Cerebral glucose metabolic response to combined total sleep deprivation and antidepressant treatment in geriatric depression.

OBJECTIVE: The treatment of geriatric depression is complicated by a variable and delayed response to antidepressant treatment. The present study was undertaken to test the hypothesis that combined total sleep deprivation and paroxetine treatment would produce a persistent reduction in glucose metabolism in the anterior cingulate cortex similar to that reported after long-term antidepressant treatment. METHOD: Six elderly depressed patients who met the DSM-IV criteria for major depressive disorder and six age-matched comparison subjects underwent serial positron emission tomography (PET) studies at baseline, after total sleep deprivation, after recovery sleep (after the initial paroxetine dose), and after 2 weeks of paroxetine treatment (patients only). The PET data were analyzed by using statistical parametric mapping methods. RESULTS: The patients' scores on a 13-item version of the Hamilton Depression Rating Scale were decreased after total sleep deprivation, after recovery sleep, and after 2 weeks of treatment. The Hamilton depression scores of the comparison subjects were not significantly altered. In the patients, the greatest reductions in normalized, relative glucose metabolism after sleep deprivation were observed in the anterior cingulate cortex (Brodmann area 24), and they persisted after recovery sleep and antidepressant treatment. The comparison subjects demonstrated increased metabolism in these areas. CONCLUSIONS: Improvement in the patients' depressive symptoms was accompanied by reduced glucose metabolism in the right anterior cingulate cortex and right medial frontal cortex. These preliminary data indicate that in elderly depressed patients, total sleep deprivation may accelerate the clinical and glucose metabolic response to antidepressant treatment.     

Glucose metabolic response to total sleep deprivation, recovery sleep, and acute antidepressant treatment as functional neuroanatomic correlates of treatment outcome in geriatric depression.

OBJECTIVE: The variable speed and durability of response to antidepressant medications in geriatric depression is a significant clinical problem. The authors evaluated changes in cerebral glucose metabolism measured with positron emission tomography (PET) during a clinical trial designed to accelerate medication response by the use of one night of total sleep deprivation (TSD), and they asked whether changes would correlate with treatment outcome after 12 weeks of antidepressant treatment. METHODS: Twelve elderly, unipolar depressed patients underwent serial PET studies at baseline, post-TSD, post-recovery sleep (after an initial paroxetine dose), and after 2 weeks of paroxetine treatment. RESULTS: Decreased regional glucose metabolism after TSD, recovery sleep, and 2 weeks of treatment was associated with clinical improvement at 12 weeks. The right cingulate gyrus area was consistently correlated with clinical improvement across treatment conditions. CONCLUSION: These data indicate that the early metabolic alterations in the right cingulate gyrus and the persistence of these adaptive changes are associated with improvement in depressive symptoms.     

The clinical response to total sleep deprivation and recovery sleep in geriatric depression: potential indicators of antidepressant treatment outcome

The clinical response to antidepressant treatment in late-life depression is often delayed and highly variable. Better indicators of antidepressant efficacy are needed early in the course of treatment, so that augmentation strategies or alternative treatments may be initiated. The goal of this study was to evaluate whether the change in the Hamilton depression rating scale (HDRS) after 36 h of total sleep deprivation (TSD) and recovery sleep predicted clinical outcome after 12 weeks of antidepressant treatment, and whether greater predictive value was observed in certain aspects of depressive symptomology. Fifteen elderly patients diagnosed with major depression underwent combined treatment with an initial 36 hours of TSD and a 12-week trial with the antidepressant paroxetine. Six HDRS subscores were evaluated with respect to how the changes after TSD and after one night of recovery sleep correlated with HDRS scores after 12 weeks of treatment. A significant correlation was obtained between the change in the core depressive symptomology subscale from baseline to recovery sleep and the HDRS score at 12 weeks, but the correlation was not significant when evaluating the change from baseline to TSD. These results indicate that the decrease in symptoms after recovery sleep compared with baseline levels (indicating the persistence of the antidepressant response), rather than the symptom reduction after TSD, has greater predictive value with respect to treatment outcome.     

