Choroid plexus volume is increased in mood disorders and associates with circulating inflammatory cytokines.

Depressed patients exhibit altered levels of immune-inflammatory markers both in the peripheral blood and in the cerebrospinal fluid (CSF) and inflammatory processes have been widely implicated in the pathophysiology of mood disorders. The Choroid Plexus (ChP), located at the base of each of the four brain ventricles, regulates the exchange of substances between the blood and CSF and several evidence supported a key role for ChP as a neuro-immunological interface between the brain and circulating immune cells. Given the role of ChP as a regulatory gate between periphery, CSF spaces and the brain, we compared ChP volumes in patients with bipolar disorder (BP) or major depressive disorder (MDD) and healthy controls, exploring their association with history of illness and levels of circulating cytokines. Plasma levels of inflammatory markers and MRI scans were acquired for 73 MDD, 79 BD and 72 age- and sex-matched healthy controls (HC). Patients with either BD or MDD had higher ChP volumes than HC. With increasing age, the bilateral ChP volume was larger in patients, an effect driven by the duration of illness; while only minor effects were observed in HC. Right ChP volumes were proportional to higher levels of circulating cytokines in the clinical groups, including IFN-γ, IL-13 and IL-17. Specific effects in the two diagnostic groups were observed when considering the left ChP, with positive association with IL-1ra, IL-13, IL-17, and CCL3 in BD, and negative associations with IL-2, IL-4, IL-1ra, and IFN-γ in MDD. These results suggest that ChP could represent a reliable and easy-to-assess biomarker to evaluate the brain effects of inflammatory status in mood disorders, contributing to personalized diagnosis and tailored treatment strategies.

Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers.

Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.

Higher Seasonal Variation of Systemic Inflammation in Bipolar Disorder.

Seasonal rhythms affect the immune system. Evidence supports the involvement of immuno-inflammatory mechanisms in bipolar disorder (BD), with the neutrophil to lymphocyte ratio (NLR), and the systemic immune-inflammatory index (SII; platelets × neutrophils/lymphocytes) consistently reported to be higher in patients with BD than in HC, but seasonal rhythms of innate and adaptive immunity have never been studied. We retrospectively studied NLR and SII in 824 participants divided into three groups: 321 consecutively admitted inpatients affected by a major depressive episode in course of BD, and 255 consecutively admitted inpatients affected by obsessive-compulsive disorder (OCD; positive psychiatric control), and 248 healthy controls (HC). Patients with BD showed markedly higher markers of systemic inflammation in autumn and winter, but not in spring and summer, in respect to both HC and patients with OCD, thus suggesting a specific effect of season on inflammatory markers in BD, independent of a shared hospital setting and drug treatment. Given that systemic inflammation is emerging as a new marker and as target for treatment in depressive disorders, we suggest that seasonal rhythms should be considered for tailoring antidepressant immuno-modulatory treatments in a precision medicine approach.

Insulin resistance disrupts white matter microstructure and amplitude of functional spontaneous activity in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is linked to several structural and functional brain alterations. In addition, BD patients have a three-fold increased risk of developing insulin resistance, which is associated with neural changes and poorer BD outcomes. Therefore, we investigated the effects of insulin and two derived measures (insulin resistance and sensitivity) on white matter (WM) microstructure, resting-state (rs) functional connectivity (FC), and fractional amplitude of low-frequency fluctuation (fALFF). METHODS: BD patients (n = 92) underwent DTI acquisition, and a subsample (n = 22) underwent rs-fMRI. Blood samples were collected to determine insulin and glucose levels. The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were computed. DTI data were analyzed via tract-based spatial statistics and threshold-free cluster enhancement. From rs-fMRI data, both ROI-to-ROI FC matrices and fALFF maps were extracted. RESULTS: Insulin showed a widespread negative association with fractional anisotropy (FA) and a positive effect on radial diffusivity (RD) and mean diffusivity (MD). HOMA-IR exerted a significant effect on RD in the right superior longitudinal fasciculus, whereas QUICKI was positively associated with FA and negatively with RD and MD in the left superior longitudinal fasciculus, left anterior corona radiata, and forceps minor. fALFF was negatively modulated by insulin and HOMA-IR and positively associated with QUICKI in the precuneus. No significant results were found in the ROI-to-ROI analysis. CONCLUSION: Our findings suggest that WM microstructure and functional alterations might underlie the effect of IR on BD pathophysiology, even if the causal mechanisms need to be further investigated.

