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.

Shared reduction of oscillatory natural frequencies in bipolar disorder, major depressive disorder and schizophrenia.

INTRODUCTION: Recent studies have demonstrated that cortical brain areas tend to oscillate at a specific natural frequency when directly perturbed by transcranial magnetic stimulation (TMS). Fast electroencephalographic (EEG) oscillations, which typically originate from frontal regions, have been reported to be markedly reduced in schizophrenia. METHODS: Here we employed TMS/EEG to assess the natural frequency of the premotor area in a sample of 48 age-matched participants (12 each in major depression disorder (MDD)), bipolar disorder (BPD), schizophrenia (SCZ) and healthy controls. Event related spectral perturbations (ERSP) were obtained for each study participant using wavelet decomposition. RESULTS: TMS resulted in a significant activation of the beta/gamma band response (21-50 Hz) to frontal cortical perturbation in healthy control subjects. By contrast, the main frequencies of frontal EEG responses to TMS were significantly reduced in patients with BPD, MDD and SCZ (11-27 Hz) relative to healthy subjects. CONCLUSIONS: Patients with bipolar disorder, major depression and schizophrenia showed a significantly lower natural frequency of frontal cortico-thalamocortical circuits compared to healthy controls. These results suggest a common neurobiological mechanism of corticothalamic impairment. The most likely candidates include dysfunction of GABAergic circuits. LIMITATIONS: Further studies are needed to consider other biological markers, gene variants, and their interaction with clinical variables.

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.

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.

Optimized light therapy for non-seasonal major depressive disorder: effects of timing and season.

BACKGROUND: Light Therapy (LT) when combined with standard antidepressant treatment for unipolar depression hastens recovery. We studied the influence of LT timing on the antidepressant efficacy of LT and the influence of the season of treatment and recurrence on the response to treatment. METHODS: We studied 70 inpatients affected by Unipolar Depression, treated for three weeks with combined LT and venlafaxine. Two-third of the patients received LT following a predictive algorithm based on MEQ scores; the others received LT at 11:00 a.m. Severity of depression was rated on the Hamilton Depression Rating Scale (HDRS). A subgroup of patients wore activity monitors. RESULTS: HDRS scores significantly decreased during treatment (Friedman's ANOVA: χ2=186.82, p<0.00001). LT administered in the early morning showed a better relative efficacy than late morning (F=4.576; p=0.012) with the clinical improvement correlating with an advance in rest-activity rhythm acrophase (r=-0.336; p=0.017). Season of hospitalization interacted with LT timing and time in influencing response to treatment (F=3.101; p=0.049) and season of episode recurrence significantly interacted with LT timing, season of hospitalization and time (F=5.925; p=0.0035). LIMITATIONS: The major limitation of the study is the small sample size when considering simultaneously LT schedules, season of treatment and recurrence. Moreover, even if none of the patients fulfilled DSM-IV criteria for seasonal pattern of recurrence, they were not administered any questionnaire about seasonality. CONCLUSIONS: We confirmed the usefulness of LT as a non-pharmacological antidepressant therapy for non-seasonal depression. Season and timing of administration and timing of the rest-activity cycle affected response to treatment.

Dysfunctional brain circuitry in obsessive-compulsive disorder: source and coherence analysis of EEG rhythms.

BACKGROUND: Morphological and functional studies suggested involvement of several cortical and subcortical circuitries in patients with obsessive-compulsive disorder (OCD). The aim of the present study was to investigate networks involved in OCD pathophysiology, using power (coupling of EEG bands, low-resolution electromagnetic tomography-LORETA) and coherence analysis in drug-naïve patients. METHOD: EEG was obtained from 37 drug-naïve patients with OCD and 37 age- and sex-matched controls. Resting EEG was recorded from 29 scalp channels. Coupling (ratio and correlation) between low and high frequencies was analyzed on Fz. For each frequency band, LORETA current density distribution, intra-hemispheric and inter-hemispheric coherence analysis were computed. RESULTS: OCD had increased current density for delta in the insula and for beta in frontal, parietal and limbic lobes. OCD also had decreased inter-hemispheric coherence and reduced coupling between delta and beta frequencies. CONCLUSIONS: In OCD, increased frontal beta is consistent with previous evidence of frontal dysfunction. Hyperactivity of insular delta sources, together with rhythms decoupling and reduced interhemispheric alpha coherence are consistent with additional involvement of cortico-subcortical functional connections. Combined use of power and coherence analysis may provide functional measures on different levels of involvement of cortico-subcortical circuits in neuropsychiatric disorders.