Accelerating response in geriatric depression: A pilot study combining sleep deprivation and paroxetine

Elderly depressed patients often require an average of 12 weeks of pharmacotherapy before attaining remission. The delay between treatment initiation and remission may decrease compliance and prolongs suffering; hence, interventions that decrease the time to onset of antidepressant activity are needed. Our objective was to evaluate, in an open trial, the use of one night of total sleep deprivation combined with paroxetine to accelerate antidepressant response in elderly patients. Thirteen elderly patients with major depression were sleep-deprived for one night and started paroxetine on the night of recovery sleep. Patients were followed for twelve weeks, and clinical improvement was rated using the 17-item Hamilton Depression Rating Scale and a version of the Hamilton modified for sleep deprivation studies. 8/13 (62%) patients experienced significant improvement of depressive symptoms by 2 weeks. Within 12 weeks 11/13 (85%) patients responded to the combination of sleep deprivation and paroxetine. Median response time was 2 weeks. Clinical response at 12 weeks was correlated with changes in Sleep Deprivation Depression Rating Scale Scores between baseline and recovery sleep. In an open trial, the combined use of total sleep deprivation and paroxetine appears to be an effective method for speeding the onset of clinical antidepressant activity in geriatric depression and for improving early recognition of non-response. Depression and Anxiety 6:113–118, 1997. © 1997 Wiley-Liss, Inc.     

Serotonin 5-HT2A receptor gene variants influence antidepressant response to repeated total sleep deprivation in bipolar depression

5-HT_2A receptor density in prefrontal cortex was associated with depression and suicide.5-HT_2A receptor gene polymorphism rs6313 was associated with 5-HT_2A receptor binding potential, with the ability of individuals to use environmental support in order to prevent depression, and with sleep improvement after antidepressant treatment with mirtazapine. Studies on response to antidepressant drugs gave inconsistent results.Here we studied the effect of rs6313 on response to repeated total sleep deprivation (TSD) in 80 bipolar depressed inpatients treated with three consecutive TSD cycles (each one made of 36 h awake followed by a night of undisturbed sleep). All genotype groups showed comparable acute effects of the first TSD, but patients homozygotes for the T variant had better perceived and observed benefits from treatment than carriers of the C allele. These effects became significant after the first recovery night and during the following days, leading to a 36% higher final response rate (Hamilton depression rating < 8).The higher density of postsynaptic excitatory 5-HT_2A receptors in T/T homozygotes could have led to higher behavioural effects of increased 5-HT neurotransmission due to repeated TSD. Other possible mechanisms involve allostatic/homeostatic adaptation to sleep loss, and a different effect of the allele variants on epigenetic influences. Results confirm the interest for individual gene variants of the serotonin pathway in shaping clinical characteristics of depression and antidepressant response.     

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.     

Accelerating antidepressant response in geriatric depression: a post hoc comparison of combined sleep deprivation and paroxetine versus monotherapy with paroxetine, nortriptyline, or placebo.

Speed of response is an important clinical issue in the treatment of depressed elderly patients. Our objective was to compare rapid response rates in a study combining therapeutic sleep deprivation (TSD) with paroxetine with two earlier randomized, double-blind studies in late-life depression, one of paroxetine versus nortriptyline and another of nortriptyline versus placebo. We measured depressive symptoms with the 17-item Hamilton Rating Scale of Depression (HRSD), defining rapid response as an HRSD < or = 10 by 2 weeks. With combination therapy (TSD + paroxetine), 9 of 13 patients (69%) experienced a rapid response. In the nortriptyline versus paroxetine study, nortriptyline brought about rapid response in 12 of 37 (32%) and paroxetine in 11 of 43 patients (26%). In the third study, rapid response to nortriptyline occurred in 10 of 41 patients (24%) and to placebo in 6 of 39 patients (15%). The overall chi square, including the rate of rapid response to placebo, was 14.87 (P = .005). The chi square on the four active treatment groups, excluding placebo, was 10.28 (P = .016). This preliminary observation suggests that combined therapy with TSD plus paroxetine may be twice as successful at achieving rapid response in elderly depressed patients than conventional monotherapy with medication or placebo. A prospective, placebo-controlled evaluation of this dual therapy is warranted.     

