Real-World Effectiveness of Repeated Ketamine Infusions for Treatment-Resistant Bipolar Depression
Abstract
Background:
Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real-world effectiveness of repeated ketamine infusions for treatment-resistant bipolar depression.
Methods:
This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment-resistant bipolar I/II depression (n = 66) received four sub-anesthetic doses of IV ketamine (0.5–0.75 mg/kg) over a two-week period. Symptoms of depression, suicidality, anxiety, and functioning were assessed with validated self-report measures.
Results:
Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16) with further reductions in depressive symptoms observed after each subsequent infusion (n = 66; mean QIDS-SR16 reduction of 6.08+/−1.39; p < 0.0001). Significant reductions of suicidal thoughts (QIDS-SR16-Suicide Item) and anxiety (Generalized Anxiety Disorder-7) were also observed with functional improvements on the Sheehan Disability Scale (p < 0.0001 on all measures). Moreover, the response rate (QIDS-SR16 total score decrease ≥50% from baseline) was 35% and remission rate (QIDS-SR16 total score ≤5) was 20% after four infusions. Infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis.
Conclusions:
Real-world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability.
Reprinted from Bipolar Disord 2023; 25:99–109, with permission from John Wiley and Sons. Copyright © 2023
INTRODUCTION
Bipolar disorder (BD) is a severe and persistent mental illness with a lifetime prevalence of 2%–3%.19,22,23 Unfortunately, treatment outcomes remain poor, particularly for depressive episodes, with over one-third of patients failing to adequately respond to multiple first-line treatments (i.e., treatment-resistant bipolar depression; TRBD).7,11,20,38 Lithium has been shown to reduce suicide rates; however, BD continues to be associated with extremely high rates of suicide (primarily during depressive and mixed episodes) with 23%–26% attempting suicide and 5%–10% completing suicide.28,36 Pharmacotherapy (e.g., conventional mood stabilizers and antipsychotics) remains the primary treatment for BD, however, there remains high rates of treatment resistance, relapse, and problematic adverse effects, including metabolic effects, sedation, cognitive dysfunction, and renal impairment.43,44 Therefore, novel treatments are urgently needed for BD, with a focus on treatments that will have greater antidepressant and anti-suicidal effects with less adverse effects, including considerations for treatment-emergent manic symptoms.8,19,22,23,41
Ketamine is a dissociative anesthetic with growing evidence to support acute antidepressant effects at sub-anesthetic doses (e.g., 0.5–1.0 mg/kg infused over 40–60 min).19,21,22,23,24,25,35 Ketamine primarily targets the glutamate system, rather than the more conventionally targeted monoamine systems.34,46 Over the past two decades, growing evidence has supported rapid and robust antidepressant effects of sub-anesthetic doses of intravenous (IV) ketamine for treatment-resistant depression (TRD).3,4,19,22,23,48 However, the majority of IV ketamine randomized controlled trials (RCTs) have been single-dose, proof-of-concept studies, primarily in major depressive disorder (MDD) samples.2,4,19,22,23,48 More recently, the importance of repeated doses of IV ketamine (twice or thrice weekly over 2 weeks) has been demonstrated to have greater antidepressant effects compared to a single dose, approximately doubling the antidepressant response rate and sustaining antidepressant effects longer.1,18,19,22,23,37,39 However, no RCT has evaluated the effects of repeated doses of IV ketamine specifically for TRBD, as previous studies were either exclusively with MDD samples, or mixed MDD/BD samples with only a small proportion of BD participants.18,19,22,23,29
As summarized in recent reviews, results from completed RCTs primarily support the effect of IV ketamine in MDD samples, with minimal research in BD samples.4,16,18,19,22,23,29 Only small, single-dose IV ketamine RCTs were identified in BD samples with no completed repeat dose BD RCTs (neither IV ketamine nor intranasal (IN) esketamine).4,16,18,29 While ketamine is not FDA-approved for any mental disorder, its isomer, esketamine, is the first FDA-approved non-monoamine-based psychotropic agent for adults with TRD. The FDA approval of the intranasal esketamine was based on results from replicated, randomized, double-blind, placebo-controlled trials.15 In addition to the proven efficacy of esketamine, the short-term efficacy of intravenous (IV) ketamine is established.3,4,5,17,27,30,39,42 Currently, ketamine is recommended in select medication treatment guidelines for MDD as a treatment option when two prior antidepressants are insufficient.14,26
Two small, proof-of-concept, crossover RCTs in BD samples found that a single ketamine infusion (0.5 mg/kg over 40 min) was associated with rapid and robust antidepressant effects, with reductions in depression severity observed within hours and effects lasting for 3 days, with moderate to large effect sizes (d = 0.6–1.1).6,48 An additional proof-of-concept RCT demonstrated rapid reductions in suicidal ideations in TRBD with a single ketamine infusion.10 Notably, the generalizability of these findings in the real-world setting remains unclear given the higher degree of complexity and comorbidity of TRBD in clinical settings.
The objective of the present study is to evaluate the real-world effectiveness of repeated ketamine infusions for TRBD in a community clinic setting. Our group has previously published effectiveness studies for TRD and various subgroups from our clinical sample19,22,23,32,33; however, the present analysis is the first comprehensive report focused exclusively on our TRBD sample. These realworld effectiveness studies may complement RCT data to provide a more well-rounded understanding of the clinical utility of ketamine for TRBD.45
METHODS
Participants and study design
All of the data presented herein were obtained from patients who were referred to the Canadian Rapid Treatment Center of Excellence (CRTCE) in Mississauga, Ontario, Canada. The CRTCE is the first Canadian clinic offering IV ketamine to adults (i.e., age ≥18 years) with TRD as part of MDD or BD outside of clinical trials. Eligibility criteria to receive IV ketamine and the protocol for the CRTCE have been previously described (19,22,23). In brief, patients must have failed at least two adequate medication trials and not have any medical (uncontrolled hypertension, pregnancy) or psychiatric contraindications (active psychosis or current substance use disorder).
