A paper published in the journal Neuropsychopharmacology presented evidence that ketamine treatments may help reduce depression during benzodiazepine withdrawal. The study evaluated 22 patients with severe unipolar or bipolar TRD (treatment resistant depression) undergoing discontinuation from long-term (>6 months) benzodiazepine use. The patients in the study received ketamine infusions over a period of four weeks.
AUTHORS: Nicolas Garel, Kyle T. Greenway, Lê-Anh L. Dinh-Williams, Julien Thibault-Levesque, Didier Jutras-Aswad, Gustavo Turecki, Soham Rej & Stephane Richard-Devantoy
DATE: August 2, 2023
Depression is a common symptom of withdrawal from BZDRs (benzodiazepines/Z-drugs). In addition, patients with depression are far more likely to be prescribed BZDRs than others.
Approximately 30–50% of patients with depression are prescribed benzodiazepines and/or Z-drugs at some point during their illness. Although international depression guidelines generally recommend only short-term BZDR use, chronic use eventually arises in 10–15% of patients with depression – particularly those with treatment resistant depression (TRD). — Garel 2023
Since BZDR use is linked closely to depression for a number of reasons, and depression can have severe detrimental effects on a person's health, including suicide, finding an effective treatment for depression associated with discontinuation is a top priority.
The study evaluated 22 individuals, of which 91% "successfully discontinued all BZDRs [benzodiazepines/Z-drugs] by the end of the 4-week intervention." During follow-ups 3-24 months later, 64% remained off BZDRs. According to the article, "These preliminary results suggest that ketamine infusions for TRD may facilitate the deprescription of BZDRs, even in patients with active depressive symptoms and significant comorbidity."
Only a minority (≤25%) of participants experienced clinically significant deterioration in depression, anxiety, sleep, or suicidality at any timepoint during the treatment process by PCC analysis. These results contrast with typical rates of BZDR withdrawal symptoms occurring in 40–100% of discontinuers, even with gradual tapering, most commonly in the days-weeks following the last quarter of the original dose. — Garel 2023
In closing, the authors summarized "we present the first quantitative and qualitative evidence that ketamine may facilitate discontinuation of chronic BZDRs," and they suggested that further research is warranted.
New studies that provide hope for treatment of benzodiazepine withdrawal and/or BIND always grab our attention. We endlessly wish for the day when a treatment or protocol or medicine comes along a makes it all go away. Unfortunately, medicine, and life, are rarely that easy.
This study does provide some hope, but it also has its limitations. The sample size was small, so a much larger study would be warranted. In addition, all of the patients had severe unipolar or bipolar TRD, so this is not a general sample and is limited to individuals with diagnosed TRD. The authors also stated other limiting factors such as "lack of a control group, varying length of follow-up, inability to examine the impact of sex on outcomes of interest, and, most importantly, the lack of standardized scales of BZDRs withdrawal."
And then there is homeostasis.
Homeostasis is a common topic in the benzo community. It is also a common theory of recovery — which at is core is about the "rebalancing" of the neurotransmitters glutamate (excitatory) and GABA (inhibitory), and how they are received by their respective receptors. The goal of this "rebalance" is to allow the body to return to normal functioning, without medication interfering with that process anymore. This definitely over simplifies the theory, and there are many other processes in the body affected by BZDR exposure, but for now I'm going to focus on the one that gets most of the attention.
According to a 2020 study in Frontiers in Psychiatry, "Converging evidence suggests that ketamine elicits antidepressant effects via enhanced neuroplasticity precipitated by a surge of glutamate and modulation of GABA." Ketamine has also been found to directly affect cortical glutamate levels (Stone 2012). While it may be possible that a medication or treatment may assist in the "rebalance" we all seek, it is also possible that these treatments may hinder the natural healing process that is already taking place.
I must admit that I am very skeptical about treating BIND with additional medication, but I also realize that for some individuals it is worth the risk. BIND can be distressing and debilitating for some people, and may also increase the risk of suicidality. In these cases, it is important for the patient to work closely with his/her doctor to determine the best course of action.
I also want to state that I am not a medical professional and my analysis here is definitely that of a lay person. Still, sometimes common sense provides wisdom in these situations. When it comes to healing from benzodiazepine use, I will rely on the natural approach for now. We were told that benzos were completely safe time and time again by the medical establishment. That didn't turn out so well. Should it be a surprise, then, that we are now cautious of additional medication?
I will remain open, and continue to analyze research on new treatments — and do so with a touch of caution and hope. Ketamine very well may help treat depression for individuals discontinuing benzodiazepines. But, as with many mediations, it may also hinder the healing process in the long-run, or even worse, cause its own added complications. We truly don't know.
Garel, N., Greenway, K.T., Dinh-Williams, LA.L. et al. Intravenous ketamine for benzodiazepine deprescription and withdrawal management in treatment-resistant depression: a preliminary report. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01689-y.
Ritvo AD, Foster DE, Huff C, Finlayson AJR, Silvernail B, et al. (2023) Long-term consequences of benzodiazepine-induced neurological dysfunction: A survey. PLOS ONE 18(6): e0285584. https://doi.org/10.1371/journal.pone.0285584.
Silberbauer LR, Spurny B, Handschuh P, Klöbl M, Bednarik P, Reiter B, Ritter V, Trost P, Konadu ME, Windpassinger M, Stimpfl T, Bogner W, Lanzenberger R, Spies M. Effect of Ketamine on Limbic GABA and Glutamate: A Human In Vivo Multivoxel Magnetic Resonance Spectroscopy Study. Front Psychiatry. 2020 Sep 8;11:549903. doi: 10.3389/fpsyt.2020.549903. PMID: 33101078; PMCID: PMC7507577. https://pubmed.ncbi.nlm.nih.gov/33101078/.
Stone JM, Dietrich C, Edden R, Mehta MA, De Simoni S, Reed LJ, Krystal JH, Nutt D, Barker GJ. Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology. Mol Psychiatry. 2012 Jul;17(7):664-5. doi: 10.1038/mp.2011.171. Epub 2012 Jan 3. PMID: 22212598; PMCID: PMC3883303. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883303/.
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