Scientists explain how ketamine vanquishes depression within hours

October 4, 2012

(Medical Xpress)Many chronically depressed and treatment-resistant patients

experience immediate relief from symptoms after taking small amounts of the drug ketamine.
For a decade, scientists have been trying to explain the observation first made at Yale University.
Today, current evidence suggests that the pediatric anesthetic helps regenerate synaptic
connections between brain cells damaged by stress and depression, according to a review of
scientific research written by Yale School of Medicine researchers and published in the Oct. 5
issue of the journal Science.
Ketamine works on an entirely different type of neurotransmitter system than current
antidepressants, which can take months to improve symptoms of depression and do not work
at all for one out of every three patients. Understanding how ketamine works in the brain could
lead to the development of an entirely new class of antidepressants, offering relief for tens of
millions of people suffering from chronic depression.
"The rapid therapeutic response of ketamine in treatment-resistant patients is the biggest
breakthrough in depression research in a half century," said Ronald Duman, Elizabeth Mears and
House Jameson Professor of Psychiatry and Professor of Neurobiology.
Duman and George K. Aghajanian, also professor of psychiatry at Yale, are co-authors of
the review.
Understanding how ketamine works is crucial because of the drug's limitations. The
improvement in symptoms, which are evident just hours after ketamine is administered, lasts
only a week to 10 days. In large doses, ketamine can cause short-term symptoms of psychosis
and is abused as the party drug "Special K."
In their research, Duman and others show that in a series of steps ketamine triggers release
of neurotransmitter glutamate, which in turn stimulates growth of synapses. Research at Yale
has shown that damage of these synaptic connections caused by chronic stress is rapidly
reversed by a single dose of ketamine.
The original link between ketamine and relief of depression was made at the Connecticut
Mental Health Center in New Haven by John Krystal, chair of the department of psychiatry at
Yale, and Dennis Charney, now dean of Mt. Sinai School of Medicine, who helped launch clinical
trials of ketamine while at the National Institute of Mental Health.
Efforts to develop drugs that replicate the effects of ketamine have produced some
promising results, but they do not act as quickly as ketamine. Researchers are investigating
alternatives they hope can duplicate the efficacy and rapid response of ketamine.

More information:
Ketamine Timeline: A new model of rapid-acting antidepressant

1980's
Evidence emerges that the neurotransmitter glutamate and N-methyl-D-aspartate (NMDA)
glutamate receptors play a key role in higher cortical functions.
1990's
Yale investigators at the VA Connecticut Healthcare System and Abraham Ribicoff Research
Facilities of the Connecticut Mental Health Center utilize ketamine as a probe to explore the
underlying mechanisms of common psychiatric disorders including schizophrenia and
alcoholism. A test of ketamine's effects on patients with major depression is initiated. Almost
immediately, the scientists begin hearing evidence of the rapid-acting antidepressant effects of
ketamine. These effects appeared within hours and lasted for several days.1, 2
2000
The results of the first placebo-controlled, double-blinded trial to assess the treatment effects
of ketamine in patients with depression are published in Biological Psychiatry. The findings, by
Yale researchers working at the VA Connecticut Healthcare System and the Connecticut Mental
Health Center, outline the rapid antidepressant effects of the compound. The compelling results
suggest a potential role for NMDA receptor modulating drugs in the treatment of depression.3
2006
The 2000 Yale findings are replicated by a team at the National Institute of Mental Health.4 The
NIMH team includes a Yale Department of Psychiatry alumnus and co-author of the original
Biological Psychiatry article.
2010
Yale research suggests an explanation for the rapid antidepressant effects of ketamine. Results
published in Science demonstrate that a single dose of ketamine leads to an increased number
and function of new synapses in the rodent prefrontal cortex. This restoration of connections
between brain cells, a process called "synaptogenesis," is a much quicker process than forming
entirely new neurons while accomplishing the same result of enhanced brain connectivity and
circuit activity.5
2011
Yale-led study published in Biological Psychiatry demonstrates that the atrophy of dendrites
caused by chronic stress in rodents may be reversed by administration of ketamine.6

