This open-label study (n=94) finds that baseline plasma BDNF concentrations (a protein related to nerve growth) correlate with ketamine (6 infusions, 35mg/70kg) antidepressant effects (MADRS).
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Objectives
Accumulating evidence has implicated that brain derived neurotrophic factor (BDNF) is thought to be involved in the pathophysiology of depression, but its correlation with ketamine’s antidepressant efficacy focusing on Chinese individuals with depression is not known. This study was aim to determine the correlation of plasma BDNF (pBDNF) concentrations and ketamine’s antidepressant efficacy.
Methods
Ninety-four individuals with depression received six intravenous infusions ketamine (0.5 mg/kg). Remission and response were defined as Montgomery-Asberg Depression Rating Scale (MADRS) scores less than 10 and a reduction of 50% or more in MADRS scores, respectively. Plasma was collected at baseline and at 24 h and 2 weeks after completing six ketamine infusions (baseline, 13 d and 26 d).
Results
A significant improvement in MADRS scores and pBDNF concentrations was found after completing six ketamine infusions compared to baseline (all ps < 0.05). Higher baseline pBDNF concentrations were found in ketamine responders/remitters (11.0 ± 6.2/10.1 ± 5.8 ng/ml) than nonresponders/nonremitters (8.0 ± 5.5/9.2 ± 6.4 ng/ml) (all ps < 0.05). Baseline pBDNF concentrations were correlated with MADRS scores at 13 d (t = − 2.011, p = 0.047) or 26 d (t = − 2.398, p = 0.019) in depressed patients (all ps < 0.05). Subgroup analyses found similar results in individuals suffering from treatment refractory depression.
Conclusion
This preliminary study suggests that baseline pBDNF concentrations appeared to be correlated with ketamine’s antidepressant efficacy in Chinese patients with depression.
Accumulating evidence links glutamatergic dysfunction to the pathophysiology of mood disorders, and subanesthetic doses of the NMDA (N-methyl-D-aspartate) receptor antagonist ketamine have been reported to produce rapid antidepressant and antisuicidal effects in unipolar and bipolar depression. Neurotrophic mechanisms, particularly brain-derived neurotrophic factor (BDNF), have been implicated in depression and in antidepressant treatment responses: lower peripheral BDNF levels have been observed in depressed patients versus healthy controls and have risen after successful treatments. Prior studies examining the relationship between peripheral BDNF and ketamine's antidepressant efficacy have produced inconsistent results, and most have considered single infusions rather than repeated administrations; no published work had examined this question in a Chinese sample receiving serial ketamine infusions. Zheng and colleagues designed the present study to test whether six subanesthetic intravenous ketamine infusions (0.5 mg/kg, administered three times weekly over two weeks) change plasma BDNF (pBDNF) concentrations, and whether baseline pBDNF is associated with subsequent antidepressant response. The investigators hypothesised that serial ketamine would increase pBDNF and that higher baseline pBDNF would be associated with better antidepressant outcomes in individuals with unipolar or bipolar depression.
This was an open-label clinical study conducted between November 2016 and December 2017 (registration: ChicCTR-OOC-17012239) with ethical approval from the Affiliated Brain Hospital of Guangzhou Medical University. Participants provided written informed consent. Eligibility criteria required age 18–65 years, a DSM-5 diagnosis of unipolar or bipolar depression established by SCID-5, HAMD-17 score ≥17, absence of psychotic symptoms, negative urine toxicology, no neurological disease or substance abuse, not pregnant or breastfeeding, and no unstable medical illness. Treatment-resistant depression (TRD) was defined as nonresponse to two or more antidepressant treatments; suicidal ideation also qualified some participants under the study inclusion criteria. All enrolled patients received six intravenous infusions of ketamine at 0.5 mg/kg delivered over 40 minutes, administered three times per week for two weeks, with a subsequent two-week follow-up. Vital signs and clinical status were monitored during infusions. Participants continued their existing psychotropic medications during the study (no washout). Depressive symptoms were assessed with the Montgomery–Åsberg Depression Rating Scale (MADRS) at baseline, 1 day after the sixth infusion (day 13), and two weeks after the last infusion (day 26). Response was defined as a ≥50% reduction in MADRS score and remission as a MADRS score <10. Plasma samples for pBDNF were collected at the same three time points, stored at −80 °C, and analysed by a commercial ELISA kit (EMD Millipore). Statistical analyses included Mann–Whitney U tests for non-normally distributed continuous data, independent t tests for normally distributed continuous data, and Fisher’s exact or Chi-squared tests for categorical comparisons. Linear mixed models tested changes over time and subgroup (responders versus nonresponders; remitters versus nonremitters). Bivariate correlations examined associations between baseline pBDNF and MADRS at days 13 and 26; multiple linear regression models tested whether baseline pBDNF predicted MADRS while adjusting for covariates (age, sex, weight, BMI, psychiatric family history, previous hospitalisation, psychiatric comorbidity, and age at onset). An additional analysis focused on the TRD subsample. Significance was set at p<0.05 and analyses were performed in IBM SPSS v23.
