Antidepressant chronotherapeutics normalizes prefrontal 1H-MRS glutamate in bipolar depression.

BACKGROUND: Dysfunctional glutamatergic neurotransmission has been proposed both, as a biological underpinning of mood disorder and as a target for rapid-acting antidepressant treatments. Total sleep deprivation and light therapy (TSD + LT) can prompt antidepressant response in drug-resistant bipolar depression. Here we explored the effects of TSD + LT on dorsolateral prefrontal cortex (DLPFC) glutamate and/or glutamine+glutamate (Glx) levels. METHODS: We studied single voxel 1H-MRS measures of DLPFC Glu and Glx levels of 48 healthy participants and 55 inpatients with a major depressive episode in course of Bipolar Disorder, a subset of which (N = 23) underwent three cycles of repeated TSD + LT and were evaluated before and after treatment. Treatment effects of mood and on Glu and Glx concentrations were analyzed in the context of the Generalized Linear Model (GLM), correcting for age, sex and ongoing lithium treatment. RESULTS: Higher concentration of Glu (adjusted Z = -2189, p = 0,0285) and Glx (adjusted Z = -3,13, p = 0,0017) were observed in BD patients compared to HC. Treatment caused a significant rapid reduction of depressive symptom severity over time (F = 63.98, p < 0.01). Change in depression levels after TSD + LT treatment was significantly influenced by delta change in Glu levels (LR χ2 = 4.619, p = 0.0316) and in Glx levels (LR χ2 = 4.486, p = 0.0341). CONCLUSION: A reduction in Glu and Glx levels associated with depression could contribute to the mechanism of action of TSD + LT, directly acting on glutamatergic neurons, or to the interaction between the glutamatergic system and dopamine (DA) and serotonin (5-HT) levels, known to be targeted by TSD. This is in line with several studies showing a glutamatergic modulation effects of antidepressants and mood stabilizing agents. This finding deepens our understanding of antidepressant effect of chronoterapeutics.

Changes of white matter microstructure after successful treatment of bipolar depression.

BACKGROUND: Diffusion tensor imaging (DTI) measures suggest a widespread alteration of white matter (WM) microstructure in patients with bipolar disorder (BD). The chronotherapeutic combination of repeated total sleep deprivation and morning light therapy (TSD+LT) can acutely reverse depressive symptoms in approximately 60% of patients, and it has been confirmed as a model antidepressant treatment to investigate the neurobiological correlates of rapid antidepressant response. METHODS: We tested if changes in DTI measures of WM microstructure could parallel antidepressant response in a sample of 44 patients with a major depressive episode in course of BD, treated with chronoterapeutics for one week. We used both a tract-wise and a voxel-wise approach for the whole-brain extraction of DTI measures of WM microstructure: axial (AD), radial (RD), and mean diffusivity (MD), and fractional anisotropy (FA). RESULTS: Compared to baseline level, at one-week follow up we observed a significant increase in average FA measures paralleled by a significant decrease in MD measures of several WM tracts including cingulum, corpus callosum, corona radiata, cortico-spinal tract, internal capsule, fornix and uncinate fasciculus. The degree of change was associated to clinical response. CONCLUSIONS: This is the first study to show changes of individual DTI measures of WM microstructure in response to antidepressant treatment in BD. Our results add new evidence to warrant a role for chronotherapeutics as a first-line treatment for bipolar depression and contribute identifying generalizable neuroimaging-based biomarkers of antidepressant response.

A Homer 1 gene variant influences brain structure and function, lithium effects on white matter, and antidepressant response in bipolar disorder: A multimodal genetic imaging study.

BACKGROUND: The Homer family of postsynaptic scaffolding proteins plays a crucial role in glutamate-mediated synaptic plasticity, a phenotype associated with Bipolar Disorder (BD). Homer is a target for antidepressants and mood stabilizers. The AA risk genotype of the Homer rs7713917 A>G SNP has been associated with mood disorders and suicide, and in healthy humans with brain function. Despite the evidence linking Homer 1 gene and function to mood disorder, as well as its involvement in animal models of depression, no study has yet investigated the role of Homer in bipolar depression and treatment response. METHODS: We studied 199 inpatients, affected by a major depressive episode in course of BD. 147 patients were studied with structural MRI of grey and white matter, and 50 with BOLD functional MRI of emotional processing. 158 patients were treated with combined total sleep deprivation and light therapy. RESULTS: At neuroimaging, patients with the AA genotype showed lower grey matter volumes in medial prefrontal cortex, higher BOLD fMRI neural responses to emotional stimuli in anterior cingulate cortex, and lower fractional anisotropy in bilateral frontal WM tracts. Lithium treatment increased axial diffusivity more in AA patients than in G*carriers. At clinical evaluation, the same AA homozygotes showed a worse antidepressant response to combined SD and LT. CONCLUSIONS: rs7713917 influenced brain grey and white matter structure and function in BD, long term effects of lithium on white matter structure, and antidepressant response to chronotherapeutics, thus suggesting that glutamatergic neuroplasticity and Homer 1 function might play a role in BD psychopathology and response to treatment.

