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Ketamine For Bipolar Disorder: Treats Anhedonia Prior To Depression

For years, researchers have been investigating illicit drugs to determine whether they could be used under supervision to treat mental illnesses like depression and bipolar disorder. Although many of these substances have shown promise, in many cases the side effects and addiction potential outweigh any therapeutic benefits. Other times, many drugs may be temporarily helpful over a short-term, but may not be a good treatment option for the long-term.

One substance that has come to the forefront of recent research is that of ketamine. Awhile ago, I wrote about ketamine nasal spray providing rapid antidepressant relief. Ketamine, also referred to as “Special K” has even been investigated by various pharmaceutical companies – some hope to create a drug that mimics its effects without the hallucinogenic properties. For example, the company AstraZeneca had developed the compound Lanicemine (ADZ6765) to mimic the therapeutic antidepressant effects of ketamine, without causing dissociation and hallucinations.

New Study: Ketamine Helps Improve Bipolar Depression (2014)

A new study suggests that ketamine may not only be helpful for those with clinical depression, but also bipolar depression. Ketamine differs from traditional antidepressants in its mechanism of action – it affects different brain systems, neurotransmitters, and neural pathways.  This was all new to researchers, as most hypothesized that the antidepressant response would activate similar areas of the brain to antidepressants.

Small-scale study: How it worked…

The study involved administering ketamine or a placebo to 36 patients in the depressive phase of bipolar disorder. Researchers then noted any changes in mood on a rating scale that measured anhedonia (inability to feel pleasure) and another that measured depression. By isolating the ratings of anhedonia and depression, researchers came to realize that ketamine administration results in an “anti-anhedonia” or pleasurable response quickly – well before it reduces other symptoms of depression.

In other words, individuals were able to notice feeling more interested in pleasurable activities prior to their mood improvement. Anhedonia was noted to improve in under an hour (approximately 40 minutes), while all other depressive symptoms took up to 2 hours for a patient to notice improvement. This suggests that people are feeling somewhat better from the drug because it is specifically treating anhedonia, a symptom that is often prominent among those who are depressed.

Even without other antidepressant effects, the anti-anhedonic response was significant. This suggests that ketamine may be useful for directly targeting those with severe anhedonia. Furthermore, anti-anhedonia agents like ketamine may be beneficial for those dealing with negative symptoms of schizophrenia as anhedonia is a debilitating symptom.

Ketamine stimulates the right hemisphere to reduce anhedonia

During this study, researchers conducted brain scans on participants to track how ketamine was affecting the brain. They discovered that the mechanism by which ketamine decreased anhedonia was a result of increasing activity within the frontal and deep right hemisphere of the brain. Specifically, the PET scans showed major change within the dorsal anterior cingulate cortex.

Initially, researchers suspected that ketamine would stimulate activity in the mid-brain to elicit an antidepressant response. Contrary to their suspicion, ketamine didn’t influence the mid-brain area that they anticipated, rather it stimulated activity in the dorsal anterior cingulate cortex, near the front of the brain and the putamen, located deep within the right hemisphere. When activity in this area of the brain increased, previously-depressed participants began anticipating pleasurable experiences.

Many for which ketamine is effective in treating their depression regard it as being superior to traditional antidepressants due to the fact that it works rapidly. Traditional antidepressants can take a significant period of time to improve a person’s mood – often 4 to 6 weeks (Read: Why antidepressants take so long to work).  With ketamine, the anti-anhedonic response occurred within 40 minutes and antidepressant effects began just 2 hours after administration – this is significantly quicker than most pharmaceutical antidepressants.

For those who are depressed, trying an antidepressant for weeks, not getting relief, and switching to another in hopes that it will work within a month can be frustrating. This new research is intriguing because increasing activity in these specific areas of the brain can now be associated with an anti-anhedonia response.  If this area of the right hemisphere can be targeted or stimulated either artificially or by smart drugs, it may lead to quicker reductions in depression.

Some believe that although anhedonia and depression are relatively synonymous, specifically targeting anhedonia may be the key to its quick efficacy.  It can now be speculated that certain individuals with depression may have naturally inadequate activity in the dorsal anterior cingulate cortex and/or that it may become functionally impaired. As a result, stimulating activity in this part of the brain may lead to an anti-anhedonic and antidepressant response – the same as provided by ketamine.

Note: It is worth mentioning that although brain pathways and activity may be important in influencing ketamine’s effets, alterations in levels of neurotransmitters must be taken into account.  For example, ketamine affects glutamate and dopamine levels – both of which may boost mood.

How long did the anti-anhedonic response last?

The improvement in anhedonia lasted up to two weeks (14 days). Carlos Zarate M.D. of the National Institute of Mental Health explained that they were able to discover “a component that responds uniquely to treatment that works through different brain systems than conventional antidepressants – and link that response to different circuitry other than depression symptoms.”  Anhedonia is considered a major symptom of both depression and bipolar disorder.

Based on the findings in this study, it may be worth assessing how various types of brain activity correlates with mood, depression, and anhedonia. This study suggests that it may be worth pursuing treatments for anhedonia as they are likely to help with “depression.”  In the past, specifically targeting depressive symptoms has been an important treatment goal.  However, now it may be worth treating anhedonia first and feeling less depressed may be a natural consequence.

Further research is needed to confirm findings

Currently there is a follow-up study in the works involving the ketamine to treat unipolar depression.  This follow-up study will serve to confirm their initial findings from this sample of those with bipolar depression. Should similar results be found, it will further support the existing literature that suggests ketamine can be beneficial for those with treatment-resistant forms of depression.  It also supports the idea that treating anhedonia may be a key component towards alleviating depression.

Before researchers get too excited though, it needs to be mentioned that the study discussed above had an extremely small sample size.  Before researchers can confirm these findings, they must use a significantly larger sample than 36 patients.  It is also important to understand that ketamine is not a utopian treatment option for depression. It is currently NOT approved by the FDA to treat depression and usage can result in unwanted side effects such as hallucinations, amnesia, memory impairment, and in some cases, addiction.

Both pharmaceutical drugs as well as illicit drugs like ketamine will always have benefits and drawbacks. Although the benefits of ketamine may be short-term, feeling more pleasure (less anhedonia) and getting an antidepressant response for someone with treatment-resistant depression may be a huge milestone.

  • Source: http://www.nature.com/tp/journal/v4/n10/full/tp2014105a.html

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