Abstract
Background
Habenula, a hub brain region controlling monoaminergic brain center, has been implicated in major depressive disorder (MDD) and as a possible target of antidepressant response. Nevertheless, the effect of antidepressant drug treatment on habenular volumes remains unknown. The objective of the present research was to study habenular volume change after antidepressant treatment in patients with MDD, and assess whether it is associated with clinical improvement.
Methods
Fifty patients with a current major depressive episode (MDE) in the context of MDD, and antidepressant‐free for at least 1 month, were assessed for habenula volume (3T MRI with manual segmentation) before and after a 3 months sequence of venlafaxine antidepressant treatment.
Results
A 2.3% significant increase in total habenular volume (absolute volume: P = 0.0013; relative volume: P = 0.0055) and a 3.3% significant increase in left habenular volume (absolute volume: P = 0.00080; relative volume: P = 0.0028) were observed. A significant greater variation was observed in male patients (4.8%) compared to female patients. No association was observed between habenular volume changes and response and remission. Some habenula volume changes were associated with improvement of olfactory pleasantness.
Conclusion
Habenular volumes increased after 3 months of venlafaxine treatment in depressed patients. Further studies should assess whether cell proliferation and density or dendritic structure variations are implied in these volume changes.
Keywords: affective disorders, neuroimaging in psychiatry, pharmacopsychiatry, psychoneurobiology
Major depressive disorder (MDD) is currently the leading cause of disability in the world. 1 There are various treatments for major depressive episode (MDE), including antidepressant drugs. In MDD, the efficacy of antidepressant drugs in the acute phase remains insufficient. 2 Antidepressant drugs, act on cerebral monoaminergic transmission, 3 but their effects on cerebral structures remain insufficiently understood. Improving the understanding of their brain effects may help to identify new therapeutic targets.
The habenula is a medial, symmetrical diencephalic structure. Habenula is a hub brain structure connected to brain regions involved in monoamines secretion such as ventral tegmental area and the substantia nigra for dopamine, the raphe nuclei for serotonin and the locus coeruleus for noradrenalin. 4 It also regulates brains areas implicated in MDD (prefrontal cortex, striatum, part of the limbic system). 5
We previously failed to show significant differences between MDE patients and healthy controls for habenular volume. 6 Nevertheless, antidepressant drugs may increase habenular volumes since they can promote brain plasticity. 7 Indeed, in mice, fluoxetine treatment has increased Brain Derived Neurotrophic Factor (BDNF) messenger RNA in the habenula. 8 Furthermore, in patients with treatment‐resistant mood disorders treated with deep brain stimulation of subcallosal cingulate area, responders tended to have an increase of habenula volumes over time, while non‐responders showed decreased habenular volumes. 9
The effect of antidepressant drug treatment on habenular volumes in MDE patients remains unknown. We aimed to study habenular volume change after antidepressant treatment in patients with MDD, and assess whether it is associated with clinical improvement.
Methods
Design
The ancillary study based on the DEP‐ARREST‐CLIN (ClinicalTrials.gov NCT02051413, EudraCT 2013‐004326‐29), which was a prospective, single center (Bicêtre hospital Psychiatry department) study, including 69 MDD patients with a current MDE, free of antidepressants for at least 1 month, and 32 healthy controls matched for age and sex. At inclusion, the patients underwent a clinical evaluation by a psychiatrist, then received antidepressant treatment with venlafaxine and follow up for 3 months. Patients underwent brain imaging by magnetic resonance imaging (MRI) at inclusion, then after 3 months of antidepressant treatment. One patient had no imaging due to MRI contraindication (intrabuccal metallic compound) and 18 patients had at least one missing MRI assessment due to technical issues. We thus analyzed the data of 50 patients with available good quality brain MRI before treatment and after 3 months of venlafaxine treatment. The inclusion of the participants took place between February 2014 and January 2017. The protocol was approved by the ethics committee (CPP IDF 8, ref.13 11 67) and the French National Agency for Medicines and Health Products Safety (ANSM) on November 5 2013 and the written consent of the participants had been obtained.
