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Commonly prescribed antidepressants, like selective serotonin reuptake inhibitors (SSRIs), have benefited many patients. Nevertheless, partial response or no response to these antidepressants is common. What can be done in these cases? Perhaps ketamine could help.
In an article published in the November issue of the Journal of Affective Disorders, researchers McIntyre and colleagues present a review of research on the efficacy of intravenous, intranasal, and oral ketamine in the management of treatment-resistant depression. This study is the first-ever meta-analysis to evaluate effect sizes across different methods of ketamine administration at the same time.
Ketamine and treatment-resistant depression
Before discussing the present investigation, let me briefly describe ketamine and treatment-resistant depression. As noted earlier, some people with depression, despite trying different first-line medications (e.g., sertraline, fluoxetine), still struggle with depressive symptoms that significantly interfere with their functioning, well-being, and happiness. For instance, a large study found that one in three depressed patients failed to achieve remission after trying multiple antidepressant treatments. In other words, one in three patients may have treatment-resistant depression.
A number of drugs have been studied recently for the management of treatment-resistant depression. One is ketamine. Ketamine has been used as an anaesthetic and a painkiller for many years. It is available as arketamine (R-ketamine) and esketamine (S-ketamine). A formula containing equal amounts of R-ketamine and S-ketamine is called racemic ketamine.
Aside from being an aesthetic and a painkiller, ketamine is also a dissociative drug, meaning it can cause sensations of disconnection from reality (e.g., sense of floating). Indeed, because of its dissociative and hallucinogenic effects, ketamine has been used recreationally for decades.
More recently, ketamine has been used clinically and investigated for the treatment of a variety of symptoms and mental health conditions, such as anxiety, post-traumatic stress disorder (PTSD), and particularly treatment-resistant depression.
For example, intravenous ketamine (IV ketamine) is used, off-label, for the treatment of many health conditions, and has been receiving considerable research attention too.
The research on the beneficial effects of ketamine on depression has been so promising that, in 2019, the US Food and Drug Administration approved Spravato (a nasal spray containing esketamine) for the management of treatment-resistant depression.
One of the benefits of ketamine, whether in the form of IV ketamine or nasal spray (esketamine or Spravato), is that it can act quickly and improve depressive symptoms in a very short time. In contrast, an SSRI antidepressant may take weeks to work, if it does work.
Many questions about ketamine remain unanswered. For instance, are all methods of ketamine administration, including oral ketamine (i.e. pills), equally effective? Or could one method of administration be more effective than another, in the long term? To answer these questions, we turn to the paper by McIntyre and coauthors.
Meta-analysis of studies of ketamine for depression
The authors used terms related to ketamine and depression to search Pubmed and Google Scholar for randomized placebo-controlled human studies. The final results included a list of 21 studies.
To compare effect sizes, mean differences were calculated. The outcomes were converted to Hedge’s g—a measure of effect size, or the strength of the relationship between the variables under consideration.
The results were promising: Specifically, a random-effects meta-analysis showed “large and significant effects for all formulations of ketamine administration.”
The following pooled effect sizes were found for different methods of administration:
Intranasal ketamine/esketamine (24 hours): g=1.25 (n=5, 95% CI: 0.591-1.903, p<0.01).
Intravenous ketamine/esketamine (2-6 days): g=0.95 (n=14, 95% CI: -0.308-2.206, p=0.139).
Intranasal ketamine (7-20 days): g=1.02 (n=4, 95% CI: 0.499-1.538, p<0.01).
Oral ketamine (21-28 days): g=0.63 (n=2, 95% CI: 0.368-0.898, p<0.01).
For IV ketamine, the greatest effect size was obtained at 2-6 days. For intranasal ketamine, the greatest effect size was obtained at 24 hours. Of course, it is difficult to compare these results directly, since IV ketamine studies typically give only one infusion, while intranasal ketamine treatments use multiple doses.
Of note, oral ketamine showed efficacy at 21-28 days. Why did oral ketamine show efficacy much later than other forms of ketamine administration? Perhaps due to bioavailability accumulation. So the antidepressant effects of oral ketamine become more apparent after the patient receives multiple doses over time.
Concluding thoughts on ketamine for treatment-resistant depression
SSRIs do not work for everyone. Nor do they work quickly. Therefore, ketamine could be used as an adjunct treatment in cases of individuals with treatment-resistant depression or individuals with suicidal tendencies who are just starting a course of SSRI treatment.
The current findings support the general short-term efficacy of ketamine for treatment-resistant depression administered via the intranasal route (both racemic ketamine and esketamine), IV route (racemic ketamine and esketamine), and oral route (racemic ketamine). More research is needed before the efficacy of oral ketamine is confidently established.