Acute antidepressant response to sleep deprivation combined with light therapy is influenced by the catechol-O-methyltransferase Val(108/158)Met polymorphism.

Catechol-O-methyltransferase (COMT) inactivates norepinephrine and dopamine via methyl conjugation, and a G-A transition in the COMT gene (rs4680) influences the enzyme activity. It is a current area of debate whether rs4680 can influence antidepressant response in major depressive disorder, and whether this influence extends to bipolar depression. Chronotherapeutic interventions, such as sleep deprivation and light therapy, are multi-target in nature and are effective in bipolar depression. Here we studied the effect of rs4680 on response to sleep deprivation combined with light therapy (36 h awake followed by a night of undisturbed sleep, with 10,000 lx light administered for 30 min during the night awake and upon awakening) in 87 bipolar depressed inpatients. Patients who were homozygotic for the Val/Val variant showed a significantly less efficient antidepressant effect after the night awake than those who were heterozygotic and homozygotic for the Met variant. This effect of rs4680 is similar to its observed influence on response to serotonergic and noradrenergic drug treatments in major depressive disorder. This is the first study reporting an influence of rs4680 on antidepressant response in bipolar depression. This finding supports the hypothesis of a major role for catecholamines in the mechanism of action of chronotherapeutics, and for rs4680 in modulating this effect.

Neuroimaging and genetics of antidepressant response to sleep deprivation: implications for drug development.

Despite confirmed evidences about some neurochemical effects of antidepressant treatments, there is still a high level of uncertainty about which biological changes are needed to recover from a major depressive episode. Changes of monoaminergic neurotransmission are paralleled by profound changes in brain metabolism, neural responses to stimuli, sleep architecture, biological rhythms, and, at the intracellular level, neuronal signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms. Sleep deprivation targets the biological mechanisms which are responsible for the possibility, unique to mood disorders, of rapid switching between depression, euthymia, and mania. The rapidity of action of sleep deprivation enables the study of the correlates of antidepressant response at close time points, providing a good model to study the biological basis of the antidepressant response and of the pathophysiology of affective illness. Current knowledge suggests that multiple neurobiological effects of sleep deprivation are responsible for the clinical mood amelioration, suggesting a multi-target mechanism of action. An impressive group of brain imaging studies using different brain imaging techniques (positron emission tomography, single photon emission tomography, functional magnetic resonance imaging, proton spectroscopy, arterial spin labeling) showed that clinical response is associated with changes in the functioning of specific brain areas. The combination of these new methodological acquisitions with the classical neurobiological and pharmacogenetic perspective provides an evolving knowledge about brain changes associated with antidepressant response, and will then help to identify the real targets of antidepressant treatment.

Spectroscopic correlates of antidepressant response to sleep deprivation and light therapy: a 3.0 Tesla study of bipolar depression.

Glutamate is the primary excitatory neurotransmitter of the human brain, and recent findings suggest a role for the glutamatergic system in the pathophysiology and treatment of mood disorders. Single proton magnetic resonance spectroscopy (1H-MRS) was used to study the relative in vivo levels of brain neural metabolites. We evaluated the effect of antidepressant treatments on the relative concentration of unresolved glutamate and glutamine (Glx) with GABA contamination (2.35 ppm peak) using single voxel 1H-MRS at 3.0 Tesla. We studied 19 inpatients (7 males, 12 females) affected by bipolar disorder type I, current depressive episode without psychotic features, before and after 1 week of treatment with repeated total sleep deprivation (TSD) combined with light therapy (LT). Chronobiological treatment caused a significant amelioration in mood levels. Changes in the brain Glx/creatine ratio followed a general trend toward decrease, with individual variability. We observed that the decrease in the Glx/creatine ratio significantly correlated with the improvement of both objective and subjective measures of depression.

Phase advance is an actimetric correlate of antidepressant response to sleep deprivation and light therapy in bipolar depression.