The effect of bright light therapy on irritability in bipolar depression: a single-blind randomised control trial.

OBJECTIVE: The symptom-complex irritability, widely used in descriptions of bipolar patients' manic and mixed states, also represents a common feature in depressive phases. Irritability negatively affects the clinical course of depression, leading to a higher risk of treatment non-adherence, violence, and suicide attempts. Nevertheless, proportional attention from the scientific literature seems to be scarce. We conducted the first randomised controlled trial with the aim of evaluating BLT as a possible therapeutic strategy for irritability in bipolar depression. METHODS: 180 inpatients were randomly assigned to: Group A exposed to bright light therapy (BLT) daily, or Group B treated with pharmacotherapy only. A qualitative assessment of irritability was performed after a 4-week program. RESULTS: Group A showed about one-third fewer cases of irritability compared to Group B, this reduction was not related to the overall remission of depressive symptoms. CONCLUSIONS: The present study supports the usefulness of BLT in irritability in bipolar depression.

Irritability is an underestimated feature of bipolar depression.Irritability is related to higher suicide risk and lower quality of life.Bright light therapy is an effective strategy to reduce irritability in bipolar depression.

Adiponectin predicts poor response to antidepressant drugs in major depressive disorder.

OBJECTIVE: Produced by adipocytes, adiponectin crosses the blood-brain barrier to bind with specific receptors in the hypothalamus, brainstem, hippocampus, and cortex. In patients with major depressive disorder (MDD), circulating levels of adiponectin inversely related with antidepressant response to ketamine, and predicted a better response to multi-target drug combinations than to escitalopram. We investigated the effect of adiponectin on response to antidepressants in a naturalistic setting. METHODS: We assessed baseline plasma levels of adiponectin in 121 MDD inpatients, treated with antidepressant drug monotherapy based on clinical need (selective serotonin reuptake inhibitors, venlafaxine, duloxetine) in a specialized hospital setting. Severity of depression was weekly assessed with Hamilton scale ratings. RESULTS: Adiponectin plasma levels were higher in patients with MDD compared with healthy controls, and negatively influenced the pattern of antidepressant response (higher baseline levels, worse response) independent of the drug class and of the baseline severity of depression, and of age, sex, and body mass index. CONCLUSIONS: The identification of adiponectin as a predictor of antidepressant response to drugs of different mechanism of action, such as ketamine, SSRIs, and SNRIs, and both in experimental and in clinical settings, warrants interest for further study of its pathways to search for novel biomarkers and therapeutic targets.

Precision psychiatry in clinical practice.

The treatment of depression represents a major challenge for healthcare systems and choosing among the many available drugs without objective guidance criteria is an error-prone process. Recently, pharmacogenetic biomarkers entered in prescribing guidelines, giving clinicians the possibility to use this additional tool to guide prescription and improve therapeutic outcomes. This marked an important step towards precision psychiatry, which aim is to integrate biological and environmental information to personalise treatments. Only genetic variants in cytochrome enzymes are endorsed by prescribing guidelines, but in the future polygenic predictors of treatment outcomes may be translated into the clinic. The integration of genetics with other relevant information (e.g., concomitant diseases and treatments, drug plasma levels) could be managed in a standardised way through ad hoc software. The overcoming of the current obstacles (e.g., staff training, genotyping and informatics facilities) can lead to a broad implementation of precision psychiatry and represent a revolution for psychiatric care.Key pointsPrecision psychiatry aims to integrate biological and environmental information to personalise treatments and complement clinical judgementPharmacogenetic biomarkers in cytochrome genes were included in prescribing guidelines and represented an important step towards precision psychiatryTherapeutic drug monitoring is an important and cost-effective tool which should be integrated with genetic testing and clinical evaluation in order to optimise pharmacotherapyOther individual factors relevant to pharmacotherapy response (e.g., individual's symptom profile, concomitant diseases) can be integrated with genetic information through artificial intelligence to provide treatment recommendationsThe creation of pharmacogenetic services within healthcare systems is a challenging and multi-step process, education of health professionals, promotion by institutions and regulatory bodies, economic and ethical barriers are the main issues.

