From the Guidelines
Ketamine is not recommended for long-term use due to the lack of efficacy and safety trials, and its potential risks, including bladder toxicity, cognitive effects, tolerance development, and possible addiction risk. The current evidence suggests that ketamine can provide rapid antidepressant effects, but these benefits typically diminish within 1-2 weeks after a single infusion, necessitating repeated treatments 1. Maintenance protocols often involve infusions every 2-4 weeks at doses of 0.5-1.0 mg/kg administered intravenously over 40 minutes, though optimal long-term dosing remains unclear.
Some key points to consider when evaluating the use of ketamine for long-term treatment include:
- The limited long-term safety data available for ketamine, with most studies focusing on short-term efficacy (2-4 weeks) and few trials extending beyond 6-12 months 1.
- The potential risks associated with long-term ketamine use, including bladder toxicity (ketamine cystitis), cognitive effects, tolerance development, and possible addiction risk 1.
- The importance of thorough medical screening, regular monitoring of cognitive function, urinary symptoms, and mood, with periodic reassessment of the risk-benefit profile as treatment continues 1.
- The availability of alternative treatments, such as esketamine nasal spray (Spravato), which has more robust long-term safety data through its FDA approval process, requiring administration in certified healthcare settings 1.
In terms of specific recommendations, patients considering long-term ketamine treatment should undergo thorough medical screening and regular monitoring. Additionally, combining ketamine with psychotherapy may extend benefits, and esketamine nasal spray (Spravato) may be a viable alternative for treatment-resistant depression. However, ketamine and esketamine are not recommended as initial treatment but are reserved for patients for whom previous therapies have failed or who have not tolerated previous therapies 1.
From the FDA Drug Label
Ketamine dependence and tolerance are possible following prolonged administration. A withdrawal syndrome with psychotic features has been described following discontinuation of long-term ketamine use. The long-term use of ketamine may lead to dependence and tolerance, and a withdrawal syndrome with psychotic features may occur after discontinuation of long-term use 2.
- Key points:
- Ketamine dependence is possible with prolonged administration
- Tolerance to ketamine may develop with long-term use
- Withdrawal syndrome with psychotic features may occur after discontinuation of long-term ketamine use
From the Research
Ketamine Long-Term Trials
- The long-term safety of ketamine treatment is a topic of ongoing research, with some studies suggesting that it may be associated with cognitive impairments and other adverse effects 3.
- However, other studies have found that the most common side effects of ketamine are generally transient, mild, and self-limited, including dissociation, nausea, headache, elevated heart rate, and blood pressure 4.
- The use of esketamine, the S-enantiomer of racemic ketamine, has been approved by the FDA for treatment-resistant depression, and studies have found that it may be associated with a lower risk of cognitive impairment compared to ketamine 4.
- Heavy recreational ketamine use has been linked to ketamine dependency and other serious adverse events, including cognitive and mental disorders, and gastrointestinal and urinary tract symptoms, but these effects are thought to be dose-dependent and may not be relevant to clinical use 5.
- Chronic administration of ketamine has been found to induce cognitive deterioration by restraining synaptic signaling, and may be associated with long-term impairments in cognition 3.
- Practitioners are advised to be aware of the potential for common adverse effects of ketamine and esketamine, including dissociation, anxiety, nausea, increased blood pressure, and headache, and to take steps to prevent and manage these effects 6.
- More research is needed to fully understand the long-term safety and efficacy of ketamine treatment, particularly in terms of its potential impact on cognition and other aspects of mental health 5, 4, 7.