Studies with no control group

There were 11 studies that administered ketamine to all participants with no control condition: their characteristics are detailed in and results are given in . Six studies evaluated single-dose ketamine administration on depressive symptoms, three multiple-dose schedules and two primarily evaluated changes to suicidal ideation. Trial size varied from 11 to 33 participants, and recorded follow up from 230 minutes to 83 days post-ketamine administration. A total of 206 participants, all with major depressive episodes (MDEs; diagnosed using DSM), completed these trials, and all were undertaken within the past 5 years. Ketamine was administered at 0.5 mg/kg in all trials except one [Larkin and Beautrais, 2011]. All studies adopted the Montgomery–Asberg Depression Rating Scale (MADRS) as the primary outcome measure: response was defined as ≥50% reduction in scores throughout, and remission a score of < 10. Outcomes affected by ketamine in these studies were very strong, although this must be contextualized by their open-label and loosely controlled design.

Of the six open-label studies assessing response to single-dose ketamine in MDD, two were primarily evaluating postulated drug-induced changes to cortical proteins via 1H-MRS [Salvadore et al. 2012] (n = 14) and serum analysis [Machado-Vieira et al. 2009] (n = 23), and two investigated anterior cingulate cortex activity with regards to drug response [Salvadore et al. 2009, 2010] (n = 11, 15, respectively), but all also reported clinical responses as secondary measures. These four studies showed statistically significant improvement in mood at 230-minute post-infusion time points (p = 0.005 in Salvadore et al. [2009]; p = 0.001 in Salvadore et al. [2010]; p = 0.006 in Salvadore et al. [2012]; p < 0.001 in Machado-Vieira et al. [2009]). A somewhat different model was undertaken in open-label work by Larkin and Beautrais who trialled the feasibility of undertaking single-dose ketamine administration, administered, somewhat atypically for ketamine studies, as a 0.2mg/kg single bolus over 1–2 minutes, in 14 participants with MDD and suicidal ideation in an emergency department [Larkin and Beautrais, 2011]. A primary aim with this work was to evaluate a key conceptual concern about the viability of ketamine use in such ‘real-world’ scenarios. Fitting with previous data they found rapid antidepressive effects within 240 minutes, with 13 (92.3%) meeting response criteria and mean scores falling from a baseline MADRS score of 40.4 (standard error of the mean [SEM] = 1.8) to 11.5 (SEM = 2.2).

There are high rates of comorbidity between depressive disorders and substance misuse [Davis et al. 2007]. A family history of alcohol dependency has been shown to result in altered responses to ketamine in healthy participants, and changes to the glutamatergic system and NMDA binding has been implicated in both disorders [Petrakis et al. 2004]. Phelps and colleagues used linear mixed models to evaluate differential response in 26 MDD participants with and without a (self-reported) family history of alcohol dependency to open-label ketamine administration [Phelps et al. 2009]. Those with positive family histories showed a statistically significant improvement over those who did not in MADRS, Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) scores within 230 minutes of ketamine infusion. Individual past alcohol dependency and past family history of depression were not correlated with outcome. The authors note that alcohol acts on NMDA receptors (amongst others) and genetic data have shown inheritable variations of these receptors associated with alcohol dependence: they speculate that both clinical histories and genetic markers may in future act as predictors of drug response.