Current ketamine administration guidelines21,24,25 suggest that patients begin by receiving a series of two to three infusions per week over 2–4 weeks followed by maintenance infusions. Prior to their first infusion, all patients were medically cleared by CRTCE staff anesthesiologists that evaluated patients for any unstable medical disorder contraindicated against IV ketamine (e.g., malignant hypertension, supraventricular tachycardia, etc.). All CRTCE patients started with two infusions of ketamine hydrochloride 0.5 mg/kg diluted in 0.9% saline solution infused over 40 min, with a potential to increase dose up to 0.75 mg/kg for the 3rd and 4th infusions if inadequate response (i.e. ≤20% reduction in total depression symptom severity as measured by the QIDS-SR16) is observed at the starting dosage. To this end, patients at the CRTCE received four infusions delivered across 8–14 days based on their availability/scheduling. For each patient, a post-treatment assessment visit was scheduled 1 week after the fourth infusion.
Tolerability and safety were assessed during, and immediately following each infusion. The CRTCE anesthesiologists and nurses assessed safety by measuring vital signs, oxygen saturation, and pulse oximetry. Tolerability to ketamine was assessed through reported treatment-emergent adverse events (e.g., nausea, dizziness, depersonalization, etc.). Lastly, dissociative symptoms from ketamine were evaluated by the 6-item Clinician-Administered Dissociative States Scale (CADSS-6) 5–10 min immediately after infusion.33
The primary clinical measure obtained in this study was the Quick Inventory for Depressive Symptomatology Self-Report 16-Item (QIDS-SR16). The Generalized Anxiety Disorder 7-item (GAD-7), Sheehan Disability Scale (SDS) were also used as secondary measures. Participants completed the QIDS-SR16 prior to their first infusion (i.e., baseline infusion), at each subsequent infusion during the initial protocol, and finally during the follow-up with the clinic psychiatrist (i.e., post-treatment assessment visit). Participants completed the GAD-7 and SDS at baseline, post-infusion 3, and posttreatment assessment visits.
Herein, we report on 66 outpatients (Mage = 45.7, age range: 22–77) from the CRTCE who received care from July 2018 to November 28, 2019, with either TRBD type I or II. This analysis was approved by a community Institutional Review Board and registered under NCT04209296 on the clinicaltrials.gov website.
Data Collection, Reporting, and Analysis
The primary outcome was the change in the total QIDS-SR16 score from baseline to the post-treatment assessment visit. Secondary outcomes were changes from baseline to the post-treatment assessment visit in the QIDS-SR16 suicidality item, total GAD-7, and SDS scores. Psychosocial functioning was measured using the Sheehan Disability Scale (SDS). The CADSS-6 was used and developed from questions 1, 2, 6, 7, 15, and 22 from the full-length CADSS.31
Missing data and unequal timing between study visits were managed by a one-way mixed model. The covariance matrix that was used was autoregressive based on a lower Akaike's Information Criterion (AIC). Sex and age were used as covariates in the mixed model analysis to evaluate GAD-7 scores, SDS work, social, and family item scores, and mean QIDS-SR SI scores. Baseline depressive severity was also taken into account in evaluating specifically the QIDS-SR16 total scores. Lastly, a two-way mixed model was used to evaluate the differences between BD1 and BD2.
Pairwise comparisons were corrected for multiple comparisons using the Bonferroni method. A responder/remitter analysis was then conducted to ascertain our results. The response and remission rates were calculated as follows: QIDS-SR16 total score reduction from baseline ≥50% for response and QIDS-SR16 total score ≤5 for remitter.
RESULTS
Sample
A total of 66 patients received IV ketamine at the CRTCE when this analysis was conducted. Seven patients were excluded from the responder/remitter analysis due to the absence of baseline and post-infusion QIDS-SR16 scores. Of the total sample of 66 patients, 28 were BDI, 35 were BDII, and we were unable to stratify the remaining 3 due to lack of clarity in reviewed medical records. Demographic information, including patient sex, age, BMI, mean number of prior and current psychotropics and the number of patients that received a dose increase are reported in Table 1 for the total sample and BDI/ BDII samples.
| Characteristics | Total sample (n = 66) | BDI (n = 28) | BD2II (n = 35) |
|---|---|---|---|
| Mean age in years (SD) | 45.7 (13.4) | 43.9 (13.4) | 47.4 (13.5) |
| Sex, (%) | | | |
| Male | 27 (40.9) | 12 (42.9) | 13 (37.1) |
| Female | 39 (59.1) | 16 (57.1) | 22 (62.9) |
| Mean body mass index (SD) | 29.9 (6.55) | 29.5 (6.46) | 30.3 (6.61) |
| Mean number of prior lifetime psychotropics trials (SD) | 5.63 (4.38) | 5.88 (4.23) | 5.48 (4.43) |
| Mean number of psychotropics at time of infusion (SD) | 1.40 (1.39) | 2.06 (1.43) | 1.00 (1.38) |
| Number of patients receiving a dose increase | 34 | 18 | 16 |
a
3 patients were unable to be classified into BDI or BDII due to lack of clarity in reviewed medical records.
Depressive Symptom Severity
The first set of analyses consisted of the combined analysis of the BDI and BDII subgroups. Overall, there was a significant main effect with a moderate effect size of infusion on QIDS-SR16 total score: F(4, 197.9) = 16.8, p < 0.001, Cohen's f = 0.56. There was a significant reduction in QIDS-SR16 score from baseline to all subsequent timepoints (ps < 0.001). Moreover, there was a significant reduction in QIDS-SR16 score from post-infusion 1 to post-infusion 3 (p < 0.001) and post-treatment assessment visit (p < 0.05). There was also a significant reduction in depression score in the post-infusion 2 score compared to the post-infusion 3 and post-treatment assessment visit (ps < 0.05). There were no significant differences in scores between post-infusion 1 to post-infusion 2 and also no significant differences in scores between post-infusion 3 to post-treatment assessment visit (ps >0.05).