Accumulating evidence suggests that glutamatergic abnormalities are associated with the pathophysiology of mood disorders. Numerous early studies had consistently reported that an antagonist of glutamatergic N-methyl-D-aspartate (NMDA) receptors ketamine at subanesthetic doses could result in fast-acting and sustained antidepressant effects in individuals suffering from unipolar and bipolar depression. For example, ketamine's repeated administration had quick and enduring antidepressant and antisuicidal effects in depressed patients. The precise mechanisms underlying subanesthetic intravenous ketamine's antidepressant actions are still incompletely understood. A recent animal study found that blockade of NMDA receptors increased the induction of α-amino-3hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor expression in models of depression, and subsequent activation of the mammalian target of rapamycin (mTOR) pathway was needed for the rapid and robust antidepressant action of ketamine. Growing evidence implicated neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), played an important in the pathophysiology of mood disorders. BDNF is a key protein in facilitating and supporting memory growth and neuronal survival. Rapid and transient upregulation of BDNF reversed or blocked atrophy and cell loss in patients with depression, and it may be a critical component in subanesthetic intravenous ketamine's antidepressant actions. In general, BDNF plays a role in the pathophysiology of schizophrenia) and mood disorders. For example, several studies found that individuals suffering from depression had lower serum BDNF concentrations and pBDNF concentrations than that of healthy subjectsand recovered after successful antidepressant therapy. Central and peripheral BDNF is positively correlated with the response and remission of antidepressant treatment. Notably,reported that remitted than nonremitted depressed patients appeared to have higher pBDNF concentrations, and these concentrations were associated with the Montgomery-Asberg Depression Rating Scale (MADRS) scores. BDNF as a predictor of ketamine's antidepressant efficacy in individuals suffering from treatment-refractory depression (TRD) has been investigated, but with inconsistent findings. For example, several open-label studies on ketamine and BDNF found a negative association of the increase in BDNF following a single ketamine infusion with the severity of depression. Another study found that BDNF did not mediate single subanesthetic intravenous ketamine's antidepressant efficacy. However, no studies had been published to examine the relationship of pBDNF concentrations and serial subanesthetic intravenous ketamine infusions' antidepressant efficacy in Chinese individuals suffering from depression. The present study was performed to examine the correlation of pBDNF concentrations and six subanesthetic intravenous ketamine's antidepressant efficacy (0.5 mg/kg) administered thrice weekly over two weeks in Chinese individuals suffering from unipolar and bipolar depression. In this study, we hypothesized that serial intravenous subanesthetic ketamine would increase pBDNF concentrations, and baseline pBDNF concentrations would be associated with ketamine's antidepressant efficacy in individuals suffering from depression.