Inclusion criteria
The patients were recruited in the adult psychiatry department of the Bicêtre hospital in Kremlin‐Bicêtre, France. They were between 18 and 65 years old. The diagnosis of MDE was made by a psychiatrist in the psychiatry department, according to DSM‐5 criteria and based on the standardized MINI interview (Mini International Neuropsychiatric Interview). 11 No patient had received antidepressant treatment in the month prior to inclusion, at least. The psychiatrist assessed the severity of the current MDE using the 17‐item Hamilton Depression Scale (HAMD‐17). 12 Patients had to have a score greater than or equal to 18 on the HAMD‐17 scale and required antidepressant treatment.
Exclusion criteria
Patients with bipolar disorder, psychotic disorder, eating disorder or with alcohol, opiate, and psychostimulant use disorder were not included in the cohort (other comorbidities were allowed). Pregnant or breastfeeding women were also excluded. As for treatments, patients with ongoing antidepressant, mood stabilizer or antipsychotic treatment were excluded. Furthermore, patients with contraindication to MRI were excluded from this study.
Antidepressant treatment
The participants were all medicated with the same antidepressant treatment: venlafaxine, a noradrenalin and serotonin reuptake inhibitor (NaSRI), introduced at inclusion. The starting dose was 75 mg once daily in the morning. The dosage could then be increased to 375 mg per day on the decision of the attending psychiatrist.
Anxiolytic treatments (benzodiazepines, antihistaminic, sedative neuroleptics) were authorized at the minimum effective dosage and for a duration as short as possible. Antipsychotic and mood stabilizer treatments were not allowed.
Habenular segmentation
The anterior limit is formed by the posterior thalamus. The posterior limit is formed by the pineal gland and the pretectal area. The habenula is bounded medially by the 3rd cerebral ventricle cerebrospinal fluid. Finally, it is delimited laterally by the posterior thalamus. It is composed of two asymmetrical nuclei: lateral nucleus and medial nucleus, both rich in white matter, which makes delimitation easy in cerebral neuroimaging (the adjacent structures being rich in gray matter or liquid, are therefore more hypointense on T1‐weighted sequences).
Habenular segmentation method from brain MRI was previously described. 6 The habenular volume was measured manually by JE, using the Brain VISA imaging software, version 4.6 and more particularly the Anatomist module, version 4.6.1 (Fig. 1). The measurements were carried out blind for the evaluation time (M0 or M3). We used the T1 signal intensity as an objective parameter for manual segmentation of all the MRIs. A second segmentation was performed by AB, which allowed us to have very good intraclass correlation coefficients (left: 0.95, 95% CI [0.88; 0.98], right: 0.83, 95% CI [0.63; 0.93], total: 0.89, 95% CI [0.74; 0.95]). The main variables were the absolute habenular volumes: total, left and right. We created the ‘relative habenular volume’ variables corresponding to the absolute habenular volume corrected by the total cerebral volume. Finally, we calculated the deltas of habenular volumes between M0 and M3 (difference in volume between M0 and M3).
Fig. 1.
Manual segmentation of habenula.
Clinical improvement
Overall clinical improvement was assessed with clinical response (reduction of at least 50% in the total HAMD‐17 score between M0 and M3), remission (HAMD‐17 <8 at M3) and HAMD‐17 improvement (percentage improvement between HAMD‐17 scores at M0 and M3). 13
Variables for post‐hoc analyses
Since habenula is implicated in the response to pleasant stimuli 10 we assessed the olfactory pleasantness score. The olfactory pleasantness score is decreased in MDE patients and improved after venlafaxine treatment. 14 Patients were asked for the pleasantness of 16 selected smells from the Sniffin’ Sticks test 15 as it was previously published. 14 , 16 The pleasantness score corresponding to the number of pleasant smells (scores range from 0 to 16).
The number of previous episodes, duration of MDE and number of suicide attempts, which are vulnerability factors for recurrence were assessed at baseline for MDE patients.