The combination of total sleep deprivation (TSD) and light therapy (LT) in bipolar depression causes rapid antidepressant effects, and its mechanism of action has been hypothesized to involve the enhancement of all of the monoaminergic systems targeted by antidepressant drugs (serotonin, dopamine, norepinephrine). It is still unknown if the clinical effects are paralleled by changes in biological rhythms. In a before/after design of a study of biological correlates of response, 39 inpatients affected by Type I Bipolar Disorder whose current depressive episode was without psychotic features were treated for one week with repeated TSD combined with morning LT. Wrist actigraphy was recorded throughout the study. Two-thirds of the patients responded to treatment (50% reduction in Hamilton Depression score). Responders showed an increase in daytime activity, phase-advance of the activity-rest rhythm of 57 min compared to the pre-treatment baseline, and reduced nighttime sleep. Non-responders did not show significant changes in the parameters of their activity-rest rhythm. Phase advance of the activity-rest rhythm is an actimetric correlate of the antidepressant response to TSD and LT in bipolar depression. Results are consistent with the known effects of sleep-wake manipulations and neurotransmitter function on the suprachiasmatic nucleus.

Chronotherapeutics in a psychiatric ward.

Psychiatric chronotherapeutics is the controlled exposure to environmental stimuli that act on biological rhythms in order to achieve therapeutic effects in the treatment of psychiatric conditions. In recent years some techniques (mainly light therapy and sleep deprivation) have passed the experimental developmental phase and reached the status of powerful and affordable clinical interventions for everyday clinical treatment of depressed patients. These techniques target the same brain neurotransmitter systems and the same brain areas as do antidepressant drugs, and should be administered under careful medical supervision. Their effects are rapid and transient, but can be stabilised by combining techniques among themselves or together with common drug treatments. Antidepressant chronotherapeutics target the broadly defined depressive syndrome, with response and relapse rates similar to those obtained with antidepressant drugs, and good results are obtained even in difficult-to-treat conditions such as bipolar depression. Chronotherapeutics offer a benign alternative to more radical treatments of depression for the treatment of severe depression in psychiatric wards, but with the advantage of rapidity of onset.

Neural and genetic correlates of antidepressant response to sleep deprivation: a functional magnetic resonance imaging study of moral valence decision in bipolar depression.

CONTEXT: Total sleep deprivation combined with light therapy causes rapid amelioration of bipolar depression. A polymorphism in the promoter for the serotonin transporter influences both antidepressant response and the structure and function of specific brain areas. OBJECTIVE: To determine whether antidepressant therapy or the genotype of the serotonin transporter influence the pattern of neural response to a task targeting the depressive biases in information processing (moral valence decision). DESIGN: Before-and-after trial studying the biologic correlates of response to treatment. SETTING: University hospital. Patients Twenty inpatients with bipolar depression. Intervention Repeated total sleep deprivation combined with light therapy for 1 week. MAIN OUTCOME MEASURES: Brain blood oxygen level-dependent functional magnetic resonance imaging using a 3.0-T scanner before and after treatment. Self-ratings and observer ratings of mood (visual analog scale 3 times daily and Hamilton Depression Rating Scale) before and after treatment. RESULTS: We found significant interactions of treatment (before and after), response to treatment (Hamilton Depression Rating Scale score <8), and moral valence of the stimuli (positive or negative) in the anterior cingulate cortex, dorsolateral prefrontal cortex, insula, and parietal cortex. In these areas, responders changed their blood oxygen level-dependent responses to emotional stimuli in a pattern opposite of that in nonresponders. Genotype of the promoter for the serotonin transporter predicted response to treatment and influenced baseline neural responses in the anterior cingulate cortex and the dorsolateral prefrontal cortex. CONCLUSION: Multiple factors that affect or are affected at the individual level by major depressive episodes in the course of bipolar disorder significantly interact in influencing brain cortical activity in specific areas.

Combined total sleep deprivation and light therapy in the treatment of drug-resistant bipolar depression: acute response and long-term remission rates.

