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Ketamine: a Novel Antidepressant with a Fast Onset of Action?† COMMENTARY ON… COCHRANE CORNER Katharine Smith & Mary Jane Attenburrow

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Ketamine: a Novel Antidepressant with a Fast Onset of Action?† COMMENTARY ON… COCHRANE CORNER Katharine Smith & Mary Jane Attenburrow BJPsych Advances (2016), vol. 22, 216–221 doi: 10.1192/apt.22.4.216 ROUND THE CORNER Ketamine: a novel antidepressant with a fast onset of action?† COMMENTARY ON… COCHRANE CORNER Katharine Smith & Mary Jane Attenburrow Katharine Smith is an honorary For bipolar depression, the treatment challenge SUMMARY consultant psychiatrist at the is even greater. There is scarce evidence that National Institute for Health Glutamate receptor modulators, including antidepressants are effective as a first-line Research (NIHR) Oxford cognitive ketamine, are possible candidates for new health Clinical Research Facility treatment (Sidor 2012), and mood instability is an antidepressants with a novel mode of action. and Oxford University Department additional challenge. Current recommendations The pair of reviews discussed in this month’s of Psychiatry. Mary Jane (Kendall 2014) focus on the use of quetiapine; Attenburrow is Clinical Lead at Round the Corner considered their use in treating the NIHR Oxford cognitive health unipolar major depression and bipolar depression. lamotrigine, fluoxetine plus olanzapine and Clinical Research Facility, a Senior Promising results were seen for ketamine, but lithium are also recommended. A recent trial Research Fellow at Oxford University further studies are needed, in particular to (CEQUEL) demonst ra ted that there may be benefit Department of Psychiatry and an investigate whether the benefits are sustained in the combination of lamotrigine with quetiapine honorary consultant psychiatrist. Correspondence Dr Katharine or can be extended by repeated or adjunctive (Geddes 2016). Smith, NIHR Oxford cognitive health treatment, whether ketamine is effective in Although the differences in treatment response Clinical Research Facility, Warneford treatment resistance, whether other modes of between unipolar and bipolar depression Hospital, Oxford OX3 7JX, UK. Email: administration are as effective as the intravenous suggest underlying mechanistic differences, they [email protected] route and the long-term adverse effects of use. nevertheless share common clinical features, DECLARATION OF INTEREST including the central features of low mood and lack †See pp. 214–215. For a discussion None of interest and enjoyment. Feelings of guilt, lack of the controversy surrounding of motivation, and anxiety and suicidal thoughts ketamine as a rapid antidepressant, are also common to both. Both unipolar (Hawton see Ho & Zhang, pp. 223–233, this issue. Clinical setting 2009) and bipolar (Merikangas 2011) depression Major depressive disorder and bipolar disorder have an increased risk of suicide. often take a chronic course and are associated with There is a clear need to investigate novel significant disability (World Health Organization approaches to treatment for both unipolar and 2008). They generally have a relapsing and bipolar depression that might either enhance remitting pattern, with significant impairment remission rates, or shorten the speed of therapeutic even during periods of remission (Conradi 2011). action or both. The shared symptom profiles across Pharmacological and psychological treatments are bipolar and unipolar depression suggest that there available but are not always effective, even when may be a common underlying pathway that could given adequate trials (Malhi 2015; Goodwin 2016). be the focus of new approaches. Pharmacological treatments for unipolar depression focus on antidepressants (National Ketamine and other glutamate receptor Institute for Health and Care Excellence 2009). modulators Their effects and side-effects vary, but the In the search for novel targets in treating depres- beneficial mood-elevating effects are thought to sion, investigation has turned to the glutamatergic be mediated through increasing intra-synaptic system, as glutamate is involved in memory, levels of monoamines, including noradrenaline learning and cognition. There is substantial and serotonin. However, in the clinical setting, evidence of abnormal glutamate conduction in one-third of patients remain unwell even after depression (Altamura 1995). In addition, there is several trials of antidepressants. These patients some evidence for the effectiveness of drugs that can be described as having ‘treatment-resistant target the glutamate system, including lamotrigine depression’ and, although the exact definition of in bipolar depression (Geddes 2009) and ketamine this term remains a matter of some debate (Malhi in major depression (McGirr 2014). 