A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression

Diazgranados, Nancy; Ibrahim, Lobna; Brutsché, Nancy E.; Newberg, Andrew; Kronstein, Phillip D.; Khalife, Sami; Kammerer, William; Quezado, Zenaide M.N.; Luckenbaugh, David A.; Salvadore, Giacomo; Machado‐Vieira, Rodrigo; Manji, Husseini K.; Zarate, Carlos A.

doi:10.1001/archgenpsychiatry.2010.90

Cited by 869 publications

(764 citation statements)

References 45 publications

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“…In clinical settings, ketamine brings about both rapid and long-lasting antidepressant effect (Berman et al, 2000;Diazgranados et al, 2010;Price et al, 2009;Zarate et al, 2006). Probably, there is a mechanism to switch the initial transient effects to longlasting antidepressant effect.…”

Section: Resultsmentioning

confidence: 99%

“…Five monkeys participated in the PET experiments, and another three were used for the microdialysis experiment. The doses of ketamine hydrochloride were based on human clinical studies (Diazgranados et al, 2010). Saline or each dose of ketamine was infused intravenously for 40 min.…”

Section: Subjects and Drugmentioning

confidence: 99%

“…In addition to robust and rapid antidepressant effects after a single dose, ketamine has sustained antidepressant effects in depressed patients for 1-2 weeks (Berman et al, 2000;Diazgranados et al, 2010;Price et al, 2009;Zarate et al, 2006). This is surprising because of an approximate 3-h half-life of ketamine in plasma (Clements et al, 1982) and its absence in brain in 24 h. These findings suggest that the neurobiological mechanism underlying the antidepressant effects of ketamine is far more complex than simple antagonism of the NMDA receptor.…”

Section: Introductionmentioning

confidence: 99%

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Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Yamamoto

Ohba

Nishiyama

et al. 2013

Neuropsychopharmacol

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Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys underwent four positron emission tomography measurements with [ 11 C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([ 11 C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ 11 C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT 1A -R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [ 11 C]DASB. No significant changes were observed in either 5-HT 1A -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased serotonin levels in the extracellular fluid of the prefrontal cortex. The present study demonstrates that subanesthetic ketamine selectively enhanced serotonergic transmission by inhibition of SERT activity. This action coexists with the rapid antidepressant effect of subanesthetic doses of ketamine. Further studies are needed to investigate whether the transient combination of SERT and NMDA reception inhibition enhances each other's antidepressant actions.

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Section: Resultsmentioning

confidence: 99%

Section: Subjects and Drugmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Yamamoto

Ohba

Nishiyama

et al. 2013

Neuropsychopharmacol

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show abstract

“…Intravenous ketamine (level 3)477, 478 has rapid onset of efficacy and may be considered for patients who are refractory to first and second‐line treatments, as well as for those in need of rapid response.…”

Section: Bipolar II Disordermentioning

confidence: 99%

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

et al. 2018

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The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third‐ line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment‐emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second‐ line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence‐based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and cariprazine alone or in combination are recommended as first‐line treatments for acute mania. First‐line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first‐line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.

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“…17 Following up leads emerging from insights into the underlying neurobiology is already producing promising results. For example, after evidence of dysfunction in the N-methyl-Daspartate-receptor complex in the glutamatergic system in bipolar disorder, two crossover trials 12,13 found that infusion of the N-methyl-D-aspartate antagonist ketamine produced rapid alleviation of depressive symptoms in bipolar depression. These findings open a new approach to drug development and provide insights into the neurobiology of the disorder.…”

Section: Future Directionsmentioning

confidence: 99%

The Treatment of Bipolar Disorder

Möller¹,

Nasrallah²

2017

Oxford Medicine Online

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We review recent developments in the acute and long-term treatment of bipolar disorder and identify promising future routes to therapeutic innovation. Overall, advances in drug treatment remain quite modest. Antipsychotic drugs are effective in the acute treatment of mania; their efficacy in the treatment of depression is variable with the clearest evidence for quetiapine. Despite their widespread use, considerable uncertainty and controversy remains about the use of antidepressant drugs in the management of depressive episodes. Lithium has the strongest evidence for long-term relapse prevention; the evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics. Substantial progress has been made in the development and assessment of adjunctive psychosocial interventions. Long-term maintenance and possibly acute stabilisation of depression can be enhanced by the combination of psychosocial treatments with drugs. The development of future treatments should consider both the neurobiological and psychosocial mechanisms underlying the disorder. We should continue to repurpose treatments and to recognise the role of serendipity. We should also investigate optimum combinations of pharmacological and psychotherapeutic treatments at different stages of the illness. Clarification of the mechanisms by which different treatments affect sleep and circadian rhythms and their relation with daily mood fluctuations is likely to help with the treatment selection for individual patients. To be economically viable, existing psychotherapy protocols need to be made briefer and more efficient for improved scalability and sustainability in widespread implementation.

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A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression

Cited by 869 publications

References 45 publications

Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

The Treatment of Bipolar Disorder

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