Os cientistas explicam como cetamina vence depresso dentro de horas

04 de outubro de 2012

(Medical Xpress) -Muitos cronicamente doentes deprimidos e resistentes ao tratamento sentir

um alvio imediato dos sintomas depois de tomar pequenas quantidades da droga ketamina. Por
uma dcada, os cientistas vm tentando explicar a observao feita pela primeira vez na
Universidade de Yale.
Hoje, a evidncia atual sugere que a anestesia peditrica ajuda a regenerar conexes sinpticas
entre as clulas cerebrais danificadas por estresse e depresso, de acordo com uma reviso da
investigao cientfica escrito por Yale School of Medicine investigadores e publicado no 05 de
outubro questo da revista Science.
Ketamina funciona em um tipo totalmente diferente de sistema neurotransmissor do que os
antidepressivos atuais, o que pode levar meses para melhorar os sintomas de depresso e no
trabalhar em conjunto para um em cada trs pacientes. Compreender como funciona a cetamina
no crebro pode levar ao desenvolvimento de uma nova classe de antidepressivos, oferecendo
alvio para dezenas de milhes de pessoas que sofrem de depresso crnica.
"A resposta teraputica rpida de cetamina em pacientes resistentes ao tratamento o maior
avano na investigao de depresso em meio sculo", disse Ronald Duman, Elizabeth Mears e
Casa Jameson Professor de Psiquiatria e professor de neurobiologia.
Duman e George K. Aghajanian, tambm professor de psiquiatria em Yale, so co-autores da
reviso.
Entender como funciona a cetamina crucial por causa das limitaes da droga. A melhoria nos
sintomas, que so evidentes apenas algumas horas aps a cetamina administrada, dura apenas
uma semana a 10 dias. Em grandes doses, a cetamina pode causar sintomas de curto prazo da
psicose e abusado como a droga de festa "K. Special"
Na sua pesquisa, Duman e outros mostram que, em uma srie de etapas cetamina desencadeia
libertao de glutamato neurotransmissor, que por sua vez estimula o crescimento de sinapses.
Investigao em Yale mostrou que os danos destas conexes sinpticas provocados pelo stress
crnico rapidamente revertida por uma nica dose de cetamina.
A ligao original entre cetamina e alvio da depresso foi feita no Centro de Sade Mental de
Connecticut em New Haven por John Krystal, presidente do departamento de psiquiatria da
Yale, e Dennis Charney, agora reitor da Mt. Sinai School of Medicine, que ajudou a lanar os
ensaios clnicos de cetamina enquanto no Instituto Nacional de Sade Mental.
Os esforos para desenvolver drogas que reproduzem os efeitos da cetamina tm produzido
alguns resultados promissores, mas eles no agir to rapidamente quanto cetamina. Os
pesquisadores esto investigando alternativas que esperam pode duplicar a eficcia e resposta
rpida de cetamina.

Mais informao:

Timeline cetamina: Um novo modelo de antidepressivo de ao rpida

1980
Surgem evidncias de que o neurotransmissor glutamato e N-metil-D-aspartato (NMDA),
receptores de glutamato desempenham um papel chave em funes corticais superiores.
1990
Investigadores de Yale nos VA Connecticut Healthcare System e Abraham Ribicoff Instalaes de
pesquisa do Centro de Sade Mental de Connecticut utilizar cetamina como uma sonda para
explorar os mecanismos subjacentes de transtornos psiquitricos comuns, incluindo
esquizofrenia e alcoolismo. Um teste de efeitos da cetamina em pacientes com depresso maior
iniciada. Quase imediatamente, os cientistas comeam a evidncia dos efeitos antidepressivos
de aco rpida da cetamina auditiva. Estes efeitos apareceu dentro de horas e durou vrios
dias.1, 2
2000
Os resultados da primeira, ensaio duplo-cego controlado por placebo para avaliar os efeitos do
tratamento de cetamina em pacientes com depresso so publicados em Biological Psychiatry.
Os resultados, por pesquisadores de Yale que trabalham no VA Connecticut Healthcare System
e do Connecticut Mental Health Center, delinear os efeitos antidepressivos rpidos do
composto. Os resultados convincentes sugerem um papel potencial para a modulao do
receptor de NMDA drogas no tratamento de depression.3
2006
Os resultados Yale 2000 so replicadas por uma equipe do Instituto Nacional de equipe Sade.4
Mental O NIMH inclui um ex-aluno do Departamento de Psiquiatria e co-autor do artigo
Biological Psychiatry originais Yale.
2010
Pesquisa Yale sugere uma explicao para os efeitos antidepressivos rpidos de cetamina.
Resultados publicados na Science demonstram que uma nica dose de cetamina leva a um
aumento do nmero e funo das novas sinapses no crtex pr-frontal de roedor. Este
restabelecimento de ligaes entre as clulas cerebrais, um processo chamado de
"sinaptognese," um processo muito mais rpido do que formar inteiramente novos neurnios
ao realizar o mesmo resultado de uma maior conectividade do crebro e do circuito activity.5
2011
Estudo liderado pela Yale publicado na Biological Psychiatry demonstra que a atrofia das
dendrites causadas por estresse crnico em roedores pode ser revertida pela administrao de
ketamine.6

VER VIDEO ANEXO (INGLS): Video 02 - New Mechanisms Elicited with Ketamine in TreatmentResistant Depression

References
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antagonist,
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Journal reference: Science
Provided by: Yale University

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