BACKGROUND: Drug resistance remains a persistent source of morbidity and mortality for patients with bipolar depression. A growing number of clinical studies support the usefulness of chronotherapeutic interventions, such as total sleep deprivation (TSD) and light therapy (LT), in the treatment of nonresistant bipolar depression. METHOD: To investigate the clinical usefulness of TSD plus LT in the treatment of drug-resistant bipolar depression, we treated 60 inpatients for 1 week with repeated TSD and LT combined with ongoing antidepressants and lithium salts. All patients had a DSM-IV diagnosis of bipolar I disorder. Drug resistance was rated according to Thase and Rush criteria. The pattern of relapses and recurrences was assessed during a prospective 9-month follow-up. Data were gathered from September 2002 to July 2004. RESULTS: A 2-way repeated-measures analysis of variance with changes in self-rated perceived mood scores as dependent variable and with time and group (history of drug resistance) as independent factors confirmed significant time-by-group interaction (p = .0339). A logistic regression on rates of achievement of response (50% reduction in Hamilton Rating Scale for Depression ratings) confirmed the significance of observed differences: overall, 70% (23/33) of nonresistant versus 44% (12/27) of drug-resistant patients achieved response (p = .045). A survival time analysis (Cox proportional hazards model) showed that history of drug resistance significantly influenced the pattern of relapses and recurrences, with 57% (13/23) of nonresistant responders and 17% (2/12) of drug-resistant responders being euthymic after 9 months (p = .0212). DISCUSSION: The combination of repeated TSD and LT in drug-resistant patients was useful in triggering an acute response. Further clinical research is needed to optimize this treatment option for drug-resistant patients in the long term.

Antidepressant effects of light therapy combined with sleep deprivation are influenced by a functional polymorphism within the promoter of the serotonin transporter gene.

BACKGROUND: A functional polymorphism within the promoter of the serotonin transporter has been shown to influence the antidepressant response to serotonergic drug treatments and to total sleep deprivation (TSD). The short-term relapse that follows acute response to TSD has been successfully prevented by combining TSD with light therapy. The mechanism of action of this combined treatment is unknown. METHODS: We tested the hypothesis that allelic variation of the serotonin transporter (5-HTT) linked polymorphic region (5-HTTLPR) could influence the response to the combination of light therapy and TSD. Twenty-two bipolar depressed inpatients were administered a night of TSD combined with 30 min light therapy given during the TSD night and in the morning after recovery sleep. 5-HTTLPR was genotyped using polymerase chain reaction techniques. Changes in perceived mood were rated on a visual analog scale. RESULTS: Light therapy sustained the effect of TSD. The effect was more marked in homozygotes for the long variant of 5-HTTLPR than in heterozygotes and homozygotes for the short variant. CONCLUSIONS: The influence of 5-HTTLPR on response to the combination of TSD and light therapy is similar to that observed on response to TSD and serotonergic drug treatments.

Morning light treatment hastens the antidepressant effect of citalopram: a placebo-controlled trial.

BACKGROUND: Selective serotonin reuptake inhibitors are effective in approximately 70% of patients with a major depressive episode, but therapeutic changes usually require 2 weeks of administration to become clinically relevant. Adjunct light therapy has been proposed to hasten the effects of drug treatment. The purpose of the present study was to evaluate the effect of morning light therapy or placebo combined with citalopram in the treatment of patients affected by a major depressive episode without psychotic features. METHOD: Thirty inpatients (DSM-IV major depressive disorder [N = 21] and bipolar disorder [N = 9]) were treated with citalopram, 40 mg, and randomized in a 3:2 manner to receive 30 minutes of 400 lux green light treatment in the morning or placebo (exposure to a deactivated negative ion generator) during the first 2 weeks of drug treatment. Timing of light therapy was individually defined to obtain a 2-hour phase advance to morning light. Outcome was measured with the Hamilton Rating Scale for Depression and the Zung Self-Rating Depression Scale every week, and with a Visual Analogue Scale 3 times a day during the first week. RESULTS: All outcome measures showed significantly (p <.05) better mood improvement in light-treated patients, resulting in faster responses to antidepressant treatment. CONCLUSION: The combination of citalopram and light treatment was more effective than citalopram and placebo in the treatment of major depression. With an optimized timing of administration, low-intensity light treatment significantly hastened and potentiated the effect of citalopram, thus providing the clinical psychiatrists with an augmenting strategy that was found effective and devoid of side effects.