Neurocognitive effects of six ketamine infusions and the association with antidepressant response in patients with unipolar and bipolar depression

This open-label study (n=84) found that 6 ketamine (35mg/70kg) infusions over 12 days led to cognitive improvements (speed of processing, verbal learning) in those with depression. The improvements were mediated by the level of improvement in depressive symptoms. Those with a higher baseline of visual learning had the greatest antidepressant response.

Abstract

“Background: Ketamine has proven to have rapid, robust antidepressant effects on treatment-resistant depression. However, whether repeated ketamine infusions would cause short-and long-term neurocognitive impairments was not clear. Our aims were to investigate the neurocognitive effects of six ketamine infusions and to examine the association between these infusions and the antidepressant response in patients with unipolar and bipolar depression.

Methods: Six intravenous infusions of ketamine (0.5 mg/kg) over a 12-day period were administered to 84 patients with unipolar and bipolar depression. Severity of depressive symptoms and four domains of neurocognition, including speed of processing, working memory, visual learning and verbal learning, were assessed at baseline, one day following the last infusion and again two weeks post-infusion.

Results: Significant improvements were found on speed of processing (F=9.344, p<0.001) and verbal learning (F=5.647, p=0.004) in a linear mixed model. The Sobel test showed significant indirect effects between time and improvement in speed of processing (Sobel test=3.573, p<0.001) as well as improvement in verbal learning (Sobel test=6.649, p<0.001), which were both significantly mediated by change in depressive symptoms. Logistic regression analysis showed ketamine responders had better visual learning at baseline than non-responders (B=0.118, p<0.001).

Conclusions: Our findings suggest that neurocognitive function would not deteriorate after six ketamine infusions, while verbal learning and speed of processing improved over 13 days and 26 days of observation, respectively. However, this change was mainly accounted for by improvements in severity of depressive symptoms over time. Greater baseline visual learning predicted an antidepressant response over six ketamine infusion.”

Authors: Yanling Zhou, Wei Zheng, Weijian Liu, Chengyu Wang, Yanni Zhan, Hanqiu Li, Lijian Chen, Mingding Li, Yuping Ning

Summary

Introduction

Ketamine is a high-affinity, non-competitive NMDA glutamate receptor antagonist that has been approved for use as an anesthetic for over 40 years. It has also demonstrated rapid-onset antidepressant effects in patients with treatment-resistant depression and rapid reductions in suicidal cognition in patients with suicidal ideation.

Ketamine has been shown to have serious effects on neurocognition in healthy volunteers and in a model of schizophrenia. This has led to concern that ketamine may cause long-term neurocognitive effects in patients with TRD.

Ketamine has proven to have rapid, robust antidepressant effects on treatment-resistant depression. However, the neurocognitive effects of six ketamine infusions were not clear.

Previous studies have shown that ketamine administration at subanesthetic doses used as antidepressants seems to have no or slight harm to neurocognitive function. However, additional studies with larger sample size of patients with depression are required to further substantiate the neurocognitive effects of repeated ketamine treatments.

A study found that individuals performing with lower neurocognitive functioning at baseline were more likely to obtain a positive antidepressant response to ketamine. Another study found that those performing with poor attention performance had higher response rates after the completion of six ketamine infusions.

The current study investigated the effect of six serial infusions of ketamine on neurocognitive function in individuals with unipolar and bipolar disorder and the relationship between baseline neurocognitive performance and the antidepressant response.

Methods

This was a single-arm, open-label, 26-day study at the Affiliated Brain Hospital of Guangzhou Medical University. All participants signed a consent form prior to entering this study.

Subjects

Patients who met the following criteria were enrolled in the exploratory study of antidepressant treatment using ketamine for depression: aged 18-65, male or female, without psychotic features, treatment resistance, and current moderate to severe depressive symptoms.

The exclusion criteria included a history of substance abuse, a positive urine toxicology screen, a serious medical or neurological illness, a traumatic brain injury, a mental illness, and pregnancy.

Ketamine infusions

Ketamine infusions were conducted in the treatment room in outpatient or inpatient department. All patients were prescribed their psychiatric medications at the stable dosage for at least four weeks prior to screening.

