Rapid effectiveness of intravenous ketamine for ultraresistant depression in a clinical setting and evidence for baseline anhedonia and bipolarity as clinical predictors of effectiveness

This retrospective, open-label, database study (n=50) examined the efficacy of ketamine (35mg/70kg) treatment for patients with ultra-resistant depression and found that baseline anhedonia and bipolar disorder strongly predicted treatment response (44%) and the rate of symptom remission (16%) across participants.

Abstract

“Background: Intravenous ketamine has been established as an efficacious and safe treatment, with transient effect, for treatment-resistant depression. However, the effectiveness of intravenous ketamine in non-research settings and with ultraresistant depression patients remains understudied.

Aims: This study aims to measure the response and remission rates in ultraresistant depression patients in a clinical setting by means of a retrospective, open label, database study. Secondarily, the study will attempt to support previous findings of clinical predictors of effectiveness with intravenous ketamine treatment.

Methods: Fifty patients with ultraresistant depression were treated between May 2015–December 2016, inclusive, in two community hospitals in Edmonton using six ketamine infusions of 0.5 mg/kg over 40 min over 2–3 weeks. Data were collected retrospectively from inpatient and outpatient charts. Statistical analysis to investigate clinical predictors of effectiveness included logistic regression analysis using a dependent variable of a 50% reduction in rating scale score at any point during treatment.

Results: At baseline, the average treatment resistance was severe, with a Maudsley Staging Method score of 12.1 out of 15, 90.0% were resistant to electroconvulsive therapy, and the average Beck Depression Inventory score was 34.2. The response rate was 44% and remission rate was 16%. As a single predictor, moderate or severe anhedonia at baseline predicted a 55% increased likelihood of response. As a combined predictor, this level of anhedonia at baseline with a diagnosis of bipolar depression predicted a 73% increase in likelihood of response.

Conclusion: In a clinical setting, intravenous ketamine showed effectiveness in a complex, severely treatment-resistant, depressed population on multiple medication profiles concurrently. This study gave support to anhedonia and bipolar depression as clinical predictors of effectiveness.”

Authors: Rejish K. Thomas, Glen Baker, John Lind & Serdar Dursun

Summary

Introduction

A population of depressed patients who have failed a comprehensive treatment regimen of antidepressants, augmentation strategies, psychotherapy, and electroconvulsive therapy (ECT) exists who are described as ultraresistant depression (URD). These patients carry a large burden of illness and may benefit from experimental treatments like intravenous ketamine.

IV ketamine at subanesthetic doses has demonstrated effect sizes similar to ECT in treating both unipolar and bipolar depression, and has also yielded exciting anti-suicidal effects.

A retrospective, open label, database study will attempt to measure the response and remission rates in ultraresistant depression patients treated with intravenous ketamine.

Fifty patients with ultraresistant depression were treated with ketamine infusions over 2 – 3 weeks. Statistical analysis was performed to determine the effectiveness of the treatment.

At baseline, 90.0% of patients were resistant to treatment.

Intravenous ketamine showed effectiveness in a complex, severely treatment-resistant, depressed population on multiple medication profiles concurrently. Anhedonia and bipolar depression were significant predictors of effectiveness.

Given the experimental nature of ketamine treatment, it would be ideal to collect biomarkers of response that would provide knowledge about which particular patients are more likely to respond. Family history of an alcohol use disorder in a first degree relative and higher body mass index may be predictive.

Database collection

Data were collected from 50 patients who received ketamine for depression at the Grey Nuns Community Hospital or Misericordia Community Hospital. Four patients had no response based on clinical notes and did not complete end rating scales. A database was created and information was extracted from electronic outpatient charts, paper inpatient charts, and paper outpatient charts. Personality and DSM-5 diagnostic information were collected only if the words ‘disorder’ or ‘traits’ were ever documented in the ‘diagnosis’ section of any of the sources.

Inclusion criteria

Patients with a major depressive episode who were refractory to pharmacological treatment, ECT, or were acutely suicidal were permitted to be given IV ketamine.