A separate two-way model with group and time as independent variables was completed. Initially, we found a significant main effect of BDI versus BDII subgroups on QIDS-SR16 total scores: F(1, 64.36) = 5.14, p = 0.027, ηp2 = 0.074. However, the effect was lost when controlling for baseline depression severity: F(1, 61.11) = 2.50, p = 0.12, ηp2 = 0.039. Nevertheless, it is important to note that there was a trend toward better outcomes in BDII. The results of the mean QIDS-SR16 score of the overall sample of patients and of the BDI and BDII subgroups are presented in Figure 1.
FIGURE 1. Mean (SE) QIDS-SR16 score of the overall sample of patients and of the BD1 and BD2 subgroups.
Ap < 0.001 compared to Baseline. Bp < 0.05 compared to Post-Infusion 1. Cp < 0.05 compared to Post-Infusion 2.
[Publisher's Note: A color version of the figure, as originally published, appears in the online version of this article at focus.psychiatryonline.org.]
The results of the responder and remitter analysis are presented in Table 2. At follow-up, 16 (35%) patients achieved a response of ≥50%; and 21 (46%) patients improved by at least 25%. Lastly, 9 (20%) patients met remission criteria.
| | Baseline | Post-infusion 1 | Post-infusion 2 | Post-infusion 3 | Post-treatment assessment |
|---|---|---|---|---|---|
| QIDS-SR16 total score (SD) | 19.19 (4.80) | 16.02 (5.86) | 15.30 (6.50) | 13.54 (5.95) | 13.11 (7.11) |
| Total number | 59 | 59 | 54 | 54 | 46 |
| Number of missing values | 7 | 7 | 12 | 12 | 20 |
| Mean QIDS-SR16 change from baseline | N/A | 3.17 | 3.89 | 5.65 | 6.08 |
| QIDS-SR16 suicidality score (SD) | 1.69 (1.02) | 1.25 (1.01) | 1.13 (0.97) | 1.04 (1.01) | 0.87 (0.93) |
| Mean QIDS-SR16 suicide item change from baseline | N/A | 0.01 | 0.04 | 0.01 | 0.09 |
| Responder and remitter analysis | | | | | |
| Responder ≥25% | N/A | 17 (28.8%) | 15 (27.8%) | 28 (51.9%) | 21 (45.5%) |
| Responder ≥50% | N/A | 6 (10.2%) | 10 (18.5%) | 14 (25.9%) | 16 (34.8%) |
| Remitter ≤5 | N/A | 4 (6.8%) | 6 (11.1%) | 5 (9.3%) | 9 (19.6%) |
Suicidality
The QIDS-SR16 suicidality item score significantly decreased over time with treatment, F(4, 197.9) = 16.8, p < 0.001, Cohen's f = 0.56. There was a significant reduction in suicidality score from baseline to post-infusion 1, post-infusion 2, post-infusion 3, and post-treatment assessment visit score (ps < 0.001). Additionally, there was a significant improvement from the post-infusion 1 score to post-treatment assessment score (p < 0.05). Lastly, there was no significant main effect of BDI versus BDII subgroups on QIDS-SR16 suicidality item score: F(1, 65.31) = 0.004, p > 0.05.
Overall, 8 (14%) patients presented at baseline without exhibiting any symptoms of suicidality (i.e., QIDS-SR16 suicidality item = 0). Suicidality scores were then sub-analyzed considering only patients who presented with high QIDS-SR16 suicidality item scores of 2 and 3 at baseline (n = 33) and there remained a significant decrease over time with treatment F(4, 104.8) = 12.93, p < 0.001, Cohen's f = 0.66.
There was a significant reduction in this sub-analysis of suicidality scores from baseline (M = 2.48, SE = 0.09) to post-infusion 1 (M = 1.9, SE = 0.16; p < 0.001), post-infusion 2 (M = 1.70, SE = 0.18; p < 0.001), post-infusion 3 (M = 1.41, SE = 0.20; p < 0.001), and post-treatment assessment (M = 1.08, SE = 0.21; p < 0.001). Moreover, suicidality symptoms significantly decreased from post-infusion 1 to post-treatment assessment and from post-infusion 2 to post-treatment assessment (ps < 0.05). The results of the mean QIDS-SR16 suicidality item score of all patients and those who reported suicidality at baseline are presented in Figure 2.
FIGURE 2. Mean (SE) QIDS-SR16 suicidality item score in all patients and those who reported suicidality at baseline.
Ap < 0.001 compared to Baseline.
Bp < 0.05 compared to Post-Infusion 1.
Cp < 0.05 compared to Post-Infusion 2.
[Publisher's Note: A color version of the figure, as originally published, appears in the online version of this article at focus.psychiatryonline.org.]
Anxiety Symptoms
A total of 59 patients had available scores in the GAD-7 at baseline, 44 patients had available scores at post-infusion 3, and 45 patients had available scores for the post-treatment assessment visit. There was a significant effect of infusion for the treatment of anxiety, measured by the GAD-7, F(2, 82.5) = 8.99, p < 0.001, Cohen's f = 0.43. After adjusting for multiple comparisons, the results indicated a significant decrease from baseline anxiety score to post-infusion 3 (p < 0.05) and from baseline to post-treatment assessment (p < 0.001). There was no significant difference in GAD-7 scores between the post-infusion 3 and post-treatment assessment visit (p = 0.357). Lastly, there was no significant main effect of BDI versus BDII subgroups on GAD-7 scores: F(1, 56.19) = 1.06, p > 0.05. Change in mean anxiety scores following ketamine infusion is presented in Figure 3.
