Ketamine for Bipolar Depression?

John McManamy Health Guide
  • “Ketamine improved bipolar depression within minutes, study suggests,” read the headline in the May 30 Science Daily. The real story is far more complicated. Read on:


    A team of researchers at the NIMH recruited 15 bipolar patients with depression (who were already on a mood stabilizer) and administered them either a small single intravenous dose of ketamine or a placebo. Two weeks later, the subjects were “crossed over,” ie those on the test drug now received the placebo and vice-versa.


    The study found that 79 percent of those taking ketamine achieved “significant improvement” in symptoms within 40 minutes (including reduced suicidal thinking), and maintained this improvement over three days vs zero on the placebo. 

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    The study replicates a similar finding by the same researchers (using 15 patients), and supports two open-label (ie no placebo) studies on small patient groups. These studies build on similar studies done on patients with unipolar depression.


    Before you shout “hallelujah,” we need to keep in mind that larger clinical trials (the type needed to win FDA approval) almost never replicate the optimistic findings of smaller studies. Moreover, test drugs are likely to fail for intolerable side effects. Indeed in a review article just published online, the study’s lead author Carlos Zarate notes that although future investigation is warranted, “due to its associated sedative and psychotomimetic [ie mimicking psychosis] effects, it is unlikely that ketamine will be adopted for widespread clinical use.”


    So what is all the fuss about? One word: glutamate. Dr Zarate’s article spells it out:


    Glutamate is an “excitatory” neurotransmitter that is widely distributed in the brain. It also regulates neuroplasticity, learning, and memory. More recently, imaging studies implicate elevated levels of glutamate in mood disorders and anxiety. What seems to be happening, according to Dr Zarate, is that excess glutamate transmission (from exposure to chronic stress) results in the loss of dendritic spines.


    Dendrites are neural extensions at the receiving end of the synapse. Thus, when bombarded by excess glutamate (which results in over-excitation and the possibility of brain cell death), the brain goes into a sort of protective crouch. Dendrites retract, which reduces the number of receptors on the neuron. The neuron is now exposed to more normal levels of glutamate. 


    The catch is that the neuron - indeed whole neural networks - are taken off-line. This is fine in emergencies, when the brain can reset to normal once the crisis is resolved, but under chronic stress the brain may experience great difficulty in resetting to normal. The dendritic spines - the basis of branching in neural networks - fail to grow back.


    Not surprisingly, says Zarate, “the glutamatergic system likely plays a significant role as a primary mediator of psychiatric pathology.” Hence the quest to find drugs that work on glutamate. Ketamine is but one of many such agents under investigation.


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    The glutamatergic system is enormously complex, but to vastly oversimplify:


    There are two major types of glutamate receptors - ionotropic and  metabotropic. The NMDA receptor is one species of ionotropic receptor. When the NMDA receptor is working right, glutamate and glycine bind to the receptor, which opens up its corresponding ion channel and permits calcium entry into the neuron. This in turn promotes intracellular signaling essential to plasticity and survival. 


    Ketamine is a “high-affinity NMDA antagonist” that blocks the NMDA receptor, thus preventing excess calcium influx and cellular damage (and thus avoiding the domino effect of causing dendrites to atrophy). The drug was originally used as an anesthetic, and is still used as such in veterinary medicine. There is also a limited use in small IV doses (at $2,000 per treatment) for pain management in humans. The drug is also a derivative of the street drug PCP (angel dust).


    Animal and human studies suggest that ketamine activates certain molecular signaling pathways inside the neuron. Just to give you a general idea, here is a sample sentence from Zarate’s article:


    In particular, recent well designed experiments have demonstrated that ketamine rapidly activates the mammalian target of rapamycin (mTOR) pathway, leading to increased synaptic signalling proteins, spine plasticity (maturation/shape formation) in the PFC, and antidepressant-like behaviors in rodents. 


    Don’t worry, I didn’t understand a word of that either.


    The point is that ketamine is an experimental drug that is being used - along with other drugs on other targets - to prize loose the secrets of the glutamate system and to understand how this system impacts mood disorders. It is NOT - I repeat not - a drug being investigated for the treatment of bipolar depression. Perhaps there will be an eventual use for the drug for this purpose, but we have no way of knowing that right now.


    What we can take away from the research of Zarate and others is that it is possible - via a glutamate agent - to induce an extremely rapid response in depressed bipolar patients. This is what researchers refer to as “proof-of-concept.” Translating the concept to safe and effective therapeutic treatments is another story. Zarate describes this as "the mismatch between our ever-expanding knowledge of the glutamatergic system and the slow pace of therapeutic development."


    Loosely translated, we need money for research - lots of it - lots more than what passes for a research budget in today's penurious climate. You can see the frustration: all these smart people, all this knowledge, all this promise, but still ...


    We have such a long way to go. 


Published On: September 30, 2012