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Réus, G. Z., Stringari, R. B., Ribeiro, K. F. et al. · Behavioural Brain Research (2011)
Rong, C., Park, C., Rosenblat, J. D. et al. · International Journal of Environmental Research and Public Health (2018)
Zheng, W., Zhou, Y-L., Liu, W. et al. · Journal of Psychiatric Research (2018)
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Calder, A. E., Hase, A., Hasler, G. · Molecular Psychiatry (2024)
Agnorelli, C., Spriggs, M. J., Godfrey, K. et al. · Preprints (2024)
Rossi, G. N., Hallak, J. E., Baker, G. et al. · European Archives of Psychiatry and Clinical Neuroscience (2022)
Medeiros, G. C., Gould, T. D., Prueitt, W. L. et al. · Molecular Psychiatry (2022)
Zhou, Y-L., Wang, C., Lan, X-F. et al. · Journal of Psychiatric Research (2021)
Ninety-four participants with unipolar or bipolar depression who provided baseline blood samples were enrolled; ages ranged from 18 to 62 years. Most participants met criteria for treatment-resistant depression: 81.9% (77/94). Baseline plasma BDNF concentrations averaged 10.1 ng/ml (range 0.9–27.2 ng/ml). Clinical outcomes after the six ketamine infusions showed a response rate of 68.1% (64/94) and a remission rate of 51.1% (48/94) at the post-treatment assessment. Within the TRD subgroup, response and remission rates were 68.8% (53/77) and 51.9% (40/77), respectively. Linear mixed-model analyses indicated significant time effects for both MADRS scores and pBDNF concentrations: ketamine produced significant reductions in MADRS and increases in pBDNF at day 13 and day 26 compared with baseline. Comparing clinical subgroups, baseline pBDNF concentrations were higher in responders than nonresponders (11.0 ± 6.2 ng/ml versus 8.0 ± 5.5 ng/ml) and higher in remitters than nonremitters (10.1 ± 5.8 ng/ml versus 9.2 ± 6.4 ng/ml); these differences reached statistical significance (p<0.05). The time-by-group analyses showed significant main effects between responders and nonresponders and between remitters and nonremitters for both MADRS and pBDNF. Correlation analyses demonstrated that baseline pBDNF was significantly associated with MADRS scores at day 13 and day 26 (all p<0.05). In multiple linear regression models that adjusted for demographic and clinical covariates, baseline pBDNF remained significantly associated with MADRS at day 13 (t = −2.011, p = 0.047) and day 26 (t = −2.398, p = 0.019). Subgroup analyses restricted to the TRD sample produced similar findings.
The investigators report this as the first study examining plasma BDNF concentrations following six subanesthetic intravenous ketamine infusions in a Chinese sample with unipolar and bipolar depression and the first to study the relationship between baseline pBDNF and serial-ketamine antidepressant outcome in this population. Key findings highlighted were that pBDNF increased at 13 and 26 days post-baseline, responders and remitters had higher baseline pBDNF than nonresponders/nonremitters, MADRS scores improved significantly at both follow-up time points, and baseline pBDNF was associated with subsequent MADRS scores; these associations were preserved in the TRD subsample. The authors place their results in the context of prior animal and human work: an animal study showed increased BDNF expression after NMDA receptor blockade, and some human studies have reported increased peripheral BDNF following ketamine, although results have been inconsistent across studies of single versus repeated infusions. Zheng and colleagues note that while baseline pBDNF differed between outcome groups, repeated ketamine infusions did not produce a significantly greater pBDNF increase in responders/remitters versus nonresponders/nonremitters in their sample, echoing mixed findings in the literature. Mechanistically, the paper reiterates the role of BDNF in synaptic plasticity and its putative place in ketamine's effects, including links to AMPA receptor trafficking and mTOR pathway activation reported in preclinical studies. The authors acknowledge several limitations: participants continued concomitant psychotropic medications without a washout, which may have influenced pBDNF; the sample size was modest; the open-label design and lack of a control group introduced the possibility of subjective bias; mediation and moderation analyses were not performed; and central measures (brain BDNF or mTOR) were not obtained, requiring reliance on the assumption that peripheral BDNF reflects central levels. Given these caveats, the authors present the results as preliminary and call for confirmation in randomised controlled trials.