FIGURE 3. Change in mean (SE) anxiety score following ketamine infusion.
Ap < 0.05 compared to Baseline.
Bp < 0.001 compared to Baseline.
[Publisher's Note: A color version of the figure, as originally published, appears in the online version of this article at focus.psychiatryonline.org.]
Psychosocial Functioning
A total of 32 patients had available scores for the SDS-WORK at baseline, 28 patients had available scores at post-infusion 3, and 21 patients had available scores for the post-treatment assessment visit. There was no significant main effect of infusion, F(2, 52.1) = 0.61, p > 0.05, Cohen's f = 0. There was no significant main effect of BDI versus BDII subgroups on SDS-WORK scores: F(1, 45.9) = 0.27, p > 0.05.
A total of 58 patients had available scores for the SDS-SOCIAL at baseline, 42 patients had available scores at post-infusion 3, and 45 patients had available scores for the post-treatment assessment visit. There was a significant main effect of infusion for the SDS-SOCIAL score, F(2, 76) = 10.83, p < 0.001, Cohen's f = 0.50. The SDS SOCIAL scores significantly decreased (i.e. improved) from baseline to post-treatment assessment visit and from post-infusion 3 to posttreatment assessment visit (ps < 0.001). There was no significant difference between baseline and post-infusion 3 for SDS-SOCIAL scores (p > 0.05). There was no significant main effect of BDI versus BDII subgroups on SDS-SOCIAL scores: F(1, 54.7) = 1.06, p > 0.05.
A total of 58 patients had available scores for the SDS-FAMILY at baseline, 37 patients had available scores at post-infusion 3, and 45 patients had available scores for the post-treatment assessment visit. There was a significant main effect of infusion for the SDS-FAMILY score, F(2, 76.5) = 8.73, p < 0.001, Cohen's f = 0.44. The SDS-FAMILY scores significantly decreased from baseline to post-infusion 3 and from baseline to post-treatment assessment visit (ps < 0.05). There was no significant difference between post-infusion 3 and post-treatment assessment visit for Family scores (p > 0.05). There was no significant main effect of BDI versus BDII subgroups on SDS-FAMILY scores: F(1, 64.18) = 2.94, p > 0.05. Change in mean score of the SDS Work, Social, and Family subscales are presented in Figure 4.
FIGURE 4. Change in mean (SE) score in the SDS Work, Social, and Family subscales.
[Publisher's Note: A color version of the figure, as originally published, appears in the online version of this article at focus.psychiatryonline.org.]
Safety and Tolerability
Safety and tolerability were assessed during, and immediately following each infusion. Ketamine infusions were generally well tolerated with treatment-emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis. In these three cases, hypomania emerged after the third or fourth infusion. No hypomania emerged after the first or second infusion. All three patients were also co-prescribing an antidepressant that may have impacted the risk of hypomania emerging. Two patients were treated with a therapeutic dose of an SGA and one was not on a mood stabilizer. Of note, after these cases were identified, we now strongly recommend all patients with BD continue mood stabilizers at a therapeutic dosage prior to starting infusions. In this regard, patients in our study were on a variety of medications including mood stabilizers (lithium, lamotrigine, etc.), psychostimulants (Vyvanse, Adderall, Concerta, etc.), sedatives (clonazepam, lorazepam, etc.), SSRIs (fluoxetine, fluvoxamine, vortioxetine, sertraline, citalopram, etc.), TCAs (imipramine, nortriptyline, etc.), SNRIs (duloxetine, desvenlafaxine, etc.), and adjunctive agents (lurasidone, modafinil, aripiprazole, etc.).
Dissociative symptoms from ketamine were evaluated by the Clinician-Administered Dissociative States Scale (CADSS) 5–10 min post-infusion. After adjusting for age and sex, there was no significant main effect of infusion: F(3, 167.8) = 0.659, p = 0.578. The cut-off score of three or higher for the presence of dissociation was determined using discriminant function analysis.31 Mean CADSS-6 scores were: 3.65 (3.27), 3.08 (3.45), 2.60 (2.96), and 2.19 (3) for infusions 1, 2, 3, and 4 respectively. In keeping with the cut-off score, patients experienced dissociative symptoms, similar to that observed in MDD in previous studies during infusion 1 and 2. No dissociative symptoms were observed in patients during infusions 3 and 4. Mean change in dissociation severity, as measured by the CADSS-6, over four infusions is presented in Figure 5.
FIGURE 5. Mean change in dissociation severity, as measured by the CADSS-6, over four infusions. Scores of dissociative symptoms from ketamine were evaluated after each infusion 1, 2, 3 and 4 respectively.
[Publisher's Note: A color version of the figure, as originally published, appears in the online version of this article at focus.psychiatryonline.org.]
Tolerability to ketamine was assessed through reported treatment-emergent adverse events (e.g., nausea, dizziness, depersonalization, etc.). The most frequently reported adverse events included drowsiness (29.3%), dizziness (28.2%), blurred vision (26.8%), and confusion (26.8%). Table 3 summarizes the number and percentages of reported treatment-emergent adverse. Adverse events were generally resolved within 1 h of each infusion.
