked,” he said, since the reduction in depression scores was the equivalent of just 1.6 points on the HAMD-17 in the second stage of the study after the placebo responders had been eliminated. “That’s a very low placebo rate,” Dr. Fava said.

Many experimental building blocks support the use of LFMS to treat depression. Investigations began after a serendipitous 2004 discovery that patients with bipolar disorder who underwent diagnostic echo-planar magnetic resonance spectroscopic imaging (EP-MRSI) experienced relief from depressive symptoms after the scan (Am J Psychiatry. 2004 Jan;161[1]:93-8). Since then, LFMS has been shown to reduce helpless behavior in mice during a forced swim test.

In humans, FDG-PET imaging studies also have shown perceptible physiological changes when individuals with depression receive LFMS, consistent with those seen in reduced depression. Patients in two earlier proof-of-concept studies who had either bipolar or unipolar depression and who received LFMS experienced significantly greater symptom relief than did those receiving sham treatment.

Study design limitations included the relatively small sample size and potential recruitment biases for those seeking this form of augmentation for depression treatment. The study included only patients with unipolar depression, although “two previous positive studies included 81 bipolar patients and 22 unipolar patients,” Dr. Fava said.

Potential technical limitations included the low dosing of LFMS, with just 20 minutes of exposure two times; however, Dr. Fava said, the duration was chosen to parallel the previous studies done in patients with bipolar disorder. Also, seeing a detectable change in depression scoring at 48-72 hours after LFMS might not be an entirely realistic expectation.

The National Institutes of Health and the Department of Health and Human Services funded the study. Dr. Fava reported having a patent for Sequential Parallel Comparison Design (SPCD), which is licensed by Massachusetts General Hospital to RCT Logic, LLC. He also reported multiple financial relationships with pharmaceutical and medical device companies.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – There’s a rapidly growing list of states that have approved marijuana for medical use, but that does not mean that there’s also an expanding body of science to support marijuana’s use for psychiatric indications, according to Dr. Deepak Cyril D’Souza.

Though moderate evidence exists to support the use of medical marijuana for nausea and vomiting in chemotherapy, HIV/AIDS cachexia, neuropathic pain, and spasticity in multiple sclerosis, there’s scant evidence for some other uses. Little evidence exists to support the use of medical marijuana in Tourette syndrome, Crohn’s disease and ulcerative colitis, and epilepsy, and the data are even weaker for Parkinson’s disease, posttraumatic stress disorder, and agitation in Alzheimer’s disease, Dr. D’Souza said at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

Even so, he said, medical marijuana has been approved in several states for all of those conditions – and more.

Courtesy Wikimedia Commons/Coaster420/Creative Commons License

Different states have required widely varying standards of evidence in making decisions about whether to approve medical marijuana use, and for which conditions. These range, in some cases, from relying on mere anecdotal evidence – as when individuals provide powerful but unscientific testimony about marijuana’s efficacy for a condition – to requiring the gold standard of randomized, double-blind, placebo-controlled trials.

Dr. D’Souza and his collaborators reviewed the data supporting the use of medical marijuana for several of the most commonly approved psychiatric indications, and found many of them hampered by poor design, poor execution, and an overreliance on the subjective effects of the studied compound.

For PTSD, only one randomized controlled study was found, and only one study had an active control, so the quality of evidence was rated as “very low” or “low” by Dr. D’Souza’s group. “Most of the studies were not blinded, and the sample sizes were generally small,” said Dr. D’Souza, professor of psychiatry at Yale University, New Haven, Conn. “It’s notable that many of these studies were with dronabinol, which is a synthetic THC analog. However, one take-home is that many of these studies reported improvement with sleep and a reduction in nightmares. This is something that should be followed up.”

For Tourette syndrome, there were just two studies by the same author, both with small sample sizes and of short duration. One study was rated “low” and the other “very low” for quality; in particular, the placebo effect could not be ruled out.

Four studies, said Dr. D’Souza, examined cannabinoids for dementia, and all had low quality of evidence. One published study had a sample size of two, he said. “The point here is that the only positive finding is that people who were diagnosed with dementia ate more and gained weight. And that wasn’t the objective of the study.”

“When we’re talking about medical marijuana, we’re talking about the whole plant,” he said. The marijuana plant has at least 450 known distinct constituent chemicals; these include about 70 cannabinoids as well as terpenoids and flavonoids. This means that the whole plant as dispensed represents a much more complex compound than medical tetrahydrocannabinol, for example, Dr. D’Souza said.

“We need to think about not just efficacy but side effects,” he said. These can include tolerance, abuse, and withdrawal syndrome. Marijuana’s cognitive effects may contribute to an increased risk of motor vehicle crashes. Though acute psychotic symptoms with quick resolution have long been noted, it’s also now thought that heavy marijuana exposure in adolescence more than doubles the risk for schizophrenia and might decrease adult IQ by about 10 points.