Exclusion criteria

Patients with active psychosis, drug or alcohol abuse/dependence, dementia/delirium, a significant personality disorder, a significant unstable medical condition, pregnancy, dissociative identity disorder, and a history of allergic reaction to ketamine were excluded.

Administration of IV ketamine

A physician assessed the patient, ordered blood work, an electrocardiogram, a urine drug screen 24 h before if deemed appropriate, and recommended IV ketamine administration. The patient received 0.5 mg/kg over 40 min, and was monitored throughout the procedure.

Rating scales

We used the Montgomery Asberg Depression Rating Scale, the Beck Depression Inventory-I or – II, the Hamilton Rating Scale for Depression 17 or 21, and the Brief Psychiatric Rating Scale.

The frequency and type of rating scales administered was left to the clinician’s discretion, but typically rating scales were administered at least four hours post-treatment. A side effect tracking scale was created for this patient population based on known short term side effects.

Statistical analysis

Clinical and demographic characteristics were compared between responder and non-responder groups, and remission was defined as a 50% reduction in BDI-I, BDI-II, or HRSD-21 between baseline and any time-point during treatment.

The analysis was performed using categorical independent variables of age, gender, FHA, suicidality, anxiety, unipolar versus bipolar depression, and anhedonia, and continuous data independent variables of BMI, age, and MSM.

Results

The population had an average MSM TRD level of severe with low variance, 90% ECT resistance, and 86% psychotherapy resistance, and 44% and 48% of the population had Cluster B and C personality traits, respectively.

Baseline characteristics of responders and non-responders were compared with independent t tests and z tests. A response rate of 44% and remittance rate of 16% were observed, with complete symptom remission in 54.0% and 68.9% of patients, respectively, during treatment.

Logistic regression was done to investigate the clinical predictors of effectiveness of IV ketamine for patients with bipolar depression and at least moderate anhedonia at baseline. The presence of bipolar depression and at least moderate anhedonia at baseline were seen as significant predictors in this regression model.

Discussion

This retrospective database study with 50 patients represents the highest level of treatment resistance that has been studied for IV ketamine. The response and remittance rates that were achieved are therefore very encouraging to a population that is underserved.

This study found that 16% of patients responded to ketamine, which is lower than the Serafini et al. (2014) systemic review findings of 26 – 67%. The response rate of 44% was also consistent with the lower end of the Coyle and Laws (2015) meta-analysis results of 40 – 90%.

The study population was heterogeneous, and the lack of biomarkers may have limited the sensitivity of the study to find clinical predictors of effectiveness to ketamine. Nevertheless, anhedonia was a significant clinical predictor of effectiveness to ketamine. The anterior cingulate cortex is involved in error detection, task shifting, conflict monitoring and reward based learning. Its dysfunction predicts patient response to ketamine treatment. Ketamine’s anti-anhedonic effects may be due to its action on the glutamate pathway, which regulates the reward system, motivation, rumination and distraction. Ketamine may also act on the anterior cingulate cortex, which regulates the ability to distract from negative experiences.

Theoretically, lamotrigine inhibits glutamate release, which is opposed to the proposed mechanism of action of ketamine. However, a study found no significant difference in side effects or antidepressant effect when lamotrigine was administered before IV ketamine.

This study gave evidence for bipolarity as a predictive factor to response to IV ketamine, which has not been previously described. However, the study is in keeping with consistent evidence that IV ketamine has a robust effect on bipolar depression and bipolar depression suicidality.

Ketamine is well-tolerated in the short term and only four out of 50 patients suffered side effects that resulted in aborted treatment.

Despite the strength of this study, it has limitations due to its design. There is a large active placebo effect, and the patient had previously responded to minimally to previous interventions.

The findings reported here could be replicated with larger clinical sample sizes, and clinical indicators could be combined with biomarkers to make composite clinical decision making tools. This could prevent many years of functionally disabling depression in the treatment resistant depression population.

Conclusion

In a clinical setting, six infusions of ketamine showed effectiveness in a complex, severely treatment-resistant, depressed population on multiple concurrent medications. A registry of all patients undergoing IV ketamine has been advocated for, and would certainly build on this study.