Statistical analyses
The statistical analyses were carried out on the R software, version 4.3.0. The distribution of the variables of interest was studied using a graphical appreciation and quantile‐quantile plots. Quantitative variables were described by means and standard deviations and qualitative variables by percentages. Regarding the main objective (habenular change after antidepressant treatment), we performed paired t‐tests (between M0 and M3) and used linear mixed models (with R lme4 package) to provide models adjusted for age and sex. Since there is sex difference in brain plasticity 17 , 18 , 19 we also assessed female and male subgroup individually. The threshold of statistical significance used was 0.05. Regarding the secondary objective, we performed Wilcoxon tests to assess the link between habenular volume variations between M0 and M3 with clinical response and remission and used linear mixed models to provide models adjusted for age and sex. We performed linear mixed models to assess the link between variations in habenular volumes between M0 and M3 and HAMD‐17 global improvement (with and without adjustment for age and sex).
Post hoc analyses were performed. We analyzed the association between olfactory pleasantness changes and habenular volume changes. The association between baseline vulnerability factors for recurrence (number of previous episodes, duration of MDE and number of suicide attempts) and habenular volumes changes were also analyzed. For these post‐hoc analyses, linear mixed models were used with two models: first the explicative variable alone and second with adjustment for age and sex.
Habenular volume distributions were tested with Shapiro–Wilk tests. All variables were normally distributed.
Results
Sociodemographics
Sociodemographics are shown in Table 1.
Table 1.
Sociodemographic and clinical characteristics of depressed patients
| Sociodemographic and clinical characteristics | MDE Patients (n = 50) |
|---|---|
| Female, n (%) | 34 (68%) |
| Age, m (SD), years | 34.36 (12.99) |
| Laterality | |
| Left‐handed, n (%) | 4 (8%) |
| Right‐handed, n (%) | 43 (86%) |
| Ambidextrous, n (%) | 3 (6%) |
| Smoker, n (%) | 16 (32%) |
| History of MDE recurrence, n (%) | 24 (48%) |
| History of suicide attempt, n (%) | 16 (32%) |
| History of antidepressant drug use, n (%) | 22 (44%) |
| MDD age of onset, m (SD), years | 28.06 (11.87) |
| Average duration of current MDE, m (SD), days | 275.56 (444.45) |
| HAMD‐17 at M0, m (SD) | 26.62 (5.28) |
| HAMD‐17 at M3, m (SD) | 6.54 (6.19) |
Note: Significance level: P < 0.05.
Abbreviations: HAMD‐17, Hamilton Depression Rating Scale – 17 items; MDD, major depressive disorder; MDE, major depressive episode.
Habenular volume changes before and after antidepressant treatment
An increase in absolute and relative total habenular volumes, respectively 2.46% (P = 0.0013) and 2.14% (P = 0.0055), and an increase in absolute and relative left habenular volumes, respectively 3.50% (P = 0.00080) and 3.15% (P = 0.0028), were observed (Fig. 2 and Supplementary Table S1). All these results remain after adjustment for age and sex (Fig. 2 and Supplementary Table S1). The linear mixed model including time, age and sex show a sex effect to explain relative total habenular change (P = 0.0027, est.: 0.0000041) and relative left habenular change (P = 0.0035, est.: 0.0000022).
Fig. 2.
Absolute habenular volumes before treatment (M0) and after 3 months of treatment (M3) in depressed patients.
In male patients, we observed a significant increase in absolute and relative total habenular volumes, respectively 4.29% (P = 0.00077) and 4.17% (P = 0.00091), in absolute and relative left habenular volumes, respectively 5.51% (P = 0.0021) and 5.35% (P = 0.0026), and in relative right habenular volumes, 3.03% (P = 0.047) (Fig. 3 and Supplementary Table S2). In female patients, we observed a 2.56% significant increase (P = 0.048) in absolute left habenular volumes (Fig. 3 and Supplementary Table S3).
Fig. 3.
Total absolute habenular volume before treatment (M0) and after 3 months of treatment (M3).
Habenular volume changes and clinical improvement
We observed no significant correlations between habenular volume changes and response, remission, and HAMD‐17 improvement nor in total sample (Fig. 4, Supplementary Table S4 and Supplementary Table S5), neither in gender subgroup (data not show).
Fig. 4.
Absolute total habenular volume variation and HAMD‐17 improvement.
Post‐hoc analyses
Absolute left habenular volume increase was associated with olfactive pleasantness score improvement (est: 0.29, P = 0.049) after adjustment for age and sex. Left relative habenular volume increases was associated with olfactive pleasantness score improvement (est: 0.00000031, P = 0.030) in non‐adjusted model but not after adjustment for age and sex (P = 0.23). No other association was observed between habenular volume changes and olfactive pleasantness score improvement.