Though cannabis is “neither necessary nor sufficient for developing psychosis” but instead is a factor in a set of complex interactions, “what’s absolutely clear is that people with a psychotic disorder or at risk for developing one are very much more vulnerable to the effects of cannabinoids,” Dr. D’Souza said.

Despite all of those concerns, he said, “public demand and legislators have usurped the [Food and Drug Administration] approval process” when it comes to state-by-state approval of medical marijuana. The current state of affairs stands in contrast to the requirements for drug approvals for new indications, which require at least two adequately powered randomized clinical trials. When it comes to marijuana, Dr. D’Souza said, “For most of the indications the evidence fails to meet FDA standards.”

However, he said, the lack of high quality evidence may reflect the difficulty of conducting medical marijuana research in the United States. If this is so, he said, the “federal and state governments need to support and encourage research to generate high quality evidence to guide decisions.”

Dr. D’Souza reported a financial relationship with Insys Therapeutics, which develops pharmaceutical cannabinoid products.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – There’s a rapidly growing list of states that have approved marijuana for medical use, but that does not mean that there’s also an expanding body of science to support marijuana’s use for psychiatric indications, according to Dr. Deepak Cyril D’Souza.

Though moderate evidence exists to support the use of medical marijuana for nausea and vomiting in chemotherapy, HIV/AIDS cachexia, neuropathic pain, and spasticity in multiple sclerosis, there’s scant evidence for some other uses. Little evidence exists to support the use of medical marijuana in Tourette syndrome, Crohn’s disease and ulcerative colitis, and epilepsy, and the data are even weaker for Parkinson’s disease, posttraumatic stress disorder, and agitation in Alzheimer’s disease, Dr. D’Souza said at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

Even so, he said, medical marijuana has been approved in several states for all of those conditions – and more.

Courtesy Wikimedia Commons/Coaster420/Creative Commons License

Different states have required widely varying standards of evidence in making decisions about whether to approve medical marijuana use, and for which conditions. These range, in some cases, from relying on mere anecdotal evidence – as when individuals provide powerful but unscientific testimony about marijuana’s efficacy for a condition – to requiring the gold standard of randomized, double-blind, placebo-controlled trials.

Dr. D’Souza and his collaborators reviewed the data supporting the use of medical marijuana for several of the most commonly approved psychiatric indications, and found many of them hampered by poor design, poor execution, and an overreliance on the subjective effects of the studied compound.

For PTSD, only one randomized controlled study was found, and only one study had an active control, so the quality of evidence was rated as “very low” or “low” by Dr. D’Souza’s group. “Most of the studies were not blinded, and the sample sizes were generally small,” said Dr. D’Souza, professor of psychiatry at Yale University, New Haven, Conn. “It’s notable that many of these studies were with dronabinol, which is a synthetic THC analog. However, one take-home is that many of these studies reported improvement with sleep and a reduction in nightmares. This is something that should be followed up.”

For Tourette syndrome, there were just two studies by the same author, both with small sample sizes and of short duration. One study was rated “low” and the other “very low” for quality; in particular, the placebo effect could not be ruled out.

Four studies, said Dr. D’Souza, examined cannabinoids for dementia, and all had low quality of evidence. One published study had a sample size of two, he said. “The point here is that the only positive finding is that people who were diagnosed with dementia ate more and gained weight. And that wasn’t the objective of the study.”

“When we’re talking about medical marijuana, we’re talking about the whole plant,” he said. The marijuana plant has at least 450 known distinct constituent chemicals; these include about 70 cannabinoids as well as terpenoids and flavonoids. This means that the whole plant as dispensed represents a much more complex compound than medical tetrahydrocannabinol, for example, Dr. D’Souza said.

“We need to think about not just efficacy but side effects,” he said. These can include tolerance, abuse, and withdrawal syndrome. Marijuana’s cognitive effects may contribute to an increased risk of motor vehicle crashes. Though acute psychotic symptoms with quick resolution have long been noted, it’s also now thought that heavy marijuana exposure in adolescence more than doubles the risk for schizophrenia and might decrease adult IQ by about 10 points.

Though cannabis is “neither necessary nor sufficient for developing psychosis” but instead is a factor in a set of complex interactions, “what’s absolutely clear is that people with a psychotic disorder or at risk for developing one are very much more vulnerable to the effects of cannabinoids,” Dr. D’Souza said.

Despite all of those concerns, he said, “public demand and legislators have usurped the [Food and Drug Administration] approval process” when it comes to state-by-state approval of medical marijuana. The current state of affairs stands in contrast to the requirements for drug approvals for new indications, which require at least two adequately powered randomized clinical trials. When it comes to marijuana, Dr. D’Souza said, “For most of the indications the evidence fails to meet FDA standards.”