Accelerating symptom-reduction in late-life depression: a double-blind, randomized, placebo-controlled trial of sleep deprivation.

OBJECTIVE: Authors tested the hypothesis that one night of total sleep deprivation (TSD) would accelerate antidepressant response to paroxetine, as compared with TSD+placebo (PBO) and paroxetine-alone, in late-life major depression. METHODS: Eighty elderly outpatients with current episodes of non-psychotic, non-bipolar major depression were randomly assigned to one of three treatment conditions: TSD+paroxetine (N = 27), TSD + PBO (N = 27), and paroxetine-only (N = 26). Primary outcome was percentage of subjects in each condition who demonstrated early response (Hamilton Rating Scale for Depression scores [Ham-D: 17-item] of < or = 10) or remission (score of < or = 7) on Day 14. RESULTS: Response rates after 14 days were 22% in subjects randomly assigned to the TSD + paroxetine condition, 41% in TSD + PBO, and 46% in paroxetine alone. Remission rates after 14 days were 11% in TSD+paroxetine, 22% in TSD + PBO, and 38% in paroxetine. After adjusting for baseline depression severity, there were no statistically significant differences in response or remission rates. CONCLUSION: Contrary to the study hypothesis, one night of total sleep deprivation did not accelerate onset of antidepressant response to paroxetine pharmacotherapy of late-life depression. The data suggest, rather, that the two interventions might have counteracted each other.     

Hippocampal volume and antidepressant response in geriatric depression

BACKGROUND: Biological markers of treatment response may include structural brain changes seen on neuroimaging. While most imaging studies have focused on cerebrovascular disease, evidence is growing that the hippocampus may play a role in depression, particularly geriatric depression. METHOD: We studied 60 depressed elderly patients enrolled in a longitudinal study who were treated with antidepressant medications using a treatment guideline-based approach. Baseline and 12-week Montgomery-Asberg Depression Rating Scale (MADRS) scores were obtained via interview with a geriatric psychiatrist. All subjects had a baseline magnetic resonance imaging (MRI) brain scan. MRI scans were processed using standard protocols to determine total cerebral volume and right and left hippocampal volumes. Hippocampal volumes were standardized for total cerebral volume. MADRS scores less than 10 were used to define remission. RESULTS: When the group with the lowest quartile of standardized hippocampal volumes was compared to those above the first quartile, those with small right and total hippocampal volumes were less likely to achieve remission. In a subsequent logistic regression model controlling for age small standardized right hippocampal volumes remained significantly associated with remission. CONCLUSION: Further studies with larger sample are needed to determine if left-right hippocampal volume differences do exist in depression, and basic neuroscience studies will need to elucidate the role of the hippocampus in geriatric depression.     

Prediction of the antidepressant response to total sleep deprivation by diurnal variation of mood

The relationship between diurnal variation of mood and response to total sleep deprivation (TSD) was investigated in 131 depressed patients. This response was related to (1) the diurnal variation on the day before TSD as assessed by self-ratings of mood, and (2) the propensity to produce diurnal variations (the "diurnality") as assessed by the Hamilton Rating Scale for Depression. Three types of diurnality are distinguished: morning type (the propensity to feel better in the morning), evening type (the propensity to feel better in the evening), and a nondiurnal type. The results show that diurnality does predict the mood response to TSD. The direction of diurnality is decisive: patients who have the propensity to feel better in the evening benefit more from TSD than other patients.     

Response to total sleep deprivation and clomipramine in endogenous depression

In 44 endogenously depressed patients, response to total sleep deprivation (TSD) was investigated as a function of several biographical and clinical variables. All patients were subjected to a schedule of sleep-TSD-sleep-TSD. Antidepressant drug treatment (clomipramine) was started on the day before the first TSD. Sex, age, educational status, number of previous hospitalizations and duration of the current depressive episode were not related to the response to either the first or the second TSD. Likewise, no significant differences were found in the responses of unipolar and bipolar patients. In contrast, diurnal variation appeared to be positively correlated with response to TSD. Depressives with psychotic features reacted more favourably than non-psychotic depressives.     