Bright light therapy accelerates the antidepressant effect of repetitive transcranial magnetic stimulation in treatment resistant depression: a pilot study.

Objectives: We performed a randomized single-blinded study to assess the superiority of the combination strategy of repetitive Transcranial Magnetic Stimulation (rTMS) and Bright Light Therapy (BLT) over rTMS treatment alone in reducing depressive symptoms in treatment-resistant depression (TRD).Methods: We enrolled 80 inpatients with a diagnosis of TRD. All patients were randomly assigned into two groups: group A was treated with rTMS, compared to group B treated with a combination of rTMS and BLT. Depressive symptoms were weekly assessed (T0, T1, T2, T3) through the 17-item Hamilton depression rating scale (HDRS-17).Results: rANOVA (F=2.766, p=0.043) and post-hoc in HDRS-17 showed significant better scores in favour of group B every week (p<0.025, T1: 22.075 vs 17.200; T2: 16.100 vs 12.775; T3: 12.225 vs 8.900).Conclusions: The antidepressant effect of rTMS was enhanced and accelerated by its combination with BLT in treating resistant depression.KEYPOINTSAlmost one third of depressed patients does not respond to antidepressants; emerging neuromodulation and chronobiological techniques are effective antidepressant augmentation treatments.The aim of this study was to assess the superiority of the combination strategy of Light Therapy and TMS over TMS treatment alone in a group of treatment resistant depressed patients.The implication of this study in clinical practice is that a safe, low risk and cost-effective treatment, as Light Therapy, improves and accelerates the antidepressant effect of TMS.

Natural killer cells protect white matter integrity in bipolar disorder.

BACKGROUND: Bipolar Disorder (BD) associates with disrupted white matter (WM) microstructure and functional connectivity, and with a perturbation of the immune system. Higher cytokines, and reduced T cells, correlated with WM disruption and fMRI responses. A core component of the innate immune system, natural killer (NK) cells were detected in brain parenchyma, but never studied in BD. METHODS: We studied Diffusion Tensor Imaging (DTI) measures of water diffusion, fMRI corticolimbic functional response and connectivity, and multi-parameter cytofluorometry analysis of NK (CD56+) subpopulations, in 30 inpatients with active Bipolar Disorder type I. NK cells were also obtained in 36 healthy controls. RESULTS: Patients had significantly higher circulating counts of CD56+GMCSF+, CD56+INFγ+, and CD56+IL17+. NK cell levels positively associated to fractional anisotropy (FA) measures. CD56+TNFα+, CD56+INFγ+, and CD56+GMCSF+ directly correlated with FA, and inversely with radial (RD) and mean (MD) diffusivity. Duration of lithium treatment associated with higher CD56+TNFα+, CD56+IL2+, and CD56+IL4+, and positively associated with FA in tracts were NKs had significant effects. A mediation model suggested a partial mediation of CD56+TNFα+ cells, higher in patients on lithium, on the effects of lithium on FA. Frequencies of the same cytokine-producing NK cells also influenced fMRI cortico-limbic functional connectivity during processing of both, emotional and non-emotional stimuli. DISCUSSION: Higher circulating cytokine-producing NK cells associated with lithium treatment, and with DTI measures of WM integrity, partially mediating the effect of lithium on WM. The same cells associated with fMRI responses and connectivity, thus suggesting an effect on structural and functional connectomics in BD.

Kynurenine pathway and white matter microstructure in bipolar disorder.

