It appears that ketamine, a drug with a really bad reputation, might be helping researchers to explore new and quicker treatments for depression.
New 'wonder drug'
Though it is not officially used to treat depression in this country, Americans are trying it, and depressed people who search the web for new options are asking their doctors for this new “wonder drug”. As with all so-called wonder drugs, there are snags, concerns and cautions.
In America, people are trying to profit from the drug before the necessary facts are known, and there are already “ketamine clinics” making unsubstantiated claims.
Ketamine is definitely an interesting substance. Developed in the early 1960s and first used by vets as an animal anaesthetic, it is now also used as an anaesthetic for humans, especially for short procedures, though it has the potential to induce hallucinations. Its advantage lies in producing less depressed breathing and lowered blood pressure than most other anaesthetics. Though it has been tried in a number of other situations, including bronchospasm and complicated pain problems, there’s a lack of good research showing effectiveness.
Ketamine tends to produce a form of dissociative trance with sedation and pain relief, and memory loss. A problem with such amnestic drugs is that users may forget the problems it may have caused and give unreliable reports on its effects. As the drug wears off, it can cause many problems, from muscle trembling and high blood pressure to confusion, often with severe agitation, and even temporary psychosis. In animal studies there has been some concern about possible structural brain damage, but this has not been confirmed in humans.
Chemically it affects many different systems of internal chemistry, and is related to the intravenous anaesthetic Phencyclidine (PCP). As with other drugs producing dissociation and similar effects, it became a popular drug of abuse in “rave” scenes, with varied effects. It has been blamed for a significant number of deaths (over 90 reported in the UK) from overdoses, accidents and suicide, and so became more carefully controlled by drug authorities in a number of countries.
It’s been used experimentally for depression and bipolar disorder, especially in people who have been resistant to ordinary antidepressants, given as a single intravenous infusion at lower than anaesthetic doses, with reports of rapid relief of depressive symptoms, commencing within an hour or two and lasting for approximately a week.
This sounds like really good news. But the quality of research supporting such claims is still poor and limited, and there are other serious reasons for caution. Drug abusers reportedly develop tolerance to the effects of the drug quite rapidly, and regular use can cause bladder and kidney problems. It can also cause raised blood pressure and hallucinations.
The rapid onset of symptom relief is exciting. It seem to work by blocking receptors for glutamate, another internal chemical attracting interest in depression, and hence in a different way to other antidepressants.
It’s had a number of street names, such as "K", "Special K" and "cat Valium", and is taken in various ways and forms. It’s similar in chemistry and actions to PCP, and can also cause really bad trips. Like the notorious Rohypnol it has also been used as a date rape drug. It’s even been used by poachers to knock out rhinos.
Ketamine from street dealers may be seriously contaminated with other chemicals, such as MDMA, so self-medicating with street ketamine for depression is really risky.
Some have used it to induce depersonalisation and derealisation, with auditory and visual hallucinations. Many people find this deeply unpleasant and frightening, while other actually seek it out.
Implications of ketamine
Among the areas where this drug is especially interesting is in regard to the idea of neuroplasticity. We tend to think of the brain as a fixed structure, but many factors influence its form and configuration, and may cause brain cells to malfunction and die, or to grow and develop new connections.
In major depression, for instance, a research review published in the Archives of General Psychiatry found a reduction of around 10 to 15 % of the volume of a vital brain structure, the hippocampus, and a marked reduction in mood and intelligent performance, so part of the reason we may struggle to get out of depression, may be that our brain is not working optimally.
A key factor in such shrinking of important brain structures is that in depression there appears to be a reduction in a significant substance called BDNF, Brain-Derived Neurotrophic Factor, a variety of protein that encourages the repair and re-growth of neurons, brain cells, and even the creation of new neurons. BDNF has been called “brain fertiliser”.
Ketamine seems to act directly on the glutamate system within the brain (one not usually targeted by existing treatments), rather than on serotonin, noradrenaline and others we’re more familiar with. Ketamine apparently blocks the action of the N-methyl-D-aspartate (NMDA) receptor, causing a rapid increase in BDNF levels.
So it seems to use the brain’s potential plasticity and encourages cells to regrow and rejoin the normal range. Whether the regrowth is precisely the required forms of neurons and in exactly the right areas, is not entirely clear.
It’s the speed of this effect that’s impressive. Drugs commonly used today, like SSRI antidepressants also increase BDNF, but far more slowly, only reaching optimal levels after 4 weeks of treatment. The eventual impact may be similar, but getting there is a much slower process than with ketamine.
Safer and more lastingly beneficial treatments
This conflicts with the customary explanation that SSRIs and other antidepressants cause their benefits by changing levels of brain chemicals such as serotonin – because while these changes happen quickly, benefits are experienced much more slowly. This apparent delay in efficacy may be due to the slower increase in BDNF levels.
Ketamine may be most important, not as a new form of treatment, but as a model for creating safer and more lastingly beneficial treatments, producing a rapid and lasting boost in BDNF levels.
We need much more research into ketamine and similar agents. Its use in anaesthesia has shown some of its immediate risks and benefits, but at higher, single doses, rather than used repeatedly over prolonged periods. We don’t yet know enough to it safely and effectively.
It’s easy for patients to feel desperate enough to try anything that might help. We need proper clinical trials to be sure about the best and safest dose and best method of administering it. We need to know often the dose needs to be repeated, and how long treatment should last. We also don’t know enough about possibly unwanted long-term effects.
There is growing evidence that ketamine, used very carefully and in much lower doses can produce a rapid and pleasant improvement in severe symptoms of depression – for a short time at least. We don’t yet know if this applies to everyone, although it seems to help people who do not respond well to the usual treatments.
Rapid relief, even if brief, could be useful in some circumstances, but until we know how to create lasting wellness, the rebound effect could be a return to an even deeper depression. Tolerance has in fact been reported by frequent recreational users.
Doctors cannot currently justifiably recommend ketamine. Any doctor who prescribes an experimental drug, is acting unprofessionally and risks losing his license. We need good research to produce usable results and to settle the outstanding questions.
Image: Ketamine from Shutterstock