| | During infusion n (%) | After infusion n (%) | ||||||
|---|---|---|---|---|---|---|---|---|
| Side Effect | Infusion 1 | Infusion 2 | Infusion 3 | Infusion 4 | Infusion 1 | Infusion 2 | Infusion 3 | Infusion 4 |
| Gastrointestinal symptoms: Nausea | ||||||||
| Mild | 7 (16.7) | 3 (7.1) | 5 (12.8) | 2 (4.9) | 10 (23.8) | 2 (4.9) | 3 (7.7) | 2 (4.9) |
| Moderate | 1 (2.4) | 4 (9.5) | 0 | 0 | 1 (2.4) | 2 (4.9) | 1 (2.6) | 3 (7.3) |
| Severe | 4 (9.5) | 1 (2.4) | 5 (12.8) | 2 (4.9) | 3 (7.1) | 0 | 3 (7.7) | 2 (4.9) |
| Vomiting | ||||||||
| Mild | 0 | 1 (2.4) | 0 | 0 | 0 | 0 | 0 | 1 (2.4) |
| Moderate | 0 | 0 | 0 | 0 | 1 (2.4) | 0 | 0 | 0 |
| Severe | 0 | 0 | 1 (2.4) | 0 | 0 | 0 | 0 | 0 |
| Neurological symptoms: Dizziness | ||||||||
| Mild | 10 (23.8) | 9 (4.8) | 11 (28.2) | 12 (29.3) | 9 (21.4) | 9 (21.9) | 5 (12.8) | 11/41 (26.8) |
| Moderate | 4 (9.5) | 2 | 1 (2.6) | 3 (7.3) | 2 (4.8) | 3 (7.3) | 2 (5.1) | 2 (4.9) |
| Severe | 4 (9.5) | 4 (9.5) | 2 (5.1) | 2 (4.9) | 3 (7.1) | 0 | 2 (5.1) | 1 (2.4) |
| Headache | ||||||||
| Mild | 2 (4.8) | 1 (2.4) | 5 (12.8) | 3 (7.3) | 5 (11.9) | 5 (12.2) | 4 (10.3) | 5 (12.2) |
| Moderate | 1 (2.4) | 0 | 1 (2.6) | 1 (2.4) | 2 (4.8) | 0 | 2 (5.1) | 1 (2.4) |
| Severe | 1 (2.4) | 1 (2.4) | 1 (2.6) | 2 (4.9) | 1 (2.4) | 0 | 1 (2.6) | 2 (4.9) |
| Double vision | ||||||||
| Mild | 5 (11.9) | 4 (9.5) | 4 (10.3) | 4 (9.8) | 2 (4.8) | 4 (9.8) | 6 (15.4) | 4 (9.8) |
| Moderate | 3 (7.1) | 6 (14.3) | 5 (12.8) | 4 (9.8) | 0 | 2 (4.9) | 5 (12.8) | 2 (4.9) |
| Severe | 2 (4.8) | 1 (2.4) | 4 (10.3) | 2 (4.9) | 1 (2.4) | 1 (2.4) | 1 (2.6) | 1 (2.4) |
| Blurred vision | ||||||||
| Mild | 3 (7.1) | 8 (19) | 5 (12.8) | 7 (17.1) | 6 (14.3) | 5 (12.2) | 9 (23.1) | 11 (26.8) |
| Moderate | 8 (1.9) | 5 (11.9) | 6 (15.4) | 4 (9.8) | 2 (4.8) | 3 (7.3) | 3 (7.7) | 1 (2.4) |
| Severe | 2 (4.8) | 2 (4.8) | 3 (7.6) | 3 (7.3) | 0 | 0 | 2 (5.1) | 1 (2.4) |
| Drowsiness | ||||||||
| Mild | 13 (31) | 12 (28.6) | 10 (26.3) | 12 (29.3) | 12 (28.6) | 9 (21.9) | 10 (26.3) | 11 (26.8) |
| Moderate | 8 (19) | 3 (7.1) | 5 (13.2) | 4 (9.8) | 5 (11.9) | 2 (4.9) | 4 (10.5) | 4 (9.8) |
| Severe | 5 (11.9) | 6 (14.3) | 8 (21) | 6 (14.6) | 1 (2.4) | 3 (7.3) | 2 (5.3) | 2 (4.9) |
| Confusion | ||||||||
| Mild | 9 (21.4) | 9 (21.4) | 9 (23.1) | 11 (26.8) | 8 (19) | 6 (14.3) | 10 (25.6) | 5 (12.2) |
| Moderate | 4 (9.5) | 5 (11.9) | 4 (10.3) | 3 (7.3) | 0 | 3 (7.1) | 2 (5.1) | 1 (2.4) |
| Severe | 7 (16.7) | 5 (11.9) | 5 (12.8) | 4 (9.8) | 2 (4.8) | 1 (2.4) | 1 (2.6) | 1 (2.4) |
| Jerky muscle movements | ||||||||
| Mild | 3 (7.1) | 2 (4.8) | 0 | 2 (4.8) | 0 | 0 | 0 | 0 |
| Moderate | 0 | 1 (2.4) | 1 (2.6) | 0 | 0 | 1 (2.4) | 0 | 0 |
| Severe | 0 | 0 | 0 | 1 (2.4) | 0 | 0 | 0 | 0 |
| Dissociation symptoms: Depersonalization | ||||||||
| Mild | 1 (6.3) | 0 | 1 (7.7) | 1 (7.7) | 3 (18.8) | 0 | 0 | 1 (7.1) |
| Moderate | 2 (12.5) | 1 (6.7) | 0 | 0 | 0 | 2 (13.3) | 0 | 0 |
| Severe | 3 (18.8) | 2 (13.3) | 1 (7.7) | 1 (7.7) | 0 | 0 | 0 | 0 |
| Derealization | ||||||||
| Mild | 3 (18.8) | 1 (6.7) | 0 | 3 (23.1) | 2 (12.5) | 1 (6.7) | 0 | 1 (7.14) |
| Moderate | 0 | 1 (6.7) | 0 | 1 (7.7) | 0 | 1 (6.7) | 0 | 0 |
| Severe | 3 (18.8) | 2 (13.3) | 1 (7.7) | 0 | 0 | 0 | 0 | 0 |
DISCUSSION
We observed a clinically and statistically significant reduction in depressive symptoms (6.08±1.39 point reduction in QIDS-SR16 score) following four ketamine infusions in our real-world treatment-resistant bipolar depression sample. We have previously established that a 3-point improvement on the QIDS-SR16 is clinically relevant in adults with treatment-resistant depression receiving IV ketamine.21,24,25 Importantly, no evidence of treatment-emergent mania or psychosis was observed with only low risk of treatment-emergent hypomania (4.5%).
