The effects of ketamine and classic hallucinogens on neurotrophic and inflammatory markers in unipolar treatment-resistant depression: a systematic review of clinical trials

This systematic review (2022, s=12) finds inconclusive results for the effects of psychedelics on several biomarkers (neurotrophic & inflammatory) in studies that used ayahuasca and ketamine in treating ‘treatment-resistant’ depression. Bigger trials are necessary, though studying the biomarkers per drug (not several together) may also be warranted.

Abstract

“Although results are still preliminary, ketamine and classical hallucinogens have shown promise in recent years as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression (TRD). Depression also seems to be related to abnormal levels of peripheral inflammatory and neurotrophic biomarkers, which may one day help to diagnose of this disorder. In this context, this systematic review of clinical trials evaluated the current evidence that relates the antidepressant effects of ketamine and classical hallucinogens on TRD with changes in inflammatory and neurotrophic biomarkers. Twelve studies were found (n = 587), 2 with oral ayahuasca (1 mL/kg) and 10 with ketamine (mostly intravenous 0.5 mg/kg) administration. Results for all biomarkers assessed were contradictory and thus inconclusive. Randomized controlled trials with bigger samples and higher statistical power are warranted to clarify if peripheral biomarkers can confidently be used to indicate and measure ketamine’s and classical hallucinogens’ antidepressant effect.”

Authors: Giordano N. Rossi, Jaime E. C. Hallak, Glen Baker, Serdar M. Dursun & Rafael G. dos Santos

Summary

Although results are still preliminary, ketamine and classical hallucinogens have shown promise as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression. However, the effects of these drugs on peripheral inflammatory and neurotrophic biomarkers are contradictory.

Ketamine, psychedelics, and BDNF

Introduction

Major depressive disorder (MDD) is a highly prevalent psychopathology, generating global expenses of billions of dollars annually for its treatment, and is projected to rank first in disease burden worldwide by 2030.

Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatments for MDD, but they cause remission in only two-thirds of patients with treatment-resistant depression. Other approved drugs such as monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants can also be used as second or third-line treatments.

With the growing mental health problem of MDD, a need for fast-acting antidepressants becomes more apparent. Research with hallucinogens and ketamine may provide this need.

Classical hallucinogens include LSD, psilocybin, DMT and mescaline, which act through agonism at serotonin 5-hydroxytryptamine type 2A (5-HT2A) receptors. Ketamine, on the other hand, acts through inhibition of glutamate N-methyl-d-aspartate receptor (NDMAR) and AMPAR activation.

Studies indicate that altered secretion of pro-inflammatory cytokines and neuroprotective/neuroplastic factors within the central nervous system contributes to the emergence and maintenance of depressive symptoms. Several studies have investigated the therapeutic effects of fast-acting antidepressants on these biomarkers.

Search strategy

The electronic search was performed using the PubMed, Web of Science, Embase, SciELO and LILACS databases and included studies published until the 5th of May 2022.

Selection criteria and study selection

Inclusion criteria included adult patients with unipolar treatment-resistant major depressive disorder, studies involving administration of ketamine or classical hallucinogens, and studies evaluating levels of neurotrophins and/or inflammatory biomarkers before and after treatment.

After excluding duplicates, titles and abstracts of all articles were reviewed. Two reviewers independently decided to include or exclude publications, and a third author/reviewer decided on the inclusion or exclusion of articles.

Recorded variables, data extraction and analysis

The following data were extracted: reference, study design, treatment-resistant definition, participant characteristics, treatments, biomarkers and analysis tools, depressive symptoms scales, and main results with statistical significance. Two independent reviewers evaluated the quality of included studies using the Study Quality Assessment Tools.

Selected studies

A search was conducted in several databases until 05/05/2022, and 26 articles were selected for full-text reading. Of these 26, 13 studies were excluded because they contained mixed samples of patients with unipolar TRD, MDD and suicidality, and PD and/or PTSD.

Treatment resistance was defined as an inadequate response to one, two or three previously failed treatment attempts, except for one study with no clear definition. Eleven studies involved ketamine intravenous administration, including 5 open-label trials, 3 randomized, double-blind, placebo-controlled trials with parallel groups, and 3 crossover trials.

A total of 617 participants were included in the studies, of which 415 were TRD patients. The samples varied from 16 to 71 volunteers, with 234 men and 314 women accounting for 42% and 57%, respectively.

Classic hallucinogens

In 2019, de Almeida et al. quantified blood biomarker levels after ayahuasca administration. They found that patients treated with ayahuasca had higher serum BDNF levels than healthy controls, and that there was a negative correlation between serum BDNF and MADRS scores. Researchers found that volunteers who took ayahuasca (TRD + CG) presented lower CRP levels when compared to baseline, and that this reduction was directly correlated with lower MADRS scores at day 2.

Ketamine and neurotrophic biomarkers

In 2009, Machado-Vieira et al. quantified peripheral BDNF after ketamine administration in an open-label trial with 23 drug-free TRD volunteers. There were no significant changes in plasma BDNF levels, even for ketamine responders.

Duncan et al. [39] conducted an open-label trial with a single 0.5 mg/kg ketamine infusion in 30 drug-free TRD patients and found that ketamine increased plasma BDNF levels.

