ASCP: Intranasal esketamine bests placebo for treatment-resistant depression

MIAMI BEACH – A molecular variation of an old anesthetic showed promise for treatment-resistant depression in a small placebo-controlled study. Patients with treatment-resistant depression who received any dose of intranasal ketamine improved more than those receiving placebo, according to Dr. Jaskaran Singh, senior director at Janssen Pharmaceutica.

In results of a double-blind, placebo-controlled multicenter study of 67 patients with treatment-resistant depression (TRD) presented during a poster session, Dr. Singh and his collaborators noted that higher doses of esketamine were associated with greater improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS). Additionally, dissociative symptoms abated with repeated dosing.

Esketamine, currently in phase II clinical trials for TRD, is the S-enantiomer of ketamine, an anesthetic in use for five decades. The trial sought to identify the antidepressant effectiveness of esketamine, compared with placebo, at various doses for those who inhaled the drug in low doses via intranasal spray. The study also tracked undesirable side effects, including the dissociative effect that can result from both esketamine and ketamine, Dr. Singh said at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

Esketamine is thought to relieve depression by its N-methyl D-aspartate receptor antagonist properties. Ongoing basic science, rodent, and human studies are underway to elucidate the proposed multiple mechanisms that cause ketamine and esketamine’s very rapid and somewhat durable antidepressant effects.

Dr. Singh reported the results from one of two panels of the multicenter study. Enrollees, aged 20-64 years, were eligible if they had a diagnosis of major depressive disorder and had not shown adequate response to at least two antidepressants and showed at least moderate depression on the 30-item Inventory of Depressive Symptomatology-Clinician rated (IDS-C30). Key exclusion criteria included significant other psychiatric diagnoses, suicidal ideation with intent to act, and history of nonresponsiveness to either ketamine/esketamine or electroconvulsive therapy.

The initial screening period for all participants was up to 4 weeks; patients were then randomized 3:1:1:1 to receive a placebo nasal spray (n = 33) or intranasal esketamine in 28-mg, 56-mg, or 84-mg doses on days 1 and 4 of the study period. Individuals who had been randomized to receive any dose of esketamine received that dose two additional times, at days 8 and 11.

Individuals on the placebo arm who showed mild to no symptoms according to the 15-item Quick Inventory of Depressive Sympomatology (IDS-QR) continued on placebo; those who continued with moderate to severe depressive symptoms (n = 33) on the IDS-QR were rerandomized 1:1:1:1 to receive placebo or one of the three doses of esketamine on study days 8 and 11. Sixty of 67 patients completed the initial 2-week study period, Dr. Singh said.

An optional open-label period allowed all participants to receive intranasal ketamine, with dose titration starting at 54 mg and dosing frequency tapering from twice weekly to every 2 weeks by study day 74. All individuals received 8 weeks of follow-up. Results from the open-label phase were not reported in this poster presentation.

Results of the intention-to-treat group of those who received the same treatment for the initial 2-week study period showed that those receiving any dose of esketamine had significant improvement in MADRS score, compared with placebo. Additional benefit was seen for higher esketamine dosing, with mean MADRS score differences from placebo of –4.2 points for 28-mg esketamine (P = .021), –6.3 points for 56 mg (P = .001), and –9.0 points for 84 mg (P <.001). Significant improvements, compared with placebo, were seen almost immediately after the first esketamine dose was administered, he said.

All individuals receiving ketamine during the double-blind period were included in safety analysis. Overall, 42 of 56 participants (75%) receiving any dose of esketamine experienced treatment-emergent adverse events, compared with 18 of 33 from the placebo arm (55%). Dizziness, headache, dissociation, dysgeusia, nausea, dissociative disorder, and hypoesthesia oral all occurred in more than 10% of the esketamine-receiving group. Addressing a side effect that is of particular concern, Dr. Singh noted: “The magnitude of dissociative symptoms is dose dependent and attenuates with repeated dosing.”

Analysis of the open-label phase of this arm of the study is underway; study of a second panel is ongoing in Japan. Dr. Singh and his collaborators recommended further study of the effects of intranasal esketamine over longer periods.

The study was funded by Janssen Research and Development. Dr. Singh is an employee of Janssen Pharmaceutica.

