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.     

Response to total sleep deprivation before and during treatment with fluvoxamine or maprotiline in patients with major depression--results of a double-blind study

To test the hypothesis that the antidepressant effects of total sleep deprivation (TSD) are linked to the serotonergic and/or noradrenergic system the authors carried out a double-blind study (fluvoxamine versus maprotiline) in 42 inpatients with endogenous depression (ICD). Patients were randomized to a four-week treatment with either fluvoxamine (100-300 mg/day) or maprotiline (100-300 mg/day). In addition, patients underwent a TSD procedure before and after one week of antidepressant medication. There was a statistically significant reduction of depression ratings (HDRS) in both the fluvoxamine and maprotiline group. The day-1 response to TSD before antidepressive medication was not associated with a clear relationship to the outcome after four weeks of treatment with either fluvoxamine or maprotiline. On the other hand, the day-2 response to TSD was significantly correlated with a good outcome to subchronic treatment with maprotiline. Furthermore, the results of the authors' data suggest that a favorable short-term outcome of TSD may be connected to antidepressants enhancing the serotonergic neurotransmission. The global comparison between fluvoxamine and maprotiline revealed that the group of patients treated with fluvoxamine had a significantly higher efficiency index (CGI) than the maprotiline group; fluvoxamine was rated to be tolerated excellently in 70% of the patients whereas this percentage was only 43% in the maprotiline group. There was also significantly more vertigo and dry mouth in the maprotiline group whereas the fluvoxamine group was rated to have significantly more sleep disturbances during the trial.     

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.     

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.     

Cerebral glucose metabolic response to combined total sleep deprivation and antidepressant treatment in geriatric depression: A randomized,placebo-controlled study

A randomized, placebo-controlled study was performed to evaluate whether the onset of the glucose metabolic effects of a selective serotonin reuptake inhibitor (paroxetine) would be accelerated by total sleep deprivation (TSD). Patients were randomly assigned to one of three groups: TSD and paroxetine treatment, TSD and 2 weeks of placebo followed by paroxetine treatment, or 2 weeks of paroxetine treatment. Sixteen elderly depressed patients who met DSM-IV criteria for major depressive disorder and nine age-matched comparison subjects underwent positron emission tomography (PET) studies of cerebral glucose metabolism at baseline, post-TSD (or a normal night's sleep for the paroxetine- only group), post-recovery sleep and 2 weeks post-paroxetine or placebo treatment (patients only). TSD was not consistently associated with a decrease in depressive symptoms between groups nor with decreases in cerebral metabolism in cortical regions that have been associated with rapid and sustained clinical improvement (e.g. anterior cingulate gyrus). The observation of a synergistic antidepressant effect of combined TSD and paroxetine treatment that was observed in a previous “open label” pilot study was not observed in the present randomized study, consistent with lack of a cerebral metabolic effect in brains regions previously shown to be associated with improvement of depressive symptoms.     

The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study

Recent studies suggested a role of brain-derived neurotrophic factor (BDNF) in depression. While BDNF levels are lower in depressed patients, antidepressant treatment increases serum BDNF levels of depressed patients. Our study aims to test the effect of chronic venlafaxine treatment on serum BDNF levels in patients with a major depressive disorder. Ten patients diagnosed as major depressive disorder according to DSM-IV are included in the study. Two of the patients had their first episode and were drug-naive, the other eight patients were drug-free for at least 4 weeks. The severity of depression was assessed with Hamilton Depression Rating Scale (HDRS). The control group consisted of ten age- and sex-matched subjects without any psychiatric disorder. Blood samples were collected at the baseline and after 12 weeks of antidepressant treatment (during remission). At the baseline the mean serum BDNF level was 17.9+/-9.1 ng/ml and the mean HDRS score was 23.2+/-4.6. Serum BDNF levels of the study group were significantly lower than in the control group (31.6+/-8.6 ng/ml). At the end of the study, the mean serum BDNF level was 34.6+/-7.1 ng/ml whereas the mean HDRS score was 8.2+/-3.9. From the baseline to the remission after 12 weeks of treatment, the increase in serum BDNF level and the decrease in HDRS score were statistically significant, respectively. When we compared the serum BDNF level of depressed patients at remission to that of the controls, there was no statistically significant difference. This study shows that venlafaxine treatment of depression improves serum BDNF level which may be considered as a nonspecific peripheral marker of depression.     