Haile et al. [44] conducted a randomized, double-blind, active placebo-controlled trial with parallel groups in 2014, and found that plasma BDNF levels were negatively correlated with MADRS scores at 240 min, 24 h, 48 h, and 72 h post-infusion.

Allen et al. [36] compared three 0.5 mg/kg ketamine infusions once a week or twice-weekly ECT (5 – 12 sessions) to healthy controls and found that responders had increased serum BDNF levels at 1 week post-first infusion.

In 2018, Kadriu et al. published an open-label trial with 16 healthy volunteers and 28 TRD drug-free patient groups. FGF-23 levels did not significantly change with treatment.

Kiraly et al. measured 41 cytokines, chemokines and growth factors in serum after ketamine administration to TRD patients in an open-label trial. BDNF, G-CSF and PDGF-AA were not changed with ketamine treatment, but low FGF-2 pretreatment levels were associated with ketamine treatment response.

Medeiros et al. [34] measured BDNF and VEGF in 39 TRD drug-free patients who received either 0.5 mg/kg ketamine infusion or placebo.

Jiang et al. evaluated neurotrophic biomarkers after ketamine treatment in TRD drug-free volunteers. They found no significant changes in any of the biomarkers.

Ketamine and inflammatory biomarkers

Yang et al. measured inflammatory biomarkers after ketamine administration to TRD patients in an open-label trial in 2015. Only responders had decreased levels of IL-1 and IL-6 230 min and 1 day post-infusion, compared with baseline.

The study by Kiraly et al. [42] in 2017 showed that ketamine decreased the levels of IL-6, IL-1, IL-13 and IP-10, while increasing the levels of IL-7 and decreasing the levels of IL-8.

Chen et al. published the results of a double-blind, placebo-controlled trial in 2018, where ketamine was administered to 71 TRD add-on volunteers. The results showed that ketamine decreased C-reactive protein, IL-6 and TNF- levels, and that this decrease was positively correlated with decreased MADRS scores.

A study was made by Mkrtchian et al. in 2020 that compared CRP levels in healthy volunteers and TRD patients with resting-state functional magnetic resonance imaging.

In an effort to present the results of this review in a more illustrative manner, we have included results from articles of interest that were not systematically analyzed.

Quality assessment

Of the RCTs, only one reported an intention-to-treat analysis, and none reported the method of randomization or calculated the sample size a priori. Moreover, none reported if all eligible participants that met the prespecified entry criteria enrolled.

Discussion

In this systematic review, 13 clinical trials were found that compared the effects of classical hallucinogens and ketamine on inflammatory and neurotrophic biomarkers in patients with TRD. Ayahuasca significantly enhanced BDNF levels and reduced CRP levels.

Ketamine significantly increased BDNF in 3 of 7 studies, decreased G-CSF and PDGF-AA levels, and increased FGF-23 in one study, but did not change levels of the main neurotrophic molecule of interest.

Ketamine decreased IL-6, TNF-, and IL-1 levels in two out of three studies, but not in two out of three studies that measured CRP.

Ayahuasca, harmine and DMT have been shown to increase BDNF levels in healthy controls and depressed patients, and ayahuasca may also induce neurogenesis. However, two recent placebo-controlled trials failed to find significant effects on BDNF levels in healthy volunteers and individuals with social anxiety disorder.

Ketamine results are less consistent, with only 3 studies reporting significant rises in peripheral BDNF. The only study that reported raised BDNF levels was when comparing responders to non-responders.

A study found that G-CSF levels were higher in TRD patients at baseline and decreased after ketamine administration. However, PDGF-AA levels were also found to significantly decrease after ketamine administration.

Two studies reviewed indicated that VEGF levels were not altered by ketamine treatment after a single 0.5 mg/kg infusion, while two previous meta-analyses indicated that VEGF levels were significantly higher in MDD patients than controls.

Ayahuasca significantly decreased CRP levels in healthy volunteers and depressed patients, but did not change IL-6 levels. Although preclinical studies demonstrate that 5HT2A receptor agonists have prominent anti-inflammatory properties, human studies quantifying inflammatory biomarkers are still scarce.

When measuring ketamine treatment response, inconsistent results remain for other inflammatory biomarkers. Furthermore, no studies have measured blood biomarkers after more than one administration of psychedelics or ketamine, and bigger samples with greater statistical power are necessary to properly assess blood biomarkers with ketamine treatment.

Studies have shown that cytokines such as IL-6, IL-1 and TNF- decrease BDNF levels and interfere with TrkB signaling, inhibiting neurogenesis and neuroplasticity. Furthermore, IL-1 stimulates lower cortisol levels, which are associated with stress-related states and depression, also related to lower BDNF levels.

The inconclusive results regarding the biomarkers may be explained by the complex etiology of MDD and TRD, the existence of subtypes of depression, and the number of previously failed treatment attempts. The studies reviewed have several limitations, including using peripheral blood and not directly analyzing BDNF levels in the brain. The heterogeneity of the methods of analysis, treatment, intra- and inter-subject comparisons, and time of blood collection may greatly interfere in biomarker analysis.

Conclusion

Based on the available evidence, we conclude that the neuroplastic or immunological parameters evaluated in these trials cannot be used confidently as biomarkers of symptoms improvement in TRD regarding treatments with classic hallucinogens and ketamine.