Data of the current study were collected from an open-label clinical study, which examined serial intravenous subanesthetic ketamine's antidepressant and antisuicidal efficacy in individuals suffering from depression and was performed between November 2016 to December 2017 (registration number: ChicCTR-OOC-17012239). The Ethics Committee of the Affiliated Brain Hospital of Guangzhou Medical University approved the current trial's protocol) and written informed consent was obtained from all participants. All subjects were recruited based on the following inclusion criteria: (1) aged between 18 and 65 years, without psychotic symptoms; (2) diagnosis of unipolar or bipolar depression by a certified psychiatrist according to the Structured Clinical Interview for DSM-V (SCID-5) criteria, with a score of 17 or more for the Hamilton Depression Rating Scale (HAMD-17); (3) suffering from TRD, which was defined as nonresponse to 2 or more antidepressant treatments, or experiencing suicidal ideation as measured with the Scale for Suicidal Ideations; (4) had no a history of neurological diseases (e.g., dementia), drug or alcohol abuse; (5) negative urine toxicology; (6) were not pregnant or breast feeding; and (7) had no any unstable medical illness (e.g., cerebrovascular diseases).
All patients received a thrice-weekly ketamine treatment regimen for 2 weeks, with a follow-up period of two weeks. The method for repeated ketamine infusions was described in detail in our early trial. Briefly, vital signs and clinical status of participants were routinely monitored, and each subject received six intravenous infusions of 0.5 mg/kg ketamine over 40 min. During the study period, all subjects continued taking psychotropic agents.
The MADRSwas used to assess depressive symptoms at baseline, 1 d after the sixth infusion (13 d), and 2 weeks after the last ketamine treatments (26 d). Remission and response were defined as MADRS scores less than 10) and a reduction of 50% or more in MADRS scores, respectively.
Plasma was collected at baseline, 13 d and 26 d, which were stored at -80 • C until further use. In accordance with the manufacturer's instructions, in this study a commercially available enzyme-linked immunosorbent assay (ELISA) kit (EMD Millipore Corporation, MA, USA) was used to measure pBDNF concentrations.
The Mann-Whitney U test was conducted to analyze nonnormally distributed continuous data, and independent t tests were applied for normally distributed continuous data. For categorical variables, the Fisher's exact test or Chi-squared test were applied for comparisons between groups (responders versus nonresponders and remitters versus nonremitters). Changes in pBDNF concentrations and MADRS scores over time and subgroup differences (responders/nonresponders and remitters/nonremitters) were examined using linear mixed models. Bivariate correlation analysis was applied in order to determine the correlation of baseline pBDNF concentrations and MADRS scores at 13 d and 26 d in individuals suffering from unipolar or bipolar depression. Multiple linear regression were also used to examine the independent association of baseline pBDNF concentrations and MADRS scores at 13 d and 26 d. MADRS scores were entered as the dependent variable, while Baseline pBDNF concentrations were entered as independent variables and other variables including age, gender, body weight, body mass index, psychiatric family history, previous hospitalization, psychiatric comorbidity, and age of onset were entered as covariate variables. Furthermore, an additional analysis was also performed on a subsample of patients with TRD in this study. IBM SPSS version 23 software (IBM Corporation, Armonk, NY, USA) was used in this study, and significance was set as p-value less than 0.05.
Ninety-four individuals (aged 18 to 62 years) with unipolar or bipolar depression who provided a baseline blood sample were enrolled. Of these patients, 81.9% (77/94) fulfilled the diagnostic criteria of TRD. Baseline pBDNF concentrations with a mean value of 10.1 ng/ml, ranged from 0.9 to 27.2 ng/ml.
After the last ketamine treatments, the rates of response and remission were 68.1% (64/94) and 51.1% (48/94), respectively. The rates of response and remission for patients with TRD were 68.8% (53/77) and 51.9% (40/77), respectively, after completion of six ketamine infusions. Higher baseline pBDNF concentrations were found in ketamine responders/remitters (11.0 ± 6.2/10.1 ± 5.8 ng/ml) than nonresponders/nonremitters (8.0 ± 5.5/9.2 ± 6.4 ng/ml) (all ps<0.05, Table). Linear mixed models showed that MADRS scores and pBDNF concentrations exhibited significant time main effects between responders and nonresponders and between remitters and nonremitters (Table). Ketamine produced a significant change in MADRS scores and pBDNF concentrations at 13 d and 26 d when compared to baseline (Figs.and). Similar results were found in patients with TRD (Table, Figs.and).
