Ketamine in Bipolar Depression – A Review

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An excellent review of Ketamine, a rapid-acting antidepressant and anti-suicidal agent, in Bipolar Depression

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Efficacy of Ketamine in Bipolar Depression: Systematic Review and Meta-analysis. 

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Parsaik AK1, Singh B, Khosh-Chashm D, Mascarenhas SS.

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OBJECTIVE: To consolidate the evidence from the literature to evaluate the role of ketamine in the treatment of bipolar depression.

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METHODS: Major databases, including MEDLINE, EMBASE, Cochrane, and Scopus, were searched through October 2014, for studies reporting the role of ketamine in the treatment of bipolar depression. Only randomized controlled trials were included in the meta-analysis. We calculated standardized mean differences (SMDs) with SE for each study included in the meta-analysis. A random effect model was used to calculate the pooled SMDs. Heterogeneity was assessed using the Cochran Q test and I statistic.

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RESULTS: Of the 721 articles that were screened, 5 studies that enrolled a total of 125 subjects with bipolar depression (mean age, 44.6+/-4.3y and 65.6% females) were included in the systematic review; 3 randomized controlled trials (69 subjects) were included in the meta-analysis. The meta-analysis showed significant improvement in depression among patients receiving a single dose of intravenous ketamine compared with those who received placebo (SMD=-1.01; 95% confidence interval, -1.37, -0.66; P<0.0001). The maximum improvement was observed 40 minutes after the ketamine infusion. No heterogeneity was observed between the studies (Cochran Q test P=0.38, I=0%). The 2 studies that were excluded from the meta-analysis also showed significant improvement in depression after ketamine therapy. Individual studies also reported improvement in anhedonia and suicidal ideation after ketamine therapy. None of the subjects had serious side effects, and the side effects were similar between the ketamine and placebo groups.

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CONCLUSIONS: This study suggests that ketamine is effective in treatment-resistant bipolar depression and may reduce suicidal ideation and anhedonia.

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The material on this site is for informational purposes only, and is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.

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If you wish an appointment, please telephone my office.

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Bipolar Disorder Treatment Resistant – Responds to Oxytocin & Ketamine

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The patient is a Spanish speaking octogenarian who has Treatment Resistant Bipolar I Disorder with rapid cycling. In manic phases, she becomes aggressive and takes chances. Three of her siblings committed suicide in their late teens and early 20’s. The only time she has not been depressed was for eight months while caring for her dying husband ten years ago, and again, briefly, when she woke from coma 1-1/2 years ago after her most recent of many suicide attempts. She has been profoundly suicidal and lives alone with 24/7 caretakers. Her family lives one block away and keep most of her medications at their home.

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She has bilateral heel pain and longstanding pain of both knees after total knee replacement. She sleeps six hours per night, often waking three times to void, and does not nap. No daytime sleepiness. She was blinded in one eye, and has partial sight in the other due to macular degeneration dry type. She weighs 57 kg.

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Medications: She has failed every known medication. Cymbalta helped knee pain but caused her to become more depressed. Recent lithium toxicity led to the dose being lowered though blood levels were low, and she began using a walker one week ago due to vertigo. Lamotrigine was dropped from 400 to 200 mg/day, and Namenda 5 mg was started for knee pain. Azilect was discontinued eight days ago.

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On examination, she had a very flat affect. She was very attentive and responded appropriately to questions translated for her. Her daughter and son-in-law demonstrated very tender care.

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Treatment

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The patient was given a small dose of oxytocin, a hormone made in the brain. Within one hour, she mentioned wanting Italian food — a clear sign to family that her depression was beginning to respond. Ketamine nasal spray was then discussed and a total of 10 mg was tested with no change in blood pressure or heart rate. Walking the long corridor to the elevator, she commented that pain was much better. The family indicates that if her depression responds to this, it will be the first time in more than fifty years.

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The next day, family reported that instead of sleeping her usual six hours, she slept well, from 10:30 pm to 9:00 am. Symptoms began at 9:15 am. At 11:10 am, she was anxious, depressed, with suicidal ideation and knee pain was 6 on a scale of 10.

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At 11:55 am, oxytocin was given and at 12:07 pm, 20 mg ketamine was given intra-nasally. By 12:15 am, depression, anxiety, suicidality and pain were zero. There was no change in blood pressure or pulse. Relief lasted almost five hours.

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 At 4:30 pm, the caretaker reported she was crying profoundly for 10 minutes. At 5:00 pm, anxiety was rated 8, depression 10, suicidal ideation 10, pain 0. Ketamine 20 mg was given at 5:50 pm, and by 6:05 she reported no anxiety, depression or suicidality and no pain.

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She returns tomorrow for her second visit. As we go forward, we will see duration of effect. She begins low dose naltrexone today after I advised her to stop tramadol a few days ago. She had been taking tramadol, a partial opioid, for pain of both knees and heels.

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In my experience prescribing ketamine for more than eleven years, it is one of the safest medications I have ever prescribed.

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My focus is on neuroinflammation and glia in the setting of chronic pain. There is tremendous overlap in pain systems and depression with strong evidence for the role of inflammation in both conditions. Ketamine is reported to be profoundly anti-inflammatory and acts more on glial receptors than its well known effect on the NMDA receptor.

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That led me to prescribe another anti-inflammatory glial modulator for depression, low dose naltrexone (LDN). LDN antagonizes the Toll-Like Receptor 4 , the glial receptor that is a major component of the innate immune system in the brain and spinal cord. LDN has helped many of my patients who had intractable pain and a case report will be added soon that details the rapid response to LDN for a person with severe suicidality.

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A review of inflammation and glia in depression was published by Yale psychiatrists in 2008 and discusses this in much greater detail.

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Patients with Treatment Resistant Bipolar Disorder have reported that ketamine and oxytocin each help depression, but the combination works far better than would be predicted. It is hoped that persons with depression will benefit as much from addition of LDN that has helped so many with intractable pain who need ketamine much less because it is so effective. Of course these are preliminary observations after only several months, but they have been deeply rewarding. Much more work needs to be done, but in my opinion, these are a few of the key medications that have brought the greatest benefit to persons who have either pain or depression.

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Third Visit

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At her third visit last week, I sent the patient back long distance under the care of her psychiatrist with instructions to continue ketamine nasal spray and oxytocin. She apologized that she had not told the truth about her response to the medications. She had reported 100% improvement because she wanted to make her family feel better. Overall, she downgraded the rating of her depression as moderately better, and felt she was not 100%, because she still did not want to be alive. I pointed out that does not mean she is depressed, simply that she does not wish to be alive, an entirely different matter. As she spoke, she was smiling throughout the meeting.

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Her family reported that she had been swimming, had walked one block to their home over the weekend, and today they tell me she has been swimming again, and plans to swim tomorrow.

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To be continued.

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The material on this site is for informational purposes only, and is not a substitute for

medical advice, diagnosis or treatment provided by a qualified health care provider.

.

~

Please understand that it is not legal for me

to give medical advice without a consultation.

If you wish an appointment, please telephone my office.

~

~

For My Home Page, click here:  Welcome to my Weblog on Pain Management!

~

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