2016), patients with this chronic and unremitting Ketamine is an N-methyl-D-aspartate (NMDA) illness experience high levels of disability receptor antagonist, as well as having effects on and mortality. the cholinergic, opioid and monoamine transmitter 216 Downloaded from https://www.cambridge.org/core. 30 Sep 2021 at 03:50:21, subject to the Cambridge Core terms of use. Ketamine: a novel antidepressant with a fast onset of action? systems. Animal data suggest that antagonism of BOX 1 Dichotomous . continuous data NMDA receptors (a subpopulation of glutamate v receptors) is associated with antidepressant Dichotomous data can only take one of two possible effects (McGirr 2014). Ketamine was originally values. Examples include present/not present or smoker/ developed for the induction of anaesthesia. It has non-smoker. In these reviews, dichotomous data were a low bioavailability orally, so the usual routes presented for response/non-response. of administration are intravenous or intranasal. Continuous data have a potentially infinite number of Following the initial report of a rapid but short- possible values within a given range. Examples include lived antidepressant effect of ketamine (Berman height, weight and blood pressure. In these reviews, 2000), there have been further studies, but these individual depression scores were used as continuous have tended to be small with methodological data. variations. There has also been concern about Sometimes, continuous data are simplified into potential adverse events (Caddy 2014); short-term dichotomous data (e.g. age in years could become <65 side-effects include hallucinations, trance-like years or ≥65 years). In these reviews, the continuous data states and intoxication. In addition, longer-term of HRSD scores were simplified into the dichotomous use as a street drug is associated with cognitive outcome of remission/no remission, using a cut-off score of 17 on the HRSD-17. This simplifies the data, but side-effects and symptoms indicating damage to means that results refer to only two groups, and there the bladder and lower urinary tract (including may be significant variation within each group. Thus, in dysuria, increased urinary frequency and urgency, this example, results relate to all patients who achieved and haematuria) (Tsai 2009). remission (whatever their HRSD-17 score within that group) and all those who did not. Methods The two reviews considered in this commentary were published separately in the Cochrane Library, studies, 11 examined ketamine and 5 memantine. one investigating unipolar depression (Caddy 2015) Ketamine was administered intravenously and the other bipolar depression (McCloud 2015), in all studies except one (Lapidus 2014), in but they used very similar methods. The reviewers which the drug was administered intranasally, searched (last update: January 2015) for double- and the majority of the remaining glutamate or single-blind randomised controlled trials receptor modulators were administered orally. (RCTs) investigating the efficacy and acceptability In the bipolar studies, participants continued on of ketamine or other glutamate receptor mood stabilisers, and some took concomitant modulators when compared to placebo, or to antidepressants. In approximately half of the other pharmacological agents or electroconvulsive unipolar studies, patients received concomitant therapy (ECT) in adult patients (aged over 18). The medication for their depression alongside the reviewers decided not to include lamotrigine, as experimental intervention. Of interest, the this had been assessed in other reviews (Thomas unipolar review identified 41 ongoing trials and 2010; Zavodnick 2012). Comorbidity was allowed, the bipolar review identified 3. as long as the primary disorder was depression. In The quality of evidence from both reviews mixed populations, studies were included in the according to GRADE criteria (Box 2) was rated unipolar analysis if 20% or less of the patients had low to very low. In addition, comparisons between bipolar depression, and vice versa. ketamine and placebo are limited by difficulty The primary outcomes assessed were efficacy in maintaining the masking (‘blinding’) of and adverse events. Efficacy was assessed as a ‘dichotomous outcome’ (Box 1),a by standard a. For Boxes 1, 2, 3 and 4, please measures of either ‘response’ (such as a 50% see the Cochrane glossary (https:// BOX 2 GRADE quality assessment community.cochrane.org/glossary) reduction in Hamilton Rating Scale for Depression and Cochrane handbook (http:// (HRSD) score) or ‘remission’ (such as a score of <17 The Grading of Recommendations Assessment, handbook.cochrane.org) for more on the HRSD-17), and as a ‘continuous outcome’ Development and Evaluation (GRADE) approach details. (Box 1), by assessing depression scores. The (www.gradeworkinggroup.org), used by the Cochrane collaboration, NICE and publications such as the BMJ, reviewers also examined suicidality, cognition, assesses the quality of evidence according to the
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