Correlation analyses showed significant associations between pBDNF concentrations at baseline and MADRS scores at 13 d and 26 d in depressed patients (all p s<0.05; Table). The significant association of pBDNF concentrations at baseline and MADRS scores at 13 d (t = -2.011, p = 0.047) and 26 d (t = -2.398, p = 0.019) remained in multiple regression analysis. Similar results were found in patients with TRD (Table).
This is the first study to determine pBDNF concentrations after six subanesthetic intravenous ketamine in Chinese individuals suffering from unipolar and bipolar depression and to investigate the correlation of pBDNF concentrations at baseline and six subanesthetic intravenous ketamine's antidepressant efficacy. The following main findings included: (1) ketamine increased pBDNF at 13 d and 26 d compared to baseline; (2) responders/remitters had significantly higher baseline pBDNF concentrations than nonresponders/nonremitters; (3) MADRS scores showed significant improvement at both time points across the total sample compared to baseline; (4) baseline pBDNF concentrations were related with MADRS scores; and (5) additional analysis of patients with TRD also found that pBDNF concentrations were related with the antidepressant outcome of ketamine in patients with TRD. Consistent with an animal study after single ketamine infusion, our study demonstrated that ketamine increased pBDNF concentrations after six ketamine infusions. Although nonresponders/nonremitters had significantly lower pBDNF concentrations at baseline than responders/remitters, repeated ketamine infusions failed to significantly increase pBDNF concentrations in responders/remitters when compared to nonresponders/nonremitters. Similarly, a previous study found no changes in pBDNF concentrations in individuals suffering from TRD after completion of an intravenous infusion of ketamine compared to baseline. However, Haile et al. found that pBDNF concentrations were significantly increased following a single ketamine infusion in responders compared to nonresponders. Therefore, these findings should be confirmed by randomized controlled trials. The observed rapid reduction in MADRS scores lasted up to 2 weeks, replicating the previous findings. However, the primary objective of this study is to examine the association of baseline pBDNF concentrations and six subanesthetic intravenous ketamine's antidepressant efficacy. Several studies examined the association of pBDNF concentrations with the antidepressant response of a single infusion of ketamine, but these findings are inconsistent. For instance, one study reported that pBDNF concentrations were related with the severity of depression. However, Machado-Vieira et al.'s study reported a negative finding on the association of pBDNF concentrations and ketamine's antidepressant efficacy. Notably, several animal studies reported that increased hippocampal and cortical BDNF expression can partly accounting for ketamine's antidepressant-like efficacy. pBDNF concentrations were lower in individuals suffering from depression compared to healthy controlsand increased after receiving antidepressants, electroconvulsive therapy, and repeated transcranial magnetic stimulation. Therefore, neurotrophic factors, such as BDNF, might be involved in ketamine's antidepressant mechanism. Notably, BDNF is implicated in the regulation of synaptic plasticity, including the synaptic recruitment of AMPA receptors. Growing studies indicate that synaptic plasticity is altered in individuals with depression, and ketamine's antidepressant efficacy may be attributed to the synaptic potentiation of neural circuits mediated by increased AMPA-to-NMDA glutamate receptors. The following limitations should be acknowledged. First, the participants continued receiving previous medications and lacked a washout period during the study, which may have affected pBDNF concentrations. However, the combination of ketamine and other antidepressants for individuals with depression is increasingly being used in the real-world clinical setting. Second, the sample size was small in the current study. Third, the possible impact of subjective evaluation was inevitable due to lack of a control group. Fourth, some comprehensive analyses, such as the mediating and moderating effect analysis, were not conducted in this study. Finally, brain BDNF concentrations and other key neurobiological mediators, such as mTOR, were not directly measured. However, BDNF crosses the blood-brain barrier, and pBDNF concentrations are closely correlated with cortical BDNF concentrations, and likely reflect brain BDNF concentrations. In conclusion, this preliminary study suggests that baseline pBDNF concentrations appeared to be correlated with ketamine's antidepressant efficacy in Chinese patients with depression.