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.     

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.     

Therapeutic use of sleep deprivation in depression

Total sleep deprivation (TSD) for one whole night improves depressive symptoms in 40-60% of treatments. The degree of clinical change spans a continuum from complete remission to worsening (in 2-7%). Other side effects are sleepiness and (hypo-) mania. Sleep deprivation (SD) response shows up in the SD night or on the following day. Ten to 15% of patients respond after recovery sleep only. After recovery sleep 50-80% of day 1 responders suffer a complete or partial relapse; but improvement can last for weeks. Sleep seems to lead to relapse although this is not necessarily the case. Treatment effects may be stabilised by antidepressant drugs, lithium, shifting of sleep time or light therapy. The best predictor of a therapeutic effect is a large variability of mood. Current opinion is that partial sleep deprivation (PSD) in the second half of the night is equally effective as TSD. There are, however, indications that TSD is superior. Early PSD (i.e. sleeping between 3:00 and 6:00) has the same effect as late PSD given equal sleep duration. New data cast doubt on the time-honoured conviction that REM sleep deprivation is more effective than non-REM SD. Both may work by reducing total sleep time. SD is an unspecific therapy. The main indication is the depressive syndrome. Some studies show positive effects in Parkinson's disease. It is still unknown how sleep deprivation works.     

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.     

The effects of total sleep deprivation and subsequent treatment with clomipramine on depressive symptoms and sleep electroencephalography in patients with a major depressive disorder

In the present study patients with a major depressive disorder were first subjected to total sleep deprivation (TSD) and then treated with clomipramine. Sleep electroencephalography (EEG) was registered prior to and after TSD, during the 2 initial nights of antidepressive treatment and after 19 days. A negative correlation between response to TSD and clomipramine was found. TSD did not differentially influence the sleep EEG (responders vs nonresponders): responders tended, however, to show a more classical depressive sleep pattern prior to TSD. Clomipramine profoundly suppressed rapid eye movement (REM) sleep; the amount of initial REM sleep reduction, however, did not correlate significantly with therapy response after 3 weeks of treatment.     

Renin-angiotensin-aldosterone system, HPA-axis and sleep-EEG changes in unmedicated patients with depression after total sleep deprivation

BACKGROUND: Changes in the activity of the renin-angiontensin-aldosterone system (RAAS) in depression have recently been reported. Renin and aldosterone secretion are coupled to sleep in healthy subjects. As total sleep deprivation (TSD) leads to a rapid mood improvement in patients with depression, it is of interest to investigate its effect on the response of the RAAS in the recovery night in this population as a possible probe for the neurobiological effects of TSD and potentially other rapid acting antidepressive interventions. Additionally we explored the HPA-system and the sleep-EEG-changes. METHODS: We compared the sleep related activity of the RAAS before and after TSD in seven depressed patients. After an accommodation night, a polysomnographic examination was performed between 23.00 h and 7.00 h. This was followed by 40 h of TSD and a second polysomnography. During the examination blood samples were taken in the night every 20 min for analysis of renin, aldosterone, ACTH and cortisol. RESULTS: During recovery-sleep renin was significantly increased (p < 0.05). Aldosterone showed no change. ACTH and cortisol were decreased by trend in the first half of the night. REM-density and intermittent wakefulness was significantly decreased (p < 0.05), whereas slow wave sleep increased by trend in the first half of the night. CONCLUSION: TSD in patients with depression leads to an increase in renin secretion and a concomitant trend for a decrease in HPA axis activity in the recovery night. These changes could be a "fingerprint" of a rapidly antidepressive treatment.     

Acute effects of mirtazapine on sleep continuity and sleep architecture in depressed patients: a pilot study.

BACKGROUND: Mirtazapine, a clinically effective antidepressant, acts by antagonizing central alpha2-adrenergic and 5-HT2/5-HT3 receptors. No data are available regarding mirtazapine's effects on sleep architecture in patients with major depressive disorder. METHODS: Six patients meeting criteria for major depressive disorder and scoring > or =4 on the three Hamilton Depression Rating Scale sleep items were studied. Polysomnographic evaluations were performed at baseline and after 1 (15 mg at bedtime) and 2 weeks (30 mg at bedtime) of open-label mirtazapine treatment. RESULTS: Mirtazapine significantly decreased sleep latency and significantly increased total sleep time and sleep efficiency from baseline levels during week 1, with similar results observed after week 2. Mirtazapine did not significantly alter rapid eye movement sleep parameters. Clinically, Hamilton Depression Rating Scale and sleep disturbance ratings improved after treatment. CONCLUSIONS: Mirtazapine significantly improves sleep continuity in major depressive disorder patients with poor sleep quality at weeks 1 and 2 of treatment, while preserving sleep architecture.     