Observed antidepressant response (35%) and remission rates (20%) were also substantial and clinically meaningful. Currently available data of repeated administration of ketamine, specifically in TRBD patients, remains scarce. Only uncontrolled, open-label studies using repeated ketamine infusions have been completed in BD samples with conflicting results.55,56 Zheng et al. treated 16 TRBD patients with six ketamine infusions over 2 weeks with 21% responding (>50% symptom reduction) after the first dose, which increased to 74% responding after the sixth dose, with effects persisting up to 2 weeks after this final dose. Conversely, Zhuo et al.49 completed an open-label study with 38 TRBD patients receiving a series of nine ketamine infusions over a 3-week period with antidepressant effects observed in the first week (e.g., after the first three infusions); however, the symptoms began to re-emerge in the second week with full relapse of symptoms by the third week of treatment. These divergent findings may have been secondary to atypical methods that were poorly described in these publications and the use of different scales (MADRS versus QIDS) and small sample sizes. Another possible explanation for the discrepancy in findings could be due to inherent variability in the levels of treatment resistance of patients in the different studies. Participants in the Zhuo study had at least two antidepressant trials, each lasting 12 weeks and required a relatively high level of severity for inclusion that could have contributed to patients relapsing. Whereas, our current study inclusion criteria are not as strict to represent a more “real-world” sample in that our study does not require that the trials occurred in the current episode. Our current study also permitted a ketamine dose increase at the third and fourth infusion, whereas the Zhuo study did not—providing another potential reason for the discrepancy in findings. Thus, further studies specifically involving TRBD patients with a larger sample size are needed to confirm these findings. To this end, our current study aimed to elucidate these findings with a larger sample. Taken together, our results support prior findings of repeated ketamine administration significantly improving the severity of depressive symptoms in TRBD patients.
Bipolar disorder is a psychiatric illness often associated with a high suicide rate and there is emerging evidence supporting ketamine's anti-suicidal effects (9,13,20,21,23,24). Herein, we observed a significant decrease in suicidal ideation upon receiving just a single dose of ketamine, as measured by the suicidal ideation item of the QIDS-SR16. We observed that with each subsequent dosage, suicidal ideation decreases correspondingly. These findings are also maintained for TRBD patients presenting with high QIDS-SR16 suicidality item scores at baseline, further demonstrating ketamine's notable anti-suicidal effects. Equally noteworthy is that no patients reported amplification of pre-existing suicidal ideation due to ketamine infusions at any timepoint.
In addition to ketamine's rapid anti-depressive and antisuicidal effects, a significant reduction was also observed in anxiety symptoms. The significant 4-point reduction from baseline to post-treatment assessment visit in GAD-7 suggests a similar reduction from severe to moderate anxiety.43 While there are currently no other published studies specifically examining the effects of repeated ketamine infusion on anxiety in TRBD patients, our observations remain in accordance with other studies on ketamine in adults with TRD, wherein a significant reduction in anxiety symptoms were also reported.12,21,24,25,42
With respect to psychosocial functioning, we observed a significant improvement in SDS “social” and “family” subdomains, but no improvement was seen in the “work” subdomain. It could be that workplace functioning has a longer latency to improvement than family/social subdomains due to practical reasons (e.g., patients may have been out of work and now that they are better, will need some time to find a job). This could possibly explain why the workplace score was not significantly improved during the time window assessed in our study. Nevertheless, there is insufficient reporting in the current literature of functional outcomes in adults with TRBD receiving repeated ketamine administration to draw conclusive findings. More research needs to be done examining the potential psychosocial and interpersonal benefits of repeated ketamine infusions in TRBD patients.
The main strengths of this study include a relatively large, complex, real-world sample, and the use of validated self-report measures. This is also the first study examining the effects of repeated ketamine infusions in a TRBD subgroup with delineating between type I and type II bipolar disorder. To our knowledge, our study represents the largest sample size of well-characterized adults with TRBD receiving repeated ketamine infusions at a community-based center. Moreover, a naturalistic dataset was used with minimal exclusion criteria (allowing patients to be enrolled with comorbidities, suicidality, and those who are currently using various antidepressants) thereby increasing the external validity and generalizability of the study in order to accurately reflect the varying population who might utilize ketamine as a treatment option.
The primary limitation of our study is the lack of a control group, as patients received open-label IV ketamine infusions. Furthermore, as our study was not conducted as part of a clinical trial, a large amount of data was missing due to patients skipping assessments and not completing all follow-up visits. Similarly, given that all patients received care at the CRTCE, they were required to cover the full cost (out of pocket or through insurance) of the treatment, resulting in a selection and possibly expectancy bias. Another limitation is that IV ketamine treatment was added on top of the variety of psychotropic medications the patients were already on, leading to potential confounds including patients having multiple comorbidities as well. Lastly, it is important to note that there is no evidence of a higher risk of mania or dissociation or psychosis in this population receiving this treatment.24
In summary, repeated infusions of IV ketamine were associated with improving depressive and anxiety symptoms, as well as psychosocial functional impairments in a well-characterized cohort of adults with TRBD. Future randomized, controlled studies are needed to further evaluate this new treatment, including consideration for acute and maintenance treatment, with these studies currently underway (NCT05339074, NCT05004896).
Footnotes
DATA AVAILABILITY STATEMENT
Due to the nature of the data collected and research ethics approval, the present data set will not be made available or shared in the absence of a signed data sharing agreement that would be evaluated on an individual basis.
