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Ketamine As a Rapid Antidepressant BJPsych Advances (2016), vol. 22, 222–233 doi: 10.1192/apt.bp.114.014274 ARTICLE Ketamine as a rapid anti depressant: the debate and implications Roger C. M. Ho & Melvyn W. Zhang Roger Ho is an Associate Professor response rates to SSRIs and NaSSAs are around SUMMARY and consultant psychiatrist in 62% and 67% respectively (Papakostas 2008). the Department of Psychological Ketamine, a synthetic derivative of phencyclidine, Environmental factors such as relationship Medicine, Yong Loo Lin School of is a commonly misused party drug that is Medicine, National University of problems, financial difficulties and comorbid restricted in high-income countries because of Singapore. He has a special interest substance misuse often lead to poor treatment its addictive potential. Ketamine is also used as in psychoneuroimmunology and response, and antidepressants combined with the interface between medicine an anaesthetic in human and veterinary medicine. and psychiatry. Melvyn Zhang In the 1990s, research using ketamine to study the CBT have shown promising results in prevention is a senior resident with the pathophysiology of schizophrenia was terminated of mood disorders (Brenner 2010). Although 70– National Addiction Management owing to ethical concerns. Recently, controversy 90% of patients with depression achieve remission, Service, Institute of Mental Health, surrounding the drug has returned, as researchers around 10–30% are refractory to initial treatment Singapore. Correspondence Dr Roger C. M. have demonstrated that intravenous ketamine but respond to switching or combination of Ho, National University of Singapore, infusion has a rapid antidepressant effect and antidepressants, electroconvulsive therapy (ECT) Department of Psychological have therefore proposed ketamine as a novel or psychotherapy. Around one-third of patients who Medicine, Level 9 NUHS Tower antidepressant. This article debates the question are refractory to initial treatment do not respond Block, 1E Kent Ridge Road, of ketamine as an antidepressant, considering the to other antidepressants and combined treatment Singapore, Singapore 119228. Email: drug’s addictive potential, ethical concerns about [email protected] (Al-Harbi 2012). Hence, 9–10% of patients with prescribing a hallucinogen, the evidence base and motives behind ketamine trials. depression have treatment-resistant depression. Recently, some studies have found that ketamine LEARNING OBJECTIVES has rapid antidepressant effects in patients with • Understand the pharmacological properties of treatment-resistant depression. ketamine as an anaesthetic, a drug of misuse and a proposed antidepressant What is ketamine? • Review the current evidence for ketamine in Ketamine was first synthesised in 1962, by Calvin treating depressive disorder and recognise Stevens in a Parke-Davis laboratory. It was potential risks associated with long-term use considered a safer alternative to the hallucinogen • Recognise the arguments for and against the use phencyclidine (PCP). Parke-Davis patented of ketamine as a novel antidepressant ketamine as an anaesthetic in 1966. Ketamine DECLARATION OF INTEREST was first used as a battlefield anaesthetic in the None Vietnam War. The drug induced a dissociative state that was helpful in treating wounded soldiers by keeping them conscious but cognitively separated Major depressive disorder (MDD) is a common from pain (Trujillo 2011). During the 1970s, young psychiatric illness that is estimated to affect people started to use ketamine as a recreational 120 million people worldwide (Li 2011a). The drug. Ketamine is still used in veterinary medicine, low heritability of MDD (39%) suggests that and also as a battlefield anaesthetic in low- and environmental rather than genetic factors are middle-income countries. contributing more to variations in its phenotype. Ketamine is a non-competitive N-methyl-D- In the past 50 years, there have been significant aspartate (NMDA) receptor antagonist. It exists in advances in the treatment of MDD, including the two optical isomer forms, S(+) ketamine and R(−) development of various antidepressants, such as ketamine. In human brain, S(+) ketamine binds to tricyclic antidepressants (TCAs), selective serotonin the PCP-binding site of the NMDA receptor with reuptake inhibitors (SSRIs) and noradrenergic and fivefold higher affinity than does R(−) ketamine. specific serotonergic antidepressants (NaSSAs). A pharmaceutical company is currently testing Psychotherapies such as cognitive–behavioural a nasal spray formulation of the S(+) ketamine therapy (CBT) and interpersonal psychotherapy as a potential antidepressant, although no results are also evidence-based treatments. Given the have been published. Ketamine is