[email protected]

On Twitter @karioakes

MIAMI BEACH – A molecular variation of an old anesthetic showed promise for treatment-resistant depression in a small placebo-controlled study. Patients with treatment-resistant depression who received any dose of intranasal ketamine improved more than those receiving placebo, according to Dr. Jaskaran Singh, senior director at Janssen Pharmaceutica.

In results of a double-blind, placebo-controlled multicenter study of 67 patients with treatment-resistant depression (TRD) presented during a poster session, Dr. Singh and his collaborators noted that higher doses of esketamine were associated with greater improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS). Additionally, dissociative symptoms abated with repeated dosing.

Esketamine, currently in phase II clinical trials for TRD, is the S-enantiomer of ketamine, an anesthetic in use for five decades. The trial sought to identify the antidepressant effectiveness of esketamine, compared with placebo, at various doses for those who inhaled the drug in low doses via intranasal spray. The study also tracked undesirable side effects, including the dissociative effect that can result from both esketamine and ketamine, Dr. Singh said at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

Esketamine is thought to relieve depression by its N-methyl D-aspartate receptor antagonist properties. Ongoing basic science, rodent, and human studies are underway to elucidate the proposed multiple mechanisms that cause ketamine and esketamine’s very rapid and somewhat durable antidepressant effects.

Dr. Singh reported the results from one of two panels of the multicenter study. Enrollees, aged 20-64 years, were eligible if they had a diagnosis of major depressive disorder and had not shown adequate response to at least two antidepressants and showed at least moderate depression on the 30-item Inventory of Depressive Symptomatology-Clinician rated (IDS-C30). Key exclusion criteria included significant other psychiatric diagnoses, suicidal ideation with intent to act, and history of nonresponsiveness to either ketamine/esketamine or electroconvulsive therapy.

The initial screening period for all participants was up to 4 weeks; patients were then randomized 3:1:1:1 to receive a placebo nasal spray (n = 33) or intranasal esketamine in 28-mg, 56-mg, or 84-mg doses on days 1 and 4 of the study period. Individuals who had been randomized to receive any dose of esketamine received that dose two additional times, at days 8 and 11.

Individuals on the placebo arm who showed mild to no symptoms according to the 15-item Quick Inventory of Depressive Sympomatology (IDS-QR) continued on placebo; those who continued with moderate to severe depressive symptoms (n = 33) on the IDS-QR were rerandomized 1:1:1:1 to receive placebo or one of the three doses of esketamine on study days 8 and 11. Sixty of 67 patients completed the initial 2-week study period, Dr. Singh said.

An optional open-label period allowed all participants to receive intranasal ketamine, with dose titration starting at 54 mg and dosing frequency tapering from twice weekly to every 2 weeks by study day 74. All individuals received 8 weeks of follow-up. Results from the open-label phase were not reported in this poster presentation.

Results of the intention-to-treat group of those who received the same treatment for the initial 2-week study period showed that those receiving any dose of esketamine had significant improvement in MADRS score, compared with placebo. Additional benefit was seen for higher esketamine dosing, with mean MADRS score differences from placebo of –4.2 points for 28-mg esketamine (P = .021), –6.3 points for 56 mg (P = .001), and –9.0 points for 84 mg (P <.001). Significant improvements, compared with placebo, were seen almost immediately after the first esketamine dose was administered, he said.

All individuals receiving ketamine during the double-blind period were included in safety analysis. Overall, 42 of 56 participants (75%) receiving any dose of esketamine experienced treatment-emergent adverse events, compared with 18 of 33 from the placebo arm (55%). Dizziness, headache, dissociation, dysgeusia, nausea, dissociative disorder, and hypoesthesia oral all occurred in more than 10% of the esketamine-receiving group. Addressing a side effect that is of particular concern, Dr. Singh noted: “The magnitude of dissociative symptoms is dose dependent and attenuates with repeated dosing.”

Analysis of the open-label phase of this arm of the study is underway; study of a second panel is ongoing in Japan. Dr. Singh and his collaborators recommended further study of the effects of intranasal esketamine over longer periods.

The study was funded by Janssen Research and Development. Dr. Singh is an employee of Janssen Pharmaceutica.