Prior research indicates that thrice-weekly infusions of ketamine over two weeks have a higher response rate and longer mean time to relapse. A 12-day regimen of ketamine infusions was used in the current study.

Participants were required to read instructions before starting treatment, and were monitored for side effects during and after the treatment. Ketamine was dosed at 0.5 mg/kg and diluted in 0.9% saline, and was infused by intravenous pump infusion over a period of 40 min.

Outcome assessments

The severity of depressive symptoms was measured by the 17-item Hamilton Depression Rating Scale (HAMD-17) before and after the study. The inter-rater reliability for all scales used was excellent to good.

All participants completed four domains of the MCCB at baseline, 13 and 26 day visits. These domains were selected because learning and memory impairment is often associated with depression.

Statistical analyses

Patients with MDD and BD were compared using the Chi-squared test and Student’s t-test. Changes in neurocognitive function were examined using linear mixed models, and the Sobel test was used to test for mediated effects.

A logistic regression model was used to detect the relationship between neurocognitive performance at baseline and antidepressant response over the six ketamine infusions. The response was defined as a 50% reduction in HAMD scores on day 13.

Patient sample

A total of 185 patients were screened for eligibility, and 100 patients were enrolled in this study. Eighty-four patients completed the six infusions, and 10 patients withdrew before the last follow-up.

Clinical and demographic characteristics

All participants were diagnosed with MDD or BD and were well matched in age, education, body mass index, age onset and previous psychiatric hospitalization.

Antidepressant outcomes

After six infusions, 46 completers met the criteria for response, and 26 met the criteria for remission in all 84 subjects. There was no difference between patients with MDD and those with BD.

Two neurocognitive domains, speed of processing and verbal learning, showed significant main effects of time when the whole sample was included in the linear mixed model. No significant main group effect was found in any assessment.

After six ketamine infusions, only two neurocognitive domains showed significant improvement: speed of processing and verbal learning. The Sobel test revealed that changes in HAMD significantly carried the influence of an independent variable (time) to a dependent variable (speed of processing and verbal learning).

Baseline neurocognitive performance predicts the antidepressant response to ketamine over six infusions

Baseline neurocognitive performance and psychiatric comorbidity were significant predictors of antidepressant response to ketamine over six infusions.

Discussion

From this open-label study, patients with unipolar or bipolar depression who received six infusions of ketamine at a subanesthetic dose experienced improvements in verbal learning and speed of processing.

Neurocognitive change after six ketamine infusions

Ketamine is a stimulant that affects the brain’s NMDA receptors, which are involved in learning, problem-solving, attention, working memory and long-term retention. Ketamine use can cause cognitive impairments, which restrict its use in depression treatment.

Recent studies have focused on the neurocognitive effects of subanesthetic doses of ketamine utilized in depression, but the results have been inconsistent. The present study provided stronger evidence that six ketamine infusions had no deleterious effect on neurocognitive function.

Ketamine’s neurocognitive effects were complicated, and were caused by its effects on NMDA receptors, dopamine, and serotonin. Ketamine abuse can cause serious cognitive problems.

Most studies using ketamine in the treatment of mood disorders used a single dose of 0.5 mg/kg or a two- or three-week course of ketamine delivered two or three times per week. However, preliminary evidence demonstrated that ketamine produced fast-acting antidepressant effects that were dependent on the rapid protein synthesis of brain-derived neurotrophic factor.

Baseline neurocognitive performance predicts an antidepressant response to ketamine over six infusions

In the current study, patients with greater visual learning at baseline tended to obtain a response in TRD following six infusions of ketamine, which was inconsistent with previous studies. However, studies of depressed populations who were receiving treatment with a selective serotonin reuptake inhibitor reached a similar conclusion.

Higher hippocampal volumes and higher BDNF levels predict higher response/remission rates to antidepressant drugs, whether they are taken with ketamine or with monoaminergic antidepressants.

Limitations

The current study had several limitations, including 13 patients who discontinued treatment due to side effects or dissatisfaction with the therapeutic efficacy. A future study should be conducted with medication-free patients to verify the current findings.

Conclusions

Six infusions of ketamine at a subanesthetic dose had no deleterious effect on neurocognitive function, but improved severity of depressive symptoms over time. Greater baseline visual learning predicted an antidepressant response over six ketamine infusions.