全部睡眠剥夺对健康男性青年情绪的影响

目的 探讨长时间睡眠剥夺（SD）对情绪的影响。方法 挑选身体健康男性青年志愿者30名,剥夺全部睡眠52h。采用情绪状态问卷、贝克焦虑问卷、考虑自评量表、状态焦虑问卷和自评抑郁量表,分别在SD前（基础值）、SD期间（1次／6h,共8次）及一夜恢复性睡眠后评定受试者的情绪状态。结果 与基础值比较,随SD时间的延长,疲惫－惰性、焦虑、抑郁、困惑-迷茫等消极情绪的因子分逐渐增加（P＜0．05－0．001）,并与SD时间呈正相关;而有力－好动积极情绪因子分逐渐下降（P＜0．001）,与SD时间呈负相关（r＝－0．846,P＜0．001）。一夜恢复性睡眠后,疲惫－惰性和有力－好动因子分与基础值的差异仍有显著性（P＜0．05－0．01）,余均恢复到基础水平。结论 长时间的SD可导致情绪逐渐恶化。;一夜的恢复性睡眠对情绪的改善有一定效果。     

Depression and insomnia: questions of cause and effect

Chronic insomnia is a risk factor for the development of psychiatric disorders, including depression, as well as a prodrome of major depressive episodes, a consequence or complication of depression that often persists beyond the clinical episode, and a prognostic indicator of long-term illness course and treatment response. In addition, sleep is physiologically abnormal in persons at risk for depression; for example, shortened REM sleep latency is present not only during clinical episodes of depression, but also before the clinical episode in subjects at risk for depressive illness. Although insomnia usually disappears as depression is treated, it may persist, indicating heightened vulnerability to depressive relapse or recurrence. Physiological changes in sleep related to depression correlate with the likelihood of response to psychotherapy alone and may also identify which patients are unlikely to do well with psychosocial treatment and, therefore, to need somatic therapy in order to preserve recovery. Electroencephalographic (EEG) sleep changes also correlate with the speed of response and with the brittleness or durability of response (i.eprobability of relapse or recurrence). These observations suggest a close relationship between the regulation of sleep and the regulation of mood. The importance of this relationship is further underscored by recent brain imaging studies of sleep and sleep deprivation in patients with major depression. For example, therapeutic sleep deprivation (TSD) may serve as both a catalyst of rapid antidepressant activity and as a probe of treatment resistance. TSD's effects on brain metabolic rates, especially in limbic areas, may correlate with a therapeutic response to a night of sleep loss and to antidepressant medication. Finally, treating chronic insomnia with newer selective serotonin reuptake inhibitor (SSRI) antidepressant medication may represent an opportunity for preventing complications of insomnia, including depressive illness.     

Reboxetine combination in treatment-resistant depression to selective serotonin reuptake inhibitors

INTRODUCTION: Treatment-resistant depression is a relatively common clinical occurrence: between 60-70% of depressive patients fail to achieve total remission to the initial treatment with selective serotonin reuptake inhibitors (SSRI). METHODS: In this prospective 12-week open-label study, we evaluated the effectiveness of the addition of reboxetine to 141 outpatients diagnosed with major depressive disorder, according to DSM-IV-TR criteria, who were partial responders or non-responders over a period of 6 weeks, to previous treatment in monotherapy with SSRI. Evaluation of antidepressant efficacy was carried out through the application of the Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impressions-Global Improvement Scale (CGI-I). Data were analyzed on an intent-to-treat basis, using the last-observation-carried-forward method. RESULTS: Mean score on the HDRS at baseline was 26.24+/-7.21, falling to 13.96+/-8.00 in week 12 (mean decrease of 46.79%; p<0.0001) The percentages of responders (HDRS total score > or =50%) and patients considered as benefiting from complete remission (HDRS score < or =10) at 12 weeks were 50