Higher Baseline Proinflammatory Cytokines Mark Poor Antidepressant Response in Bipolar Disorder.

BACKGROUND: The clinical relevance of raised levels of circulating cytokines in bipolar disorder is still unclear. Cytokines influence neurotransmitters, neuroplasticity, and white matter integrity. An inconsistent literature suggests that higher cytokine levels could hamper antidepressant response. Total sleep deprivation (TSD) and light therapy (LT) prompt a rapid antidepressant response and can provide a model treatment to study predictors of response. METHODS: We studied at baseline 15 immune-regulating compounds in 37 consecutively admitted inpatients with a major depressive episode in the course of bipolar disorder (DSM-5 criteria) and in 24 controls. Thirty-one patients (84%) had a lifetime history of drug resistance. Patients were administered 3 TSD + LT cycles in 1 week (study period: 2010-2012). Data were analyzed with age- and false-discovery-rate-corrected analysis of variance and were tested as predictors in a regressive model. RESULTS: Twenty-three patients (62%) responded to treatment (Inventory of Depressive Symptomatology IDS-C score < 12). Five highly intercorrelated compounds (IL-8, MCP-1, IFN-γ, IL-6, TNF-α) showed higher levels in nonresponder patients as compared to responders, corrected for multiple comparisons (respectively F = 6.138, PFDR = .0134; F = 6.197, PFDR = .0134; F = 4.785, PFDR = .0255; F = 3.782, PFDR = .0441; F = 3.764, PFDR = .0441). A principal component analysis identified a single component that explained 84% of variance of these cytokines (Q² = 0.15), and a high factor score significantly predicted worse response (b = -0.692; W = 4.34, P = .037). A higher body mass index correlated with higher cytokines (r = 0.430, P = .010), indirectly hampering response (b = -0.0192, P = .013). CONCLUSIONS: Proinflammatory compounds reflecting an M1-like proinflammatory state of monocytes/macrophages are associated with a poor response to antidepressant TSD + LT treatment in bipolar depression.

Stem Cell Factor (SCF) is a putative biomarker of antidepressant response.

Growth factors involved in neurogenesis and neuroplasticity could play a role in biological processes that drive depression recovery. Combined total sleep deprivation and morning light therapy (TSD + LT) can acutely reverse depressive symptoms, thus allowing to investigate the neurobiological correlates of antidepressant response. We tested if changes on plasma levels of Brain Derived Neurotrophic Factor (BDNF), S100 calcium binding protein B (S100-B), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor-BB (PDGF-BB), and Vascular Endothelial Growth Factor (VEGF) are associated with response to TSD + LT in 26 inpatients affected by a major depressive episode in the course of bipolar disorder. Regional grey matter (GM) volumes were assessed at baseline, and BOLD fMRI neural responses to a moral valence decision task were recorded before and after treatment. 61.5 % of patients responded to treatment. SCF plasma levels increased significantly more in responders, and correlated with GM volumes in frontal and parietal cortical areas. The pattern of change of SCF also associated with both GM volumes and changes of BOLD fMRI neural responses in the anterior cingulate and medial prefrontal cortex. SCF is both a hematopoietic growth factor and a neurotrophic factor, involved in neuron-neuron and neuron-(micro) glia interactions, fostering neuronal growth and an anti-inflammatory milieu. We correlated SCF levels with antidepressant response and with functional and structural MRI measures in cortical areas that are involved in the cognitive generation and control of affect. SCF may be a candidate growth factor that contributes to neurotrophic and immune effects that are involved in the process of remission/recovery from depression.

Successful antidepressant chronotherapeutics enhance fronto-limbic neural responses and connectivity in bipolar depression.