However, he said, the lack of high quality evidence may reflect the difficulty of conducting medical marijuana research in the United States. If this is so, he said, the “federal and state governments need to support and encourage research to generate high quality evidence to guide decisions.”

Dr. D’Souza reported a financial relationship with Insys Therapeutics, which develops pharmaceutical cannabinoid products.

[email protected]

On Twitter @karioakes

SCOTTSDALE, ARIZ. – There’s a rapidly growing list of states that have approved marijuana for medical use, but that does not mean that there’s also an expanding body of science to support marijuana’s use for psychiatric indications, according to Dr. Deepak Cyril D’Souza.

Though moderate evidence exists to support the use of medical marijuana for nausea and vomiting in chemotherapy, HIV/AIDS cachexia, neuropathic pain, and spasticity in multiple sclerosis, there’s scant evidence for some other uses. Little evidence exists to support the use of medical marijuana in Tourette syndrome, Crohn’s disease and ulcerative colitis, and epilepsy, and the data are even weaker for Parkinson’s disease, posttraumatic stress disorder, and agitation in Alzheimer’s disease, Dr. D’Souza said at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

Even so, he said, medical marijuana has been approved in several states for all of those conditions – and more.

Courtesy Wikimedia Commons/Coaster420/Creative Commons License

Different states have required widely varying standards of evidence in making decisions about whether to approve medical marijuana use, and for which conditions. These range, in some cases, from relying on mere anecdotal evidence – as when individuals provide powerful but unscientific testimony about marijuana’s efficacy for a condition – to requiring the gold standard of randomized, double-blind, placebo-controlled trials.

Dr. D’Souza and his collaborators reviewed the data supporting the use of medical marijuana for several of the most commonly approved psychiatric indications, and found many of them hampered by poor design, poor execution, and an overreliance on the subjective effects of the studied compound.

For PTSD, only one randomized controlled study was found, and only one study had an active control, so the quality of evidence was rated as “very low” or “low” by Dr. D’Souza’s group. “Most of the studies were not blinded, and the sample sizes were generally small,” said Dr. D’Souza, professor of psychiatry at Yale University, New Haven, Conn. “It’s notable that many of these studies were with dronabinol, which is a synthetic THC analog. However, one take-home is that many of these studies reported improvement with sleep and a reduction in nightmares. This is something that should be followed up.”

For Tourette syndrome, there were just two studies by the same author, both with small sample sizes and of short duration. One study was rated “low” and the other “very low” for quality; in particular, the placebo effect could not be ruled out.

Four studies, said Dr. D’Souza, examined cannabinoids for dementia, and all had low quality of evidence. One published study had a sample size of two, he said. “The point here is that the only positive finding is that people who were diagnosed with dementia ate more and gained weight. And that wasn’t the objective of the study.”

“When we’re talking about medical marijuana, we’re talking about the whole plant,” he said. The marijuana plant has at least 450 known distinct constituent chemicals; these include about 70 cannabinoids as well as terpenoids and flavonoids. This means that the whole plant as dispensed represents a much more complex compound than medical tetrahydrocannabinol, for example, Dr. D’Souza said.

“We need to think about not just efficacy but side effects,” he said. These can include tolerance, abuse, and withdrawal syndrome. Marijuana’s cognitive effects may contribute to an increased risk of motor vehicle crashes. Though acute psychotic symptoms with quick resolution have long been noted, it’s also now thought that heavy marijuana exposure in adolescence more than doubles the risk for schizophrenia and might decrease adult IQ by about 10 points.

Though cannabis is “neither necessary nor sufficient for developing psychosis” but instead is a factor in a set of complex interactions, “what’s absolutely clear is that people with a psychotic disorder or at risk for developing one are very much more vulnerable to the effects of cannabinoids,” Dr. D’Souza said.

Despite all of those concerns, he said, “public demand and legislators have usurped the [Food and Drug Administration] approval process” when it comes to state-by-state approval of medical marijuana. The current state of affairs stands in contrast to the requirements for drug approvals for new indications, which require at least two adequately powered randomized clinical trials. When it comes to marijuana, Dr. D’Souza said, “For most of the indications the evidence fails to meet FDA standards.”

However, he said, the lack of high quality evidence may reflect the difficulty of conducting medical marijuana research in the United States. If this is so, he said, the “federal and state governments need to support and encourage research to generate high quality evidence to guide decisions.”

Dr. D’Souza reported a financial relationship with Insys Therapeutics, which develops pharmaceutical cannabinoid products.

[email protected]

On Twitter @karioakes