Decreased availability of serotonin in the central nervous system has been suggested to be a central factor in the pathogenesis of depression. Activation of indoleamine 2-3 dioxygenase following a pro-inflammatory state could reduce the amount of tryptophan converted to serotonin and increase the production of tryptophan catabolites such as kynurenic acid, an antagonist of ionotropic excitatory aminoacid receptors, whose levels are reduced in bipolar disorder. Abnormalities in white matter (WM) integrity have been widely reported in BD. We then hypothesized that metabolites involved in serotoninergic turnover in BD could influence DTI measures of WM microstructure. Peripheral levels of tryptophan, kynurenine, kynurenic acid, 3-hydroxy-kynurenine, and 5-HIAA were analysed in 22 patients affected by BD and 15 healthy controls. WM microstructure was evaluated using diffusion tensor imaging and tract-based spatial statistics with threshold-free cluster enhancement only in bipolar patients. We observed that kynurenic acid and 5-HIAA were reduced in BD and associated with DTI measures of WM integrity in several association fibres: inferior and superior longitudinal fasciculus, cingulum bundle, corpus callosum, uncus, anterior thalamic radiation and corona radiata. Our results seem to suggest that higher levels of 5-HIAA, a measure of serotonin levels, and higher levels of kynurenic acid, which protects from glutamate excitotoxicity, could exert a protective effect on WM microstructure. Reduced levels of these metabolites in BD thus seem to confirm a crucial role of serotonin turnover in BD pathophysiology.

Th17 cells correlate positively to the structural and functional integrity of the brain in bipolar depression and healthy controls.

Abnormalities of T cell-mediated immune activation, in the absence of active somatic immune diseases, have consistently been reported in mood disorders. Apart from being important players in the regulation of cells of the immune system, T cells are essential for normal brain development. We here report studies on the relationship between circulating levels of T helper cells and structural and functional brain imaging in depressed bipolar patients. Since the CCL20-CCR6 axis is an important entry to the brain we differentiated the various T helper cell subpopulations on the basis of their chemokine receptor expression. METHODS: FACS staining was performed for Th1, Th2, Th17, Th22 and T regulatory cells on frozen leukocytes of 25 consecutively admitted inpatients affected by a major depressive episode, without psychotic features, in the course of Bipolar Disorder I and 21 healthy controls. The frequency of the T helper populations was associated with DTI and fMRI data acquired on a Philips 3.0 Tesla scanner. Tract based spatial statistic was used to obtain measures of white matter integrity (fractional anisotropy, axial, radial and mean diffusivity) from a standard DTI sequence with 35 directions. Patients were also studied for fMRI through a moral valence decision task were subjects had to decide whether morally tuned stimuli were positive or negative. RESULTS: The percentage of circulating Th17 (CCR6+CXCR3negCCR4+CCR10neg) cells correlated positively with higher fractional anisotropy in fiber tracts contributing to the functional integrity of the brain both in patients and healthy controls, while the frequency of circulating T regulatory (CD4+CD25+FOXP3+) cells correlated positively with higher radial and mean diffusivity in patients. The frequency of circulating T regulatory cells also correlated to lower neuronal responses to negative versus positive morally tuned stimuli in the right dorsolateral prefrontal cortex of patients. Th1 cells correlated negatively with white matter integrity in several tracts (healthy controls), while the cells showed a positive correlation to the levels of pro-inflammatory cytokines (patients). CONCLUSION: This study shows a new putative role for Th17 cells. Th17 cells are not only playing a role in inducing autoimmunity and auto-inflammation, but might also play a counter intuitive anabolic role in the maintenance of the functional and structural integrity of the brain.

Body mass index associates with white matter microstructure in bipolar depression.