The identification of antidepressant response predictors in bipolar disorder (BD) may provide new potential enhancements in treatment selection. Repeated total sleep deprivation combined with light therapy (TSD+LT) can acutely reverse depressive symptoms and has been proposed as a model antidepressant treatment. This study aims at investigating the effect of TSD+LT on effective connectivity and neural response in cortico-limbic circuitries during implicit processing of fearful and angry faces in patients with BD. fMRI and Dynamic Causal Modeling (DCM) were combined to study the effect of chronotherapeutics on neural responses in healthy controls (HC, n = 35) and BD patients either responder (RBD, n = 26) or non responder (nRBD, n = 11) to 3 consecutive TSD+LT sessions. Twenty-four DCMs exploring connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), Amygdala (Amy), fusiform gyrus and visual cortex were constructed. After treatment, patients significantly increased their neural responses in DLPFC, ACC and insula. nRBD showed lower baseline and endpoint neural responses than RBD. The increased activity in ACC and in medial prefrontal cortex, associated with antidepressant treatment, was positively associated with the improvement of depressive symptomatology. Only RBD patients increased intrinsic connectivity from DLPFC to ACC and reduced the modulatory effect of the task on Amy-DLPFC connection. A successful antidepressant treatment was associated with an increased functional activity and connectivity within cortico-limbic networks, suggesting the possible role of these measures in providing possible biomarkers for treatment efficacy.

Disruption of white matter integrity marks poor antidepressant response in bipolar disorder.

BACKGROUND: Changes of white matter (WM) microstructure have been proposed as structural biomarkers of bipolar disorder (BD). The chronotherapeutic combination of repeated total sleep deprivation and morning light therapy (TSD+LT) can acutely reverse depressive symptoms in approximately 60% of patients, and it has been proposed as a model antidepressant treatment to investigate the neurobiological correlates of rapid antidepressant response. METHODS: We tested if baseline DTI measures can predict response to treatment in 70 in-patients affected by a major depressive episode in the course of BD, treated with chronotherapeutics for one week. We performed whole-brain tract-based spatial statistics with threshold-free cluster enhancement for the DTI measures of WM microstructure integrity: fractional anisotropy, axial, radial, and mean diffusivity. RESULTS: Increased mean and radial water diffusivity correlated with poor antidepressant response to TSD+LT in core WM tracts which are crucial for the functional integrity of the brain, including corpus callosum, corona radiata, cingulum bundle, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and thalamic radiation. LIMITATIONS: Limitations include issues such as generalizability, possible population stratification, medications and their effects on DTI measures, and no placebo control for chronotherapeutics. We could not consider other factors such as gene-environment interactions. CONCLUSIONS: The association of increased radial and mean diffusivity with poor response to chronotherapeutic treatment warrants interest for the study of DTI measures of WM microstructure as markers for treatment response in bipolar depression.

Rapid treatment response of suicidal symptoms to lithium, sleep deprivation, and light therapy (chronotherapeutics) in drug-resistant bipolar depression.

BACKGROUND: One third of patients with bipolar disorder attempt suicide. Depression in bipolar disorder is associated with drug resistance. The efficacy of antidepressants on suicidality has been questioned. Total sleep deprivation and light therapy prompt a rapid and stable antidepressant response in bipolar disorder. METHOD: We studied 143 consecutively admitted inpatients (December 2006-August 2012) with a major depressive episode in the course of bipolar disorder (DSM-IV criteria). Among the 141 study completers, 23% had a positive history of attempted suicide and 83% had a positive history of drug resistance. During 1 week, patients were administered 3 consecutive total sleep deprivation cycles (each composed of a period of 36 hours awake followed by recovery sleep) combined with bright light therapy in the morning for 2 weeks. At admission, patients who had been taking lithium continued it, and those who had not been taking lithium started it. Severity of depression was rated according to the Hamilton Depression Rating Scale (HDRS) (primary outcome measure) and Beck Depression Inventory (BDI). RESULTS: Two patients switched polarity. Among the 141 who completed the treatment, 70% achieved a 50% reduction in HDRS score in 1 week, which persisted 1 month after in 55%. The amelioration involved an immediate and persistent decrease in suicide scores soon after the first total sleep deprivation cycle (F3,411 = 42.78, P < .00001). A positive history of suicide attempts was associated with worse early life stress and with worse suicide scores at baseline, but it did not influence response. Patients with current suicidal thinking or planning responded equally well (F3,42 = 20.70, P < .000001). Remarkably, however, nonresponders achieved a benefit, with significantly decreased final scores also including suicidality ratings (F3,120 = 6.55, P = .0004). Self-ratings showed the same pattern of change. Previous history of drug resistance did not hamper response. During the following month, 78 of 99 responders continued to stay well and were discharged from the hospital on lithium therapy alone. CONCLUSIONS: The combination of total sleep deprivation, light therapy, and lithium is able to rapidly decrease depressive suicidality and prompt antidepressant response in drug-resistant major depression in the course of bipolar disorder.