Effect of sleep deprivation as a predictor of treatment response to antidepressant medication

ABSTRACT– Sixty depressed patients were treated first with sleep deprivation (SD) and afterwards with clomipramine or maprotiline. A statistically significant correlation was found between the positive effect of SD and response to clomipramine and the negative effect of SD and response to maprotiline.     

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.     

Accelerating response to antidepressant treatment in depression: A review and clinical suggestions

Objective

The primary objective of this article is to review the literature regarding the speed of response to antidepressant drugs and potential strategies to accelerate the antidepressant response in new antidepressant-free patients with depression. Based on these data, we try to propose both an effective and safe antidepressant treatment strategy to alleviate depressive symptoms at the earliest opportunity.

Data sources

Data were identified by searches of Medline (1966 to September 2009) and references from relevant articles and books. Search terms included depression, antidepressant, predictor, response, onset, acceleration, and augmentation. As our focus was on the acute phase treatment of depression, articles relevant to treatment-resistant depression were excluded. Only articles written in English or Japanese were consulted.

Data selection

Studies, reviews, and books pertaining to the treatment of depression with a special regard to accelerating therapeutic effects were selected.

Data synthesis

Most of the available treatment guidelines for major depressive disorders recommend the continuous use of antidepressants for 4 to 8 weeks based on the idea of a delayed onset of response to these drugs. Contrary to this conventional belief, the recent data indicate that antidepressants start to exert their effects within 2 weeks and early non-response could predict a subsequent unfavorable outcome.

Conclusions

These findings suggest the need of revisiting the timing of an antidepressant switch for early non-responders, whereby switching could be commenced in as early as 2 weeks.     

Interleukine-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance

Unstimulated production of interleukine-6 (IL-6) is known to be enhanced in patients affected by a major depressive episode. Recent studies supported a role for basal IL-6 levels in predicting response to antidepressant drug treatments. In a sample of 10 consecutively admitted drug-free bipolar depressed inpatients, we investigated the possible correlation between unstimulated pretreatment production of IL-6 and antidepressant response to a night of total sleep deprivation (TSD) followed by a night of sleep phase advance (SPA), a nonpharmacologic treatment which is known to rapidly improve depressive symptomatology. Changes in perceived mood during treatment were recorded with self-administered Visual Analogue Scales (VAS). We observed a significant inverse correlation between IL-6 serum levels and VAS scores after treatment, meaning that higher IL-6 values before treatment were associated with worse response. This finding is in agreement with previous studies about amitriptyline and lithium antidepressant treatments. Our preliminary finding confirms the clinical value of IL-6 baseline concentration as a predictor of response to antidepressant treatment.     

Cerebral glucose utilization and glucose transporter expression: response to water deprivation and restoration.

The relationship between local rates of cerebral glucose utilization (ICMRglc) and glucose transporter expression was examined during physiologic activation of the hypothalamoneurohypophysial system. Three days of water deprivation, which is known to activate the hypothalamoneurohypophysial system, resulted in increased ICMRglc and increased concentrations of GLUT1 and GLUT3 in the neurohypophysis; mRNA levels of GLUT1 and GLUT3 were decreased and increased, respectively. Water deprivation also increased ICMRglc in the hypothalamic supraoptic and paraventricular nuclei; mRNA levels of GLUT1 and GLUT3 appeared to increase in these nuclei, but the changes did not achieve statistical significance. Restoration of water for 3 to 7 days reversed all observed changes in GLUT expression (protein and mRNA): restoration of water also reversed changes in ICMRglc in both the neurohypophysis and the hypothalamic nuclei. These results indicate that under conditions of neural activation and recovery, changes in ICMRglc and the levels of GLUT1 and GLUT3 are temporally correlated in the neurohypophysis and raise the possibility that GLUT1 and GLUT3 transporter expression may be regulated by chronic changes in functional activity. In addition, increases in the expression of GLUT5 mRNA in the neurohypophysis after dehydration provide evidence for involvement of microglial activation.     

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.