Association was observed between number of previous suicide attempts with absolute right and absolute total habenular volume changes (right est.: 0.68, P = 0.026; total est.: 1.13 P = 0.026) but not after adjustment for age and sex. No other associations were found with the other vulnerabilities of recurrence (number of previous episodes and duration of MDE).
Discussion
A 2.3% increase in total habenular volume and a 3.3% increase in left habenular volume were observed 3 months after venlafaxine treatment in depressed patients. The changes appeared more pronounced in male subgroup. Our results showed greater relative habenular volumes in female patients compared to male patients in line with the study of Hitti et al. 20
Even though, the effect size is small, around 3%, similar magnitude of changes has been described, especially in subcortical structures and in the hippocampus in the ENIGMA protocol. 5
There were eight previous studies (Table 2) assessing volume difference between MDE patients and HC. 6 , 21 , 22 , 23 , 24 , 25 , 26 , 27 Considering the possible effect of medication, by focusing on the five studies including only antidepressant drug free patients, four of them did not report habenular volume difference between MDD patients and HC 6 , 22 , 24 , 26 and one reported higher habenula volumes in MDD patients as compared to controls. 25 We provide the first longitudinal study with habenular volume assessment before and after antidepressant treatment in depressed patients.
Table 2.
Habenular volume in depressed patients and healthy controls, past findings
| Studies | Groups | n | Female % | Antidepressant free | Left habenula m (SD) mm3 | P | Right habenula m (SD) mm3 | P | Total habenula m (SD) mm3 | P |
|---|---|---|---|---|---|---|---|---|---|---|
|
Ranft et al. 21 Post mortem |
HC | 13 | 38% | NA | 27.6 (5.1) | 0.003 | 29.6 (4.5) | 0.003 | NA | NA |
| MDD + BD | 14 | 57% | 24.1 (4.5) | 22.8 (6.0) | ||||||
| Savitz et al. 22 | HC | 74 | 61% | 19.5 (5.2) | 0.91 | 17.0 (4.7) | 0.19 | 36.5 (8.7) | 0.42 | |
| MDD | 28 | 54% | Yes | 19.1 (4.6) | 15.6 (4.8) | 34.7 (7.4) | ||||
| Carceller‐Sindreu et al. 23 | HC | 34 | 71% | NA | NA | NA | NA | 43.0 (9.4) | 0,62 | |
| MDD | 41 | 73% | No | 44.7 (9.8) | ||||||
| Schmidt et al. 24 | HC | 20 | 60% | 17.6 (5.5) | 0.75 | 17.3 (6.1) | 0.95 | 34.9 (11.3) | 0.96 | |
| MDD | 40 | 63% | Yes (20) | 17.2 (6.0) | 17.8 (6.4) | 35.0 (12) | ||||
| No (20) | 16.5 (2.5) | 17.7 (2.8) | 34.2 (3.5) | |||||||
| Liu et al. 25 | HC | 17 | 59% | 26 (sem 1.3) | 0.01 | 24.7 (sem 1.3) | 0.01 | NA | NA | |
| MDD | 21 | 57% | Yes | 30 (sem 1) | 28.6 (sem 1) | |||||
| Lawson et al. 26 | HC | 25 | 36% | NA | NA | NA | NA | 44.6 (9.3) | 0.76 | |
| MDD | 25 | 40% | Yes | 41.7 (7.3) | ||||||
| Cho et al. 27 | HC | 36 | 78% | 18.5 (5.0) | 0.93 | 18.5 (3.9) | 0.01 | NA | NA | |
| MDD | 33 | 67% | No | 18.4 (3.4) | 16.4 (3.2) | |||||
| Etienne et al. 6 | HC | 32 | 66% | 23.9 (3.1) | 0.26 | 24.3 (3.1) | 0.30 | 48.2 (5.8) | 0.20 | |
| MDD | 64 | 69% | Yes | 23.2 (2.7) | 23.7 (2.4) | 47.0 (4.7) |
Note: Significance level: P < 0.05.
