Placebo‐controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression

Loo, Colleen; Gálvez, Verònica; O'Keefe, Emily; Mitchell, Philip B.; Hadži-Pavlović, Dušan; Leyden, John; Harper, Simon; Somogyi, Andrew A.; Lai, Rosalyn; Weickert, Cynthia Shannon; Glue, Paul

doi:10.1111/acps.12572

Cited by 188 publications

(195 citation statements)

References 24 publications

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“…In addition, we found that patients with melancholic or melancholic–anxious depression took longer to achieve response/remission than those with anxious or no subtype depression. This relatively increased remission time might have large implications since the rapid antidepressant effect of single ketamine has been validated, but no agreement of the regimen for repeated‐dose ketamine treatment has been reached .…”

Section: Discussionmentioning

confidence: 99%

Association between depression subtypes and response to repeated‐dose intravenous ketamine

Wang

Zhou

Zheng

et al. 2019

Acta Psychiatr Scand

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Association between depression subtypes and response to repeated-dose intravenous ketamine.Objective: About half or more of treatment-resistant depressed patients do not respond to ketamine, and few clinical predictors to gauge the most likely antidepressant response have been proposed. We explored whether depression subtypes are associated with response to ketamine. Method: Ninety-seven participants with depression were administered six repeated-dose intravenous ketamine and assessed for depression (Montgomery-Asberg Depression Rating Scale, MADRS), anxiety (Hamilton Anxiety Rating Scale, HAMA), and suicidal ideation (Beck Scale for Suicidal Ideation, SSI) at baseline, 24 h after each infusion, and 2 weeks after the whole treatment. Participants were classified by melancholic/ anxious subtype. Individuals who met criteria for neither or both subtypes were classified separately, resulting in four mutually exclusive groups. Results: Patients with melancholic or melancholic-anxious features were less likely to respond (e.g., day 13, melancholic-anxious vs. anxious, OR 0.138, 95% CI 0.032-0.584, P = 0.007) or remit (e.g., day 26, melancholic vs. no subtype, OR 0.182, 95% CI 0.035-0.960, P = 0.045) and took longer to achieve response/remission than those with anxious or no subtype features. Faster HAMA score reductions were observed in patients with anxious or melancholic-anxious features, and faster SSI score reductions were observed among those with melancholic-anxious features. Conclusion: Our study shows promising results for ketamine as a novel antidepressant preferentially for the treatment of non-melancholic or anxious depression. Significant outcomes• Compared to those with pure anxious or no subtype features, patients with pure melancholic or melancholic-anxious features were less likely to respond or remit.• Patients with melancholic or melancholic-anxious depression took longer to achieve response or remission and generally improved less in depression, anxiety, and suicidal ideation than those with pure anxious features or no subtype features.• All subtype groups exhibited significant symptom reductions throughout the treatment, while faster score reductions on HAMA were observed in patients with anxious or melancholic-anxious features, and faster score reductions on SSI-I and SSI-total were shown in patients with melancholic-anxious features. Limitations• Only two depression subtypes (i.e., melancholic and anxious) were classified in the present study drawing into question the confounding effect of other subtypes.• All patients included were treatment-resistant or with suicidality, which limits the generalizability of our results to patients with depression as a whole.• Although patients continued medications that they were receiving at screening at the same stable dosages throughout the study, we cannot rule out the influence of these medications on depressive symptoms.

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Section: Discussionmentioning

confidence: 99%

Association between depression subtypes and response to repeated‐dose intravenous ketamine

Wang

Zhou

Zheng

et al. 2019

Acta Psychiatr Scand

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“…Twelve patients who received ketamine achieved response and met remission criteria at doses as low as 0.1 mg/kg regardless of route of administration. Indeed, all three routes of ketamine administration resulted in comparable antidepressant effects in a dose-related fashion, with the fewest adverse effects seen via the subcutaneous route [77]. Larger sample dose optimization studies are actively being conducted (NCT01558063).…”

Section: Ketamine As a Prototypic Glutamatergic Antidepressant Agentmentioning

confidence: 99%

“…In this case series, 20 of 26 (77%) patients with bipolar depression or MDD who received sublingual racemic ketamine every two to three days or weekly reported improved and stable mood, cognition, and sleep with only mild and transient light-headedness as a common side effect (no euphoria, psychotic, or dissociative symptoms). In a small, placebo-controlled, crossover trial, subcutaneous and intramuscular injections of subanesthetic-dose ketamine were found to be associated with antidepressant response in a similar fashion to IV ketamine administrations; in that study, subcutaneous injection was associated with the fewest adverse effects [77]. Clearly, replication of both findings through larger randomized clinical trials is warranted.…”

Section: Ketamine As a Prototypic Glutamatergic Antidepressant Agentmentioning

confidence: 99%

Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression

Lener

Kadriu

Zarate

2017

Drugs

116

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Clinical and preclinical studies suggest that dysfunction of the glutamatergic system is implicated in mood disorders such as major depressive disorder (MDD) and bipolar depression. In clinical studies of individuals with MDD and bipolar depression, rapid reductions in depressive symptoms have been observed in response to subanesthetic-dose ketamine, an agent whose mechanism of action involves the modulation of glutamatergic signaling. The findings from these studies have prompted the repurposing and/or development of other glutamatergic modulators for antidepressant efficacy, both as monotherapy or as an adjunct to conventional monoaminergic antidepressants. This review will highlight the evidence supporting the antidepressant effects of subanesthetic-dose ketamine as well as other glutamatergic modulators, such as D-cycloserine (DCS), riluzole, CP-101,606, CERC-301 (previously known as MK-0657), basimglurant, JNJ-40411813, dextromethorphan, nitrous oxide (N2O), GLYX-13, and esketamine.

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“…Recently, Loo et al 24 assessed the assessed the feasibility, efficacy and safety of intravenous ( n =4), intramuscular ( n =5) and subcutaneous ( n =6) routes for treating depression with ketamine (versus midazolam active comparator) in treatment-resistant depression patients. Doses were also titrated from 0.1 mg kg −1 up to 0.5 mg kg −1 in separate treatment sessions separated by at least 1 week.…”

Section: Experimental Treatments For Depressionmentioning

confidence: 99%

Experimental medication treatment approaches for depression

Ionescu

Papakostas

2017

Transl Psychiatry

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Depression is one of the most common psychiatric conditions. Symptoms can lead to significant disability, which result in impairments in overall quality of life. Though there are many approved antidepressant treatments for depression—including selective serotonin reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors—about a third of patients do not respond to these medications. Therefore, it is imperative for drug discovery to continue towards the development of novel and rapidly acting compounds, especially for patients with treatment-resistant depression. After a brief review of the efficacy of approved antidepressant therapies, we will discuss experimental medication treatments for depression. Specifically, we examine novel medications that are thought to primarily modulate the glutamatergic, cholinergic and opioid systems to achieve antidepressant efficacy. We also give examples of anti-inflammatories, neurokinin-1 modulators, vasopressin antagonists and neurogenesis enhancers that may have a therapeutic role in treatment-resistant depression. The current pipeline of antidepressant treatments is shifting towards medications with novel mechanisms, which may lead to important, life-changing discoveries for patients with severe disease.

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Placebo‐controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression

Cited by 188 publications

References 24 publications

Association between depression subtypes and response to repeated‐dose intravenous ketamine

Association between depression subtypes and response to repeated‐dose intravenous ketamine

Ketamine and Beyond: Investigations into the Potential of Glutamatergic Agents to Treat Depression

Experimental medication treatment approaches for depression

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