ORCID
Farhan Fancy https://orcid.org/0000-0002-9638-6061
Muhammad I. Husain https://orcid.org/0000-0001-5771-5750
Hartej Gill https://orcid.org/0000-0002-3568-8816
Roger S. McIntyre https://orcid.org/0000-0003-4733-2523
References
1.
aan het Rot M, Collins KA, Murrough JW, et al. Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry. 2010;67:139-145. doi:
2.
Bahji A, Vazquez GH, Zarate CA. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2020;278:542-555. doi:
3.
Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351-354.
4.
Cipriani A, Hawton K, Stockton S, Geddes JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013;346:f3646. doi:
5.
Coyle CM, Laws KR. The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum Psychopharmacol. 2015;30:152-163. doi:
6.
Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiat. 2019;76(9):893-903.
7.
Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-d-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67:793-802. doi:
8.
Gitlin M. Treatment-resistant bipolar disorder. Mol Psychiatry. 2006;11:227-240. doi:
9.
Grande I, Berk M, Birmaher B, Vieta E. Bipolar disorder. Lancet. 2016;387:1561-1572. doi:
10.
Grunebaum MF, Galfalvy HC, Choo T-H, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2018;175:327-335.
11.
Grunebaum MF, Ellis SP, Keilp JG, et al. Ketamine versus midazolam in bipolar depression with suicidal thoughts: a pilot midazolam-controlled randomized clinical trial. Bipolar Disord. 2017;19:176-183. doi:
12.
Hidalgo-Mazzei D, Berk M, Cipriani A, et al. Treatment-resistant and multi-therapy-resistant criteria for bipolar depression: consensus definition. Br J Psychiatry. 2019;214:27-35. doi:
13.
Ionescu DF, Luckenbaugh DA, Niciu MJ, Richards EM, Zarate CA Jr. A single infusion of ketamine improves depression scores in patients with anxious bipolar depression. Bipolar Disord. 2015;17:438-443.
14.
Ionescu DF, Swee MB, Pavone KJ, et al. Rapid and sustained reductions in current suicidal ideation following repeated doses of intravenous ketamine. J Clin Psychiatry. 2016;77:e719-e725.
15.
Kennedy SH, Lam RW, McIntyre RS, et al. Canadian network for mood and anxiety treatments (CANMAT) 2016 clinical guide- lines for the management of adults with major depressive dis- order: section 3. Pharmacological Treatments. Can J Psychiatry. 2016;61:540-560.
16.
Kim J, Farchione T, Potter A, Chen Q, Temple R. Esketamine for treatment-resistant depression—first FDA-approved antidepres- sant in a new class. N Engl J Med. 2019;381:1-4. doi:
17.
Kishimoto T, Chawla JM, Hagi K, et al. Single-dose infusion ket- amine and non-ketamine N-methyl-d-aspartate receptor antag- onists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories. Psychol Med. 2016;46:1459- 1472. doi:
18.
Kraus C, Rabl U, Vanicek T, et al. Administration of ketamine for unipolar and bipolar depression. Int J Psychiatry Clin Pract. 2017;21(1):2-12. doi:
19.
Kryst J, Kawalec P, Mitoraj AM, Pilc A, Lasoń W, Brzostek T. Efficacy of single and repeated administration of ketamine in uni- polar and bipolar depression: a meta-analysis of randomized clinical trials. Pharmacol Rep. 2020;72:543-562. doi:
20.
Lee EE, Della Selva MP, Liu A, Himelhoch S. Ketamine as a novel treatment for major depressive disorder and bipolar depression: a systematic review and quantitative meta-analysis. Gen Hosp Psychiatry. 2015;37:178-184. doi:
21.
McIntyre RS, Berk M, Brietzke E, et al. Bipolar disorders. Lancet (London, England). 2020;396(10265):1841-1856. doi:
22.
McIntyre RS, Calabrese JR. Bipolar depression: the clinical characteristics and unmet needs of a complex disorder. Curr Med Res Opin. 2019;35(11):1993-2005. doi:
23.
McIntyre RS, Carvalho IP, Lui LMW, et al. The effect of intravenous, intranasal, and oral ketamine in mood disorders: a meta-analysis. J Affect Disord. 2020;276:576-584. doi:
24.
McIntyre RS, Lipsitz O, Lui L, et al. The meaningful change thres-hold as measured by the 16-item quick inventory of depressive symptomatology in adults with treatment-resistant major depressive and bipolar disorder receiving intravenous ketamine. J Affect Disord. 2021;294:592-596. doi:
25.
McIntyre RS, Lipsitz O, Rodrigues NB, et al. The effectiveness of ketamine on anxiety, irritability, and agitation: implications for treating mixed features in adults with major depressive or bipo- lar disorder. Bipolar Disord. 2020;22(8):831-840. doi:
26.
McIntyre RS, Rodrigues NB, Lee Y, et al. The effectiveness of re- peated intravenous ketamine on depressive symptoms, suicidal ideation and functional disability in adults with major depressive disorder and bipolar disorder: results from the Canadian rapid treatment center of excellence. J Affect Disord. 2020;274:903-910. doi:
27.
McIntyre RS, Rosenblat JD, Nemeroff CB, et al. Synthesizing the evidence for ketamine and esketamine in treatment-resistant depression: an international expert opinion on the available evi- dence and implementation. Am J Psychiatry. 2021;178(5):383-399. doi:
28.
McIntyre RS, Rodrigues NB, Lipsitz O, et al. The effectiveness of intravenous ketamine in adults with treatment-resistant major depressive disorder and bipolar disorder presenting with prominent anxiety: results from the Canadian rapid treatment Center of Excellence. J Psychopharmacol. 2021;35(2):128-136. doi:
29.