Abbreviations: BD, bipolar disorder; HC, healthy controls; MDD, major depressive disorder; NA, not available; SD, standard deviation; SEM, standard error of the mean.
We observed a small effect size: 3%. Thus, further studies aiming at comparing habenula volume between MDD and controls should be designed to detect small differences.
The habenular volume increase could be related to cell proliferation, cell density or dendritic structure variations induced by venlafaxine. Indeed, the study of Sachs et al. had shown increased neurogenesis and cell proliferation as well as an increase in the level of BDNF messenger RNA in the habenula after treatment with fluoxetine in mice. 8 Furthermore, another study had shown that chronic stress induced bilateral habenular atrophy in rats. 28 Another study highlighted a laterality difference in habenular volumes in human. 29 In this study, left habenula appeared enlarged compared with the right counterpart, in depressed patients.
Left habenular volume changes are associated with olfactory pleasantness score improvement suggesting an implication of habenula volume change in the response to pleasant stimuli.
Strengths
We studied a cohort of 50 depressed patients. The patients were homogeneous in terms of diagnosis and treatment and were at least 1 month antidepressant drug free before the study. We performed a longitudinal study with antidepressant treatment.
Limitations
A limitation of this study is the use of a manual segmentation method, which has less reproducibility than an automatic segmentation method. However, there is no validated automatic segmentation method. The second limitation is the absence of a placebo group so we cannot be sure that the habenular volume increase is related to the antidepressant treatment and not with other factors. Furthermore, the habenular volume increase could be associated with dimensions of clinical improvement that we have not evaluated here, for example cognitive functions.
There is a risk of false positive results in the post‐hoc analyses due to multiple testing. Nevertheless, these results are meaningful as a hypothesis generation for further studies.
Perspectives
Our results highlight the interest of habenula in depression treated with antidepressants. This topic should be further explored with complementary methods (including automated segmentation 30 or functional assessment) in human and with preclinical studies with specific attention to habenular asymmetry and gender difference.
Conclusion
Habenular volume increased after 3 months of venlafaxine treatment in depressed patients. Habenular volume increases are not associated with response/remission after antidepressant treatment but are associated with olfactory pleasantness improvement.
Disclosure statement
JE, AB, DJD, ED, FG, LB, EC, RC have no conflict of interest to disclose.
Author contributions
JE performed literature search, habenula volume segmentation, statistical analyses and wrote the first draft of the manuscript. AB took part in the MRI sequences analyses. DJD performed data collection, study design and interpretation of the results. ED performed interpretation of the results and editing. LB performed data collection, study design and interpretation of the results. FG performed data collection, study design and interpretation of the results. EC, wrote the protocol, performed data collection, study design and interpretation of the results. RC designed the study, performed data collection, supervised statistical analyses and wrote the first draft of the manuscript. All authors revised and contributed to the final version of the manuscript.
Supporting information
Table S1. Habenular volume changes before (M0) and after 3 months of venlafaxine treatment (M3).
Table S2. Habenular volume changes before (M0) and after 3 months of venlafaxine treatment (M3) in male.
Table S3. Habenular volume changes before (M0) and after 3 months of venlafaxine treatment (M3) in female.
Table S4. Association between habenular volume change (absolute and relative) and clinical response, remission and HAMD‐17 improvement.
Table S5. Total habenular volumes (absolute and relative) in remitters and in non‐remitters.
Acknowledgments
Funding for the DEP‐ARREST‐CLIN cohort was provided by a national grant (ANR SAMENTA 2012) of the Agence Nationale de la Recherche (ANR) and sponsored by the Institut National de la Santé et de la Recherche Médicale (INSERM) (C13‐25, EudraCT 2013‐004326‐29).
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Associated Data
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Supplementary Materials
Table S1. Habenular volume changes before (M0) and after 3 months of venlafaxine treatment (M3).
Table S2. Habenular volume changes before (M0) and after 3 months of venlafaxine treatment (M3) in male.
Table S3. Habenular volume changes before (M0) and after 3 months of venlafaxine treatment (M3) in female.
Table S4. Association between habenular volume change (absolute and relative) and clinical response, remission and HAMD‐17 improvement.
Table S5. Total habenular volumes (absolute and relative) in remitters and in non‐remitters.