How Ketamine Drip Works to Help Alleviate Depression
Overview of Depression: Major Depressive Disorder (MDD) or Depression is one of the most common major mood disorders in the US which can result in major impairments which interfere the ability to carry out daily activities Major Depression. It is a very common but serious mood disorder. It affects how you think, feel, and handle day to day activities, such as working, eating, or sleeping. Suicide is a major complication of depression and it is also a leading cause of death in the United States. Women are more commonly affected than men with depression Major Depression Disorder
A person with depression would experience some of the following signs and symptoms almost for the entire day, for at least two weeks:
- Feelings of sadness, restlessness, pessimism, helplessness, worthlessness, guilt, and anxiety
- Loss of interest in hobbies and activities
- Headaches, cramps, or digestive issues without any clear physical cause
- Difficulty sleeping and changes in sleep pattern
- Moving or talking very slowly
- Changes in appetite and/or weight
- Difficulty remembering, concentrating, or making decisions
- Suicidal thoughts, or suicide attempts
A class of medications called as anti-depressants are used to treat depression. These medications act on the brain to improve the chemical signaling within the brain. The mechanisms by anti-depressants act are very complex and are still not clearly understood.
Treatment Resistant Depression:
10-30% of the patients show only a partial response or no response when treated with the commonly used anti-depressants. These are the patients who are said to have Treatment Resistant Depression. Treating Treatment resistant Depression is a major challenge for psychiatrists and helth-care providers are always seeking newer or better alternatives to treat these patients. One of the drugs which physicians have tried to use for treating Treatment Related Depression is Ketamine.
Ketamine was a drug which was initially developed as an intra-venous anesthetic agent during the 1960s. It is considered as a “party drug” as well as a “horse tranquilizer.” Ketamine is used for sedation in adults and children (Roback et al. 2016).
It acts by blocking a specific type of receptors called as N-methyl-D-aspartate receptor (NMDAR) receptors.
In recent years, lower dose of ketamine has been investigated as a potential treatment of TRD in adults.
It has been reported that a single, low dose (0.5 mg/kg) of intravenous ketamine (known as ketamine drip) reduces symptoms of depression (Berman et al. 2000). More recently, intravenous ketamine has been reported as an effective intervention for TRD in adolescents (Cullen et al. 2018). These studies have shown that ketamine rapidly and effectively reduces the symptoms of depression. Usual antidepressant medicines generally take several weeks before relieving the symptoms of depression, but ketamine works very quickly.
So how does ketamine actually work so fast?
There are two major theories on how ketamine acts as an antidepressant.
- (1) NMDAR inhibition-independent antidepressant actions of ketamine
- (2) NMDAR inhibition-dependent antidepressant actions of ketamine
In order to understand how ketamine work, first we need to understand how standard antidepressants work.
Standard antidepressants are known as serotonin reuptake inhibitors (SSRIs). These SSRIs act at a molecular level (i.e. they act via complicated signalling mechanism). In order to understand the molecular mechanism, let’s go over the basic players of the mechanism.
The key players are the cell itself, G proteins, and lipid rafts.
G proteins basically act as molecular switches on the cell wall. Under normal healthy conditions, G proteins help to pass messages from the outside of the cell to the inside. Lipid rafts are sections of cell membranes that have the molecular machinery required for signalling between cells. G proteins also produce cAMP, a second messenger, which plays important roles in neuronal signalling mechanisms. In patients with depression, greater number of G proteins are packed into lipid rafts where they are meritoriously turned off. This leads to inactivation of neuronal signalling mechanisms which may be responsible for the symptoms of depression.
SSRIs gets accumulated in lipid rafts and activates G proteins by forcing them out of lipid rafts. As the process goes on, patient starts feeling better. However, this process can take a few days to complete.
NMDAR inhibition-independent antidepressant actions of ketamine
In a very recent study by Wray NH et al. (2018), it was reported that intravenous ketamine moves G proteins very rapidly (within 15 minutes) out of the lipid rafts. And this can be the answer of the question why ketamine works so fast. This study also reported that G proteins took longer time to return to the lipid rafts after ketamine treatment. (Wray NH, 2018)
NMDAR inhibition-dependent antidepressant actions of ketamine
By blocking the NMDA receptors, ketamine increases the signal flow through another specialized set of receptors in the brain called as the AMPA [α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid] receptors. This helps to strengthen the signaling in the brain and can be beneficial for alleviating the symptoms of depression.
Where do we stand with Ketamine in treatment Depression as of Today?
Currently ketamine is not FDA approved for the management of Treatment resistant depression. Clinical studies have demonstrated a signiciant clinical benefit with ketamine in improving symptoms of depression The Role of Ketamine in Treatment-Resistant Depression: A Systematic Review and the decision to use ketamine as an off-label treatment is based on robust research. IV is the most prefered route for administering ketamine and an infusion of ketamine typically lasts over 40 mins. 0.5mg/kg/day is the typically used dose and the efeects of a single dose can last up to 7 days. Patients need to monitored for any untoward effects especially those with a history of cardiovascular diseases.
Take Home Message:
IV Ketamine therapy has emerged as a promising therapy for treatment of Treatment Resistant depression backed up by robust research. However there are still certain questions which need to be adressed reagrding its optimal dosing and long-term effects. Current ongoing research on use of ketamine in depression will hopeffully provide more data to answer these questions.
Roback MG, Carlson DW, Babl FE, Kennedy RM: Update on pharmacological management of procedural sedation for children. Curr Opin Anaesthesiol 29 Suppl 1:S21–S35, 2016.
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH: Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354, 2000.
Cullen KR et al. Intravenous Ketamine for Adolescents with Treatment-Resistant Depression: An Open-Label Study. J Child Adolesc Psychopharmacol. 2018 Sep;28(7):437-444.
Wray NH et al. NMDAR-independent, cAMP-dependent antidepressant actions of ketamine. Mol Psychiatry. 2018 Jun 12.