[email protected]

On Twitter @karioakes

MIAMI BEACH – A molecular variation of an old anesthetic showed promise for treatment-resistant depression in a small placebo-controlled study. Patients with treatment-resistant depression who received any dose of intranasal ketamine improved more than those receiving placebo, according to Dr. Jaskaran Singh, senior director at Janssen Pharmaceutica.

In results of a double-blind, placebo-controlled multicenter study of 67 patients with treatment-resistant depression (TRD) presented during a poster session, Dr. Singh and his collaborators noted that higher doses of esketamine were associated with greater improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS). Additionally, dissociative symptoms abated with repeated dosing.

Esketamine, currently in phase II clinical trials for TRD, is the S-enantiomer of ketamine, an anesthetic in use for five decades. The trial sought to identify the antidepressant effectiveness of esketamine, compared with placebo, at various doses for those who inhaled the drug in low doses via intranasal spray. The study also tracked undesirable side effects, including the dissociative effect that can result from both esketamine and ketamine, Dr. Singh said at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

Esketamine is thought to relieve depression by its N-methyl D-aspartate receptor antagonist properties. Ongoing basic science, rodent, and human studies are underway to elucidate the proposed multiple mechanisms that cause ketamine and esketamine’s very rapid and somewhat durable antidepressant effects.

Dr. Singh reported the results from one of two panels of the multicenter study. Enrollees, aged 20-64 years, were eligible if they had a diagnosis of major depressive disorder and had not shown adequate response to at least two antidepressants and showed at least moderate depression on the 30-item Inventory of Depressive Symptomatology-Clinician rated (IDS-C30). Key exclusion criteria included significant other psychiatric diagnoses, suicidal ideation with intent to act, and history of nonresponsiveness to either ketamine/esketamine or electroconvulsive therapy.

The initial screening period for all participants was up to 4 weeks; patients were then randomized 3:1:1:1 to receive a placebo nasal spray (n = 33) or intranasal esketamine in 28-mg, 56-mg, or 84-mg doses on days 1 and 4 of the study period. Individuals who had been randomized to receive any dose of esketamine received that dose two additional times, at days 8 and 11.

Individuals on the placebo arm who showed mild to no symptoms according to the 15-item Quick Inventory of Depressive Sympomatology (IDS-QR) continued on placebo; those who continued with moderate to severe depressive symptoms (n = 33) on the IDS-QR were rerandomized 1:1:1:1 to receive placebo or one of the three doses of esketamine on study days 8 and 11. Sixty of 67 patients completed the initial 2-week study period, Dr. Singh said.

An optional open-label period allowed all participants to receive intranasal ketamine, with dose titration starting at 54 mg and dosing frequency tapering from twice weekly to every 2 weeks by study day 74. All individuals received 8 weeks of follow-up. Results from the open-label phase were not reported in this poster presentation.

Results of the intention-to-treat group of those who received the same treatment for the initial 2-week study period showed that those receiving any dose of esketamine had significant improvement in MADRS score, compared with placebo. Additional benefit was seen for higher esketamine dosing, with mean MADRS score differences from placebo of –4.2 points for 28-mg esketamine (P = .021), –6.3 points for 56 mg (P = .001), and –9.0 points for 84 mg (P <.001). Significant improvements, compared with placebo, were seen almost immediately after the first esketamine dose was administered, he said.

All individuals receiving ketamine during the double-blind period were included in safety analysis. Overall, 42 of 56 participants (75%) receiving any dose of esketamine experienced treatment-emergent adverse events, compared with 18 of 33 from the placebo arm (55%). Dizziness, headache, dissociation, dysgeusia, nausea, dissociative disorder, and hypoesthesia oral all occurred in more than 10% of the esketamine-receiving group. Addressing a side effect that is of particular concern, Dr. Singh noted: “The magnitude of dissociative symptoms is dose dependent and attenuates with repeated dosing.”

Analysis of the open-label phase of this arm of the study is underway; study of a second panel is ongoing in Japan. Dr. Singh and his collaborators recommended further study of the effects of intranasal esketamine over longer periods.

The study was funded by Janssen Research and Development. Dr. Singh is an employee of Janssen Pharmaceutica.

[email protected]

On Twitter @karioakes