Three open-label studies evaluated multiple-dosing ketamine. aan het Rot enrolled 10 participants from an earlier trial of the effects of ketamine on suicidality [Price et al. 2009] who had an initial depressive symptom severity ≥32 on the Inventory for Depressive Symptoms (IDS-C 30 ) and who had demonstrated a clinical response to this single ketamine infusion without significant side effects [aan het Rot et al. 2010]. Participants were given 6 infusions over 12 days: 90% of participants responded to the first infusion, and by the end of the trial 100% met response criteria and 88.89% met remission criteria. The same research group undertook a larger study [Murrough et al. 2013] of 24 individuals, including the 10 participants in the previous work, who, after a wash-out period from their antidepressants, each received thrice weekly injections of ketamine over 12 days. There was a large, statistically significant (p < 0.01) decrease in MADRS scores 2 hours after the initial infusion (mean decrease 18.9, standard deviation [SD] 6.6). A total of 21 participants completed the full 6-infusion schedule and the response rate at the study’s conclusion was 70.8% (17 of 24). Response to ketamine 4 hours after the initial infusion was strongly associated with the response by the study’s end, with 94% of those responding doing so 4 hours after the first infusion. A more recent study conducted by Rasmussen and colleagues administered 10 participants in a MDE (BPAD II/MDD) with up to 4 ketamine infusions at 0.5 mg/kg over 100 minutes [Rasmussen et al. 2013]. A total of 80% of the participants demonstrated response to ketamine, defined as at least a 50% reduction in MADRS scores, and furthermore 50% met remission, defined as a MADRS score of 9 and below. Of the 5 participants who met remission, 2 still met remission criteria at the 4-week follow up. Rasmussen and colleagues further documented the effect of ketamine on suicidal ideation, reporting significant improvements in the Scale for Suicide Ideation (SSI; p = 0.007) and the Suicide Status Form (SSF; p = 0.026). In addition, this study reported a significant correlation between SSI/SSF scores and MADRS (p < 0.01), suggesting the observed decrease in suicidality occurred in unison with that of depression scores.

Two studies, both single-dosing, looked primarily at the effects of ketamine on suicidal ideation. Price and colleagues tested changes in 26 patients with TRD [Price et al. 2009]: 24 hours post-infusion the average reduction in the six-point MADRS Suicidality Item (SI) subscale score across all participants was 2.08 (p < 0.001), with 81% scoring of 0 or 1. Of the 13 patients with clinically significant baseline suicidal ideation (MADRS-SI ≥4) 8 (62%) scored zero or one at the 24-hour follow up. Similarly positive results were reported by DiazGranados and colleagues [DiazGranados et al. 2010a]. Suicidal ideation, in the context of MDD, improved within 40 minutes of infusion in the 33 participants, with benefits sustained by the 4-hour final assessment (p < 0.001). Some of the earlier studies also reported positive effects on suicidal ideation, and Larkin and Beautrais recorded suicidal ideation completely resolved in all participants (n = 14) within 240 minutes of infusion [Larkin and Beautrais, 2011], from a baseline mean MADRS-SI of 3.9 (SEM = 0.4) to a mean of 0.6 (0.1), maintained at day 10 (0.7 (0.2)). Interestingly, the work by Murrough and colleagues demonstrated that even non-responders to the anti-depressant effects showed statistically significant improvements in suicidal ideation [Murrough et al. 2013].

Most of these trials were designed with only brief follow up of participants, particularly in the single-dose studies. Salvadore and colleagues noted that improvements in MADRS scores remained significant (p = 0.01) at 24 hours [Salvadore et al. 2012], whilst Larkin and Beautrais record that clinical gains were maintained for the 13 participants who completed the study to the end-point at day 10 (mean MADRS 9.2 (SEM = 1.7)) [Larkin and Beautrais, 2011]. The two multiple-dosing trials had longer follow ups recorded. Relapse occurred on average 19 (SD 13) days following final infusion, though one participant remained asymptomatic for three months, in the work of aan hen Rot and colleagues [aan hen Rot et al. 2010]; whilst in the study by Murrough and colleagues the median time to relapse was 18 days (interquartile range 11–27 days) after the final infusion [Murrough et al. 2013].

Overall ketamine appeared well tolerated though there were frequent reports of mild psychotomimetic symptoms, as measured with the Brief Psychiatric Rating Scale (BPRS) or Clinician Administered Dissociative States Scale (CADSS), primarily an unpleasant dissociative effect, typically occurring and resolving within an hour of administration. Fitting with its known anaesthetic profile transient hypertension and tachycardia were also recorded. In the studies that so-reported, no difference in side-effect profile was noted between depression/suicidal-ideation responders and nonresponders.