OBJECTIVES: Obesity has been reported in over 60% of bipolar disorder (BD) patients. It worsens the severity of illness, and influences cognition and functional outcomes. White matter (WM) abnormalities are one of the most consistently reported findings in neuroimaging studies of BD. We hypothesized that body mass index (BMI) could correlate with WM integrity in bipolar patients. METHODS: We evaluated BMI in a sample of 164 depressed patients affected by BD. We performed whole-brain tract-based spatial statistics with threshold-free cluster enhancement for the diffusion tensor imaging (DTI) measures of WM integrity: fractional anisotropy; axial, radial, and mean diffusivity. RESULTS: We observed that BMI was associated with DTI measures of WM integrity in several fiber tracts: anterior corona radiata, anterior thalamic radiation, inferior fronto-occipital fasciculus and corpus callosum. CONCLUSIONS: The association of BMI in key WM tracts that are crucial to mood regulation and neurocognitive functioning suggests that BMI might contribute to the pathophysiology of BD through a detrimental action on structural connectivity in critical cortico-limbic networks.

Multidimensional cognitive impairment in unipolar and bipolar depression and the moderator effect of adverse childhood experiences.

AIM: Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. These deficits are observable both in major depressive disorder (MDD) and in bipolar disorder (BD) and are present in each phase of the illness, including euthymia. Adverse childhood experiences (ACE) have been associated with an increased risk of developing psychiatric disorders and cognitive deficits. The aim of this study was to assess neuropsychological performances in a sample of MDD and BD patients during a depressive episode compared to healthy controls (HC) and, to investigate if ACE affect the cognitive profiles in the three groups. METHODS: Seventy-six BD patients, 57 MDD patients, and 57 HC underwent neuropsychological assessment for cognitive performances through the Brief Assessment of Cognition in Schizophrenia and Wisconsin Card Sorting Test. RESULTS: Both BD and MDD patients obtained significantly lower domain scores across the entire battery compared to HC. Splitting the sample according to exposure to ACE (high and low), the differences observed in the whole sample persisted only in the subsample of those patients exposed to high ACE. CONCLUSION: This study confirms that cognitive impairment is present both in MDD and BD, albeit in different degrees of severity, and highlights the importance of early stress as a moderator factor when investigating cognitive functions in mood disorders.

Changes of cortical excitability as markers of antidepressant response in bipolar depression: preliminary data obtained by combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG).

BACKGROUND: It is still unclear which biological changes are needed to recover from a major depressive episode. Current perspectives focus on cortical synaptic neuroplasticity. Measures of cortical responses evoked by transcranial magnetic stimulation (TMS) change with sleep homeostasic pressure in humans and approximate measures of synaptic strength in animal models. Using repeated total sleep deprivation as a model of antidepressant treatment, we aimed to correlate recovery from depression with these measures of cortical excitability. METHODS: We recorded electroencephalographic responses to TMS in the prefrontal cortex of 21 depressed inpatients with bipolar disorder treated with repeated sleep deprivation combined with light therapy. We performed seven TMS/electroencephalography sessions during one week and calculated three measures of cortical excitability. RESULTS: Cortical excitability progressively increased during the antidepressant treatment and as a function of time awake. Higher values differentiated responders from non-responders at baseline and during and after treatment on all measures. CONCLUSIONS: Changes in measures of cortical excitability parallel and predict antidepressant response to combined sleep deprivation and light therapy. Data suggest that promoting cortical plasticity in bipolar depression could be a major effect of successful antidepressant treatments, and that patients not responding could suffer a persistent impairment in their neuroplasticity mechanisms.

The serotonin transporter genotype modulates the relationship between early stress and adult suicidality in bipolar disorder.

