Conventional antidepressants can often take weeks to produce noticeable effects, but ketamine can significantly reduce symptoms within hours. This rapid action highlights a new perspective on depression and its mechanisms.
In this article, we’ll explore how ketamine works, its mechanisms of action, and some of the key research explaining its antidepressant effects.
Key Takeaways
- Ketamine can reduce depressive symptoms quickly, often within hours, making it an appealing option for those with treatment-resistant depression.
- Ketamine promotes neuroplasticity by enhancing the brain’s ability to form new connections, which is crucial for coping with stress and trauma.
- Ketamine is typically delivered via intravenous (IV) infusion or as an intranasal spray, with dosing tailored to individual needs.
- While generally well-tolerated, ketamine may cause side effects like dizziness and dissociation. Close monitoring is essential during treatment.
- Ketamine challenges the traditional monoamine hypothesis of depression, encouraging exploration of new neurological factors that influence mental health.
The Rapid Antidepressant Effects of Ketamine
Ketamine, originally developed as a dissociative anesthetic in the 1960s, has emerged as a powerful tool for treating depression in recent years. This therapy is particularly beneficial for those with treatment-resistant depression (TRD) who have been previously unresponsive to standard treatments.
Common antidepressants, such as serotonin selective reuptake inhibitors (SSRIs), can take weeks to show an effect. Clinicians are recommended to wait between three and eight weeks to see if a patient’s symptoms have improved after beginning SSRI treatment. Similarly, psychotherapy can take months for people to start experiencing benefits, and outcomes are hugely dependent on patient engagement.
Ketamine, on the other hand, is rapid-acting. Depressed patients often notice a significant reduction in symptoms within hours after treatment. This fast action is thought to be explained by ketamine’s unique mechanism of action in the brain.
Mechanisms of Action: Enhancing Neuroplasticity
Neuroplasticity refers to forming new neural connections and strengthening existing ones. This enables the brain to respond effectively to new experiences and challenges and is the basis of learning and forming new memories.
In people with depression, neuroplasticity is often reduced, which may explain why they struggle to cope with stress and trauma. Boosting neuroplasticity is a key goal in treating depression, as it helps shift negative, “stuck” thought patterns and can improve resilience to life’s challenges.
Multiple studies show ketamine increases measures of neuroplasticity, particularly in brain areas associated with emotional regulation. This effect is explained by ketamine’s action on NMDA receptors in the brain, which are proteins implicated in neuroplasticity. By inhibiting these receptors, ketamine also increases the production of brain-derived neurotrophic factor (BDNF), which aids the growth and survival of nerve cells.
Quantifying Microstructural Changes with Diffusion Tensor Imaging
Diffusion Tensor Imaging (DTI) is a type of scan that helps scientists see how water moves in the brain. By following this movement, DTI can make detailed maps showing how different parts of the brain are connected and how well these connections work. It can also show changes in connectivity, indicating neuroplasticity.
In a study at the University of Pittsburgh, 98 patients with depression were given either ketamine or a control drug and had DTI scans. The patients who showed more neuroplasticity also had bigger improvements in their depression symptoms. Ketamine increases neuroplasticity more than the control drug, especially in the amygdala, a brain region that deals with stress and emotions.
Clinical Studies on Ketamine’s Antidepressant Effects
Several clinical studies show ketamine has long-lasting significant benefits for people with depression, including various types. Some important studies are listed in the table below.
| Study | Patients | Treatment | Outcomes |
| A randomized control trial of repeated ketamine infusions for TRD | Forty-one patients with TRD | Participants received a course of six ketamine infusions administered thrice weekly over two weeks. | Single ketamine infusion elicited a significantly greater reduction in depressive symptoms compared to the placebo at 24 hours. The antidepressant effects became more prominent with repeated infusions. |
| Real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression | Sixty-six patients with treatment-resistant bipolar depression | Participants received four IV doses of ketamine over two weeks | Participants had significantly reduced symptoms of depression, anxiety, and disability following the treatment. |
| Ketamine for suicidal ideation in adults with psychiatric disorders – review study. | 572 participants diagnosed with various psychiatric disorders, mostly depression, suicidal thoughts, or past suicide attempts. | For most participants, ketamine was administered at 0.5 mg/kg via a single intravenous infusion over a 30- to 45-minute period. | At 4 hours post-infusion, treatment with ketamine was associated with a significant reduction in suicidal ideation. |
How Does Ketamine Therapy Work?
Ketamine therapy for depression is typically administered in two main forms: IV infusion and intranasal spray. In IV therapy, ketamine is delivered directly into the bloodstream through a drip, allowing for precise control of the dose.
A common dosing regimen for IV ketamine involves six infusions over two to three weeks, followed by maintenance doses as needed, depending on the patient’s response. Each session typically lasts about 40 minutes, and patients are closely monitored for any side effects, like dizziness or mild dissociation.
The intranasal form, known as Spravato (esketamine), is an FDA-approved nasal spray that patients self-administer under medical supervision, usually in a clinical setting, though at-home ketamine treatment is available. For the first month, the treatment is given twice a week, then reduced to weekly or biweekly sessions.
Dosing, Safety, and Efficacy of Ketamine Therapy
Dosing for ketamine therapy varies depending on the individual’s treatment plan and the delivery method. For IV infusions, doses typically range from 0.5 mg/kg to 1 mg/kg, while intranasal esketamine is usually administered at a dose of 56 mg or 84 mg. However, these doses can vary depending on the patient’s response and any side effects experienced during the initial sessions.
In terms of safety, ketamine therapy is generally well-tolerated, but it can have side effects such as dizziness, nausea, and dissociation, which is feeling disconnected from reality and time. Ketamine also increases heart rate and blood pressure, so it may not be suitable for those with cardiovascular problems.
Research indicates that around 50-70% of individuals with depression experience improvement following ketamine treatment. However, maintenance doses are required for these improvements to be sustained.
From Monoamine Hypothesis to NMDAR Antagonist Treatments
For many years, the monoamine hypothesis was the main theory explaining depression. It suggested that depression is caused by low levels of certain neurotransmitters, particularly serotonin, norepinephrine, and dopamine. This idea led to the creation of many antidepressant drugs, which aim to boost these chemicals in the brain, such as SSRIs, SNRIs, and MAOIs.
However, given ketamine’s rapid effects and benefits for treatment-resistant cases of depression, scientists now think neuroplasticity could be more important in depression than monoamine. Ketamine has encouraged researchers and doctors to explore other neurological factors that contribute to mental health issues.
FAQs
Why Might Some People Not Respond to Ketamine Treatment?
Not everyone responds to ketamine therapy, and several factors can influence its effectiveness. Individual differences in brain chemistry, the severity of depression, and the presence of co-occurring mental health conditions can all play a role. Additionally, the timing and frequency of treatments may affect outcomes, as some patients require more frequent or higher doses to experience significant relief.
Is Ketamine Useful for Other Psychiatric Disorders?
Yes, research is exploring ketamine’s efficacy in treating other psychiatric conditions, such as obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and anxiety disorders.
What are the Risks Associated with Ketamine Therapy?
While ketamine is generally considered safe when administered in a controlled medical setting, it does come with risks. Common side effects include increased blood pressure, dizziness, nausea, and dissociation. Additionally, there are concerns about its potential for substance abuse.
Sources
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8190578/
- https://pubmed.ncbi.nlm.nih.gov/30922101/#full-view-affiliation-1
- https://pubmed.ncbi.nlm.nih.gov/36516343/
- https://pubmed.ncbi.nlm.nih.gov/31729893/