metabolised by low heritability of MDD, it is not surprising that hepatic cytochromes CYP 3A4, 2B6 and 2C9 into 222 Downloaded from https://www.cambridge.org/core. 27 Sep 2021 at 12:00:26, subject to the Cambridge Core terms of use. Ketamine as a rapid anti depressant dehydronorketamine and norketamine, which can UK, ketamine is now a class B drug because the be detected in urine (Li 2011a). Ketamine has a prevalence of ketamine misuse among recreational high first-pass effect (Salvadore 2013) and short users increased from 25% to 40% between 2002 half-life (~3 h) (Lo 1975). Although ketamine and 2007 (McCambridge 2007). The British Crime can be administered via the oral, intranasal Survey of 2010–2011 reported that there were and intramuscular routes, the intravenous 125 000 recreational users of ketamine in the UK route is preferred because it allows precise (Smith 2011). In the USA, ketamine is a schedule dosing and dose adjustment if side-effects occur III drug (Schatzberg 2014), and emergency room (Canadian Agency for Drugs and Technologies in visits due to ketamine misuse increased by 2000% Health 2014). between 1995 and 2002 (Substance Abuse and Ketamine can relieve pain through the mu Mental Health Services Administration 2003). In opioid receptors. Its action on the monoaminergic Hong Kong, ketamine is a schedule I drug. It is system is similar to that of amphetamine or the most common drug of misuse and consumed cocaine (Schatzberg 2014), and the drug is liable by more than 80% of drug users (Li 2011a). to misuse owing to its dopaminergic, opiate and Ketamine is the second most commonly misused stimulant effects (Moghaddam 1997; Schatzberg drug in Taiwan (Lua 2003), where the age at onset 2014). Other pharmacodynamic mechanisms of ketamine misuse is as young as 15 years (Lee include prevention of the influx of calcium ions and 2012). There is pressure to reschedule ketamine to alteration of limbic system functioning (Bergman limit its use in Taiwan (Li 2011a). Ketamine has 1999). Calcium influx into mitochondria may lead become the second most common drug of misuse to neurotoxicity in the frontal cortex (Xu 2015). in central rural China (Deng 2012). Ketamine Ketamine is associated with memory impairment misusers have a false perception that ketamine is (Morgan 2014). By blocking NMDA receptors, relatively safe, and this has made it the preferred ketamine exacerbates the psychotic and cognitive drug. Some Asian countries have very strict laws symptoms of schizophrenia (Malhotra 1997). on drugs, imposing harsh punishment. In Malaysia At low doses, ketamine causes euphoria, sen- and Singapore, anyone caught with ketamine sory distortions, impairments in set-shifting and faces imprisonment or strokes of the cane (Central heightened feelings of empathy (Krystal 1994; Narcotics Bureau 2013). Repeat offenders may face Jansen 2001; Dillon 2003). At high doses, it causes the death penalty in Malaysia. dissociative effects, hallucination, intoxication and frightening experiences (Trujillo 2011). Lai et al Controversies surrounding ketamine (2014) have demonstrated that the psychotomimetic The use of ketamine in psychiatric research has effects of ketamine are dose-related and that its been the subject of controversy over recent decades antidepressant effects may also be. Ketamine (Table 2). misuse is associated with amnesia, dependence, dissocia tion, lower urinary tract dysfunction and Ketamine and schizophrenia poor impulse control (Li 2011a). The worldwide The first debate occurred in 1999 (Marshall incidence of ketamine seizures significantly 1999), when the National Institute of Mental increased between 2003 and 2006 (Xu 2015). Health (NIMH) suspended a US study in which In this review, we will examine recent evidence ketamine was used to induce psychosis in regarding the use of ketamine as a rapid anti- patients with schizophrenia. Researchers argued depressant and its potential for misuse (Yang 2014). that such ketamine challenge studies would In arguing that the evaluation of antidepressant ketamine must go beyond clinical trials, we hope to give psychiatrists and patients a better TABLE 1 Restriction of ketamine use in different countries understanding of the drug, its antidepressant efficacy and side-effects, and the controversies Restricted by schedule surrounding its use in psychiatry. I/II, A/B or X III/IV or C/D Restricted by other Unrestricted and (greatest restriction) (least restriction) legislation legal to use Current legal status and prevalence of ketamine misuse Canada (I) Australia (IV) Brazil (veterinary law, not for Iran China (I) Mexico (III) human use) Netherlands Ketamine misuse is common worldwide, Denmark (B) New Zealand ( C ) Malaysia (Dangerous Drugs Romania Act 1952) under street names such as K and
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