OBJECTIVE: Bipolar disorder (BD) is associated with a higher risk of suicide and with worse early life stress. A serotonin (5-hydroxytryptamine; 5-HT) transporter-linked polymorphic region (5-HTTLPR) has been shown to influence the relationship between stress and the risk of attempting suicide in the general population, but has not been investigated in BD. METHODS: We studied 136 inpatients (93 females, 43 males) with a major depressive episode in the course of BD. Early and recent stressful life events were scored on the Social Readjustment Rating Scale (SRRS). Regional gray matter (GM) volumes were analyzed, acquiring T1-weighted images on a 3.0 Tesla scanner. RESULTS: Homozygote l/l patients attempted suicide in a higher proportion than *s carriers. A separate-slopes logistic regression showed a significant effect of 5-HTTLPR on the relationship between stress, depression, and suicide among *s carriers, but not among l/l homozygotes, early stress associated with worse probability of attempting suicide and with earlier age at onset of BD. Exposure to early stress correlated with GM volumes in the right prefrontal cortex (Brodmann area 46) - again, in *s carriers only. CONCLUSIONS: 5-HTTLPR modulated the relationship between early life stress and the core features of bipolar illness. 5-HTTLPR*s carriers showed a higher sensitivity to the effects of stress; when exposed to low levels of early stress, they were protected against suicide in respect to l/l, but higher levels of stress progressively increased their risk of suicide and reduced the age at onset of illness.

Adverse childhood experiences worsen cognitive distortion during adult bipolar depression.

BACKGROUND: Cognitive distortion is a central feature of depression, encompassing negative thinking, dysfunctional personality styles and dysfunctional attitudes. It has been hypothesized that ACEs could increase the vulnerability to depression by contributing to the development of a stable negative cognitive style. Nevertheless, little research has been carried out on possible associations between adverse childhood experiences (ACEs) and cognitive distortion, and whether any gender differences exist. AIM: The aim of this study was to examine the association between ACEs and cognitive distortions and possible differences between genders in a sample of patients affected by bipolar disorder. METHOD: 130 patients with bipolar disorder (BD) (46 men and 84 females), completed the Risky Family Questionnaire to assess ACEs and the Cognition Questionnaire (CQ) to assess cognitive distortions. RESULTS: A positive association was found between ACE and the CQ total score. Investigating the 5 dimensions assessed through the CQ, only the dimension "generalization across situations" was significantly associated to ACE. An interaction between ACE and gender was found for "generalization across situations", while no differential effect among females and males was found for CQ total score. CONCLUSION: This is the first study to report a relationship between negative past experiences and depressive cognitive distortions in subjects affected by BD. Growing in a family environment affected by harsh parenting seems to a cognitive vulnerability to depression; this effect is especially strong in females.

Evaluating the impact of adjunct bright light therapy on subjective sleep quality in major depressive disorder.

BACKGROUND: Sleep disturbances are a fundamental feature of depression, with their persistence after remission serving as a key risk factor for recurrence of depressive episodes, suicide, and hypnotics abuse. Though Adjunct Bright Light Therapy (BLT) has shown efficacy in treating depression by improving sleep duration and timing, its impact on subjective sleep quality remains underexplored. OBJECTIVE: This study investigates the effect of adjunct BLT on the subjective experience of sleep quality of Major Depressive Disorder (MDD) inpatients. METHODS: A randomized controlled trial was undertaken with 100 MDD consecutively admitted inpatients on consistent antidepressant regimens. Participants were divided into two groups; Group A, received pharmacotherapy augmented with BLT, Group B, received pharmacotherapy alone. The Hamilton Depression Rating Scale assessed depressive symptoms, while the Pittsburgh Sleep Quality Index (PSQI) evaluated subjective sleep quality. RESULTS: While both groups displayed enhanced depressive symptomatology, only Group A manifested significant improvement in perceived sleep quality (PSQI scores: A T0 8.05 ± 5.07 vs. T1 5.64 ± 3.64, p < 0.001; B T0 7.11 ± 3.17 vs. T1 6.50 ± 3.04, p = 0.072). LIMITATIONS: Study limitations include its single-site design, lack of objective sleep measurement, and exclusive SSRI use, suggesting caution in generalizing findings. Further, the absence of placebo control and unmeasured expectancy effects may influence treatment outcomes. CONCLUSIONS: These findings underscore the criticality of subjective sleep quality in clinical evaluations and highlight the potential of adjunct BLT as an augmentation therapeutic strategy to ameliorate sleep perception in MDD patients, emphasizing its potential role in enhancing therapeutic outcomes.