Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression

Zheng, Wei; Zhou, Yanling; Liu, Weijian; Wang, Chengyu; Zhan, Yongle; Li, Han-Qiu; Chen, Lijian; Li, Ming Ding; Ning, Yuping

doi:10.1016/j.jpsychires.2018.09.013

Cited by 141 publications

(135 citation statements)

References 44 publications

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“…The data were from part of the Exploratory Study on the Antidepressant Treatment using Ketamine for Depression, which was a branch project of the National Key Research and Development Program of China (Study on the Discovery and Mechanism of Precise Medical Targets for Different Antidepressants). The design and procedure of the study have been described elsewhere . Briefly, this was a single‐arm, open‐label study conducted at the Affiliated Brain Hospital of Guangzhou Medical University in China between September 2016 and January 2018.…”

Section: Methodsmentioning

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: Methodsmentioning

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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“…replicated the robust antidepressant effects of ketamine in refractory patients with BD. In addition, six injections of ketamine produced antidepressant and anti‐suicidal effects in Chinese patients with MDD and BD …”

Section: Ketamine’s Antidepressant Effects In Humansmentioning

confidence: 99%

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Hashimoto

2019

Psychiatry Clin Neurosci

272

193

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Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one‐third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment‐resistant patients with MDD or BD. Accumulating evidence suggests that the N‐methyl‐D‐aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment‐resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)‐ketamine (or arketamine) and (S)‐ketamine (or esketamine). Because (S)‐ketamine has higher affinity for NMDAR than (R)‐ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)‐ketamine exerts greater potency and longer‐lasting antidepressant effects than (S)‐ketamine in animal models of depression and that (R)‐ketamine has less detrimental side‐effects than (R,S)‐ketamine or (S)‐ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid‐acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low‐voltage‐sensitive T‐type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ‐aminobutyric acid, and type A [GABAA] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine’s antidepressant effects are discussed.

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“…Although ketamine may offer a rapid antidepressant effect in cases of bipolar depression, unfortunately the effect is not sustained in the long term. While one option is repeated ketamine infusions [78], the feasibility, accessibility and resources required can limit availability and other routes of administration (oral, sublingual, intranasal, intramuscular, subcutaneous) could prove preferred alternatives for repeat administrations [79]. However, comparatively fewer studies have fully evaluated these alternative routes and further investigation is warranted.…”

Section: Ketaminementioning

confidence: 99%

The Treatment of Bipolar Depression: Current Status and Future Perspectives

Jelen

Young

2020

Curr Behav Neurosci Rep

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Purpose of Review This paper aims to review current available treatment options and to consider future directions in the treatment of bipolar depression. Recent Findings There are a limited number of established treatments that have demonstrated varied efficacy in acute bipolar depression including modern antipsychotics (quetiapine, lurasidone, olanzapine ± fluoxetine and recently cariprazine) and mood stabilisers (lamotrigine and valproate). Lithium has a role in protecting against depressive relapses and suicide. Alternative and experimental treatments including pramipexole, modafinil/armodafinil, omega-3 fatty acids and thyroxine may be used to augment the treatment of bipolar depression. Ketamine represents a major breakthrough, producing rapid reductions in depressive symptoms even in cases of treatment-resistance, but challenges remain in how best to maintain response and reduce unwanted side effects. Summary There remains uncertainty with regard to the relative efficacy and safety of established and experimental treatments for bipolar depression. Further work using consistent and optimal trial designs and further investigation into novel compounds and treatment interventions are warranted.

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Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression

Cited by 141 publications

References 44 publications

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

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

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

The Treatment of Bipolar Depression: Current Status and Future Perspectives

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