McIntyre RS, Suppes T, Tandon R, Ostacher M. Florida best prac- tice psychotherapeutic medication guidelines for adults with major depressive disorder. J Clin Psychiatry. 2017;78:703-713.
30.
Newport DJ, Jeffrey Newport D, Schatzberg AF, Nemeroff CB. Whither ketamine as an antidepressant: panacea or toxin? Depress Anxiety. 2016;33(8):685-688. doi:
31.
Nordentoft M, Mortensen PB, Pedersen CB. Absolute risk of suicide after first hospital contact in mental disorder. Arch Gen Psychiatry. 2011;68:1058-1064. doi:
32.
Peyrovian B, McIntyre RS, Phan L, et al. Registered clinical trials investigating ketamine for psychiatric disorders. J Psychiatr Res. 2020;127:1-12. doi:
33.
Phillips JL, Norris S, Talbot J, et al. Single, repeated, and mainte- nance ketamine infusions for treatment-resistant depression: a randomized controlled trial. Am J Psychiatry. 2019;176:401-409. doi:
34.
Phillips JL, Norris S, Talbot J, et al. Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression. Neuropsychopharmacology. 2020;45:606-612. doi:
35.
Popova V, Daly EJ, Trivedi M, et al. Randomized, double-blind study of flexibly dosed intranasal esketamine plus oral antidepressant versus active control in treatment-resistant depression. In: Poster Presented at: 2018 Annual Meeting of the American Psychiatric Association (APA). 2018.
36.
Rodrigues NB, McIntyre RS, Lipsitz O, et al. A simplified 6-item clinician administered dissociative symptom scale (CADSS-6) for monitoring dissociative effects of sub-anesthetic ketamine infusions. J Affect Disord. 2021;282:160-164. doi:
37.
Rodrigues NB, McIntyre RS, Lipsitz O, et al. Safety and tolerability of IV ketamine in adults with major depressive or bipolar disorder: results from the Canadian rapid treatment center of excellence. Expert Opin Drug Saf. 2020;19(8):1031-1040. doi:
38.
Rosenblat JD, Lipsitz O, Di Vincenzo JD, et al. Real-world effec- tiveness of repeated ketamine infusions for treatment resistant depression during the COVID-19 pandemic. Psychiatry Res. 2021;303:114086. doi:
39.
Rosenblat JD, McIntyre RS, Alves GS, Fountoulakis KN, Carvalho AF. Beyond monoamines-novel targets for treatment-resistant depression: a comprehensive review. Curr Neuropharmacol. 2015;13:636-655.
40.
Sanacora G, Frye MA, McDonald W, et al. A consensus state- ment on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74:399-405. doi:
41.
Schaffer A, Isometsä ET, Tondo L, et al. Epidemiology, neurobiol- ogy and pharmacological interventions related to suicide deaths and suicide attempts in bipolar disorder: part I of a report of the international society for bipolar disorders task force on suicide in bipolar disorder. Aust N Z J Psychiatry. 2015;49:785-802. doi:
42.
Shiroma PR, Thuras P, Wels J, et al. A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression. Transl Psychiatry. 2020;10:206. doi:
43.
Sienaert P, Lambrichts L, Dols A, Fruyt JD. Evidence-based treat- ment strategies for treatment-resistant bipolar depression: a systematic review. Bipolar Disord. 2013;15:61-69. doi:
44.
Singh JB, Fedgchin M, Daly EJ, et al. A double-blind, randomized, placebo-controlled, dose-frequency study of intravenous ketamine in patients with treatment-resistant depression. Am J Psychiatry. 2016;173:816-826. doi:
45.
Salloum NC, Fava M, Freeman MP, et al. Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression. Depress Anxiety. 2019;36:235-243.
46.
Spitzer RL, Kroenke K, Williams JBW, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166:1092-1097.
47.
Vieta E, Berk M, Schulze TG, et al. Bipolar disorders. Nat Rev Dis Primers. 2018;4:18008. doi:
48.
Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175:150-158.
49.
Yatham LN, Kennedy SH, Parikh SV, et al. Canadian network for mood and anxiety treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013;15:1-44. doi:
50.
Yatham LN, Kennedy SH, Parikh SV, et al. Canadian network for mood and anxiety treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20:97-170. doi:
51.
Yazen A, Chen-Li D, Krane E, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychiatr Res. 2022;151:693-709. doi:
52.
Zanos P, Gould TD. Mechanisms of ketamine action as an anti- depressant. Mol Psychiatry. 2018;23:801-811. doi:
53.
Zarate CA, Brutsche NE, Ibrahim L, et al. Replication of ketamine's antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71:939-946. doi:
54.
Zarate CA, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864. doi:
55.
Zheng W, Zhou YL, Liu WJ, et al. A preliminary study of adjunc- tive ketamine for treatment-resistant bipolar depression. J Affect Disord. 2020;275:38-43. doi:
56.
Zhuo C, Ji F, Tian H, et al. Transient effects of multi-infusion ket- amine augmentation on treatment-resistant depressive symptoms in patients with treatment-resistant bipolar depression - an open- label three-week pilot study. Brain and Behavior. 2020;10(8):e01674. doi:
Information & Authors
Information
Published In
History
Published in print: Fall 2023
Published online: 16 October 2023
Keywords
Authors
Funding Information
FUNDING INFORMATIONThis study did not receive any funding.
Metrics & Citations
Metrics
Citations
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
For more information or tips please see 'Downloading to a citation manager' in the Help menu.
View Options
View options
PDF/EPUB
View PDF/EPUBLogin options
Already a subscriber? Access your subscription through your login credentials or your institution for full access to this article.
Personal login Institutional Login Open Athens loginNot a subscriber?
PsychiatryOnline subscription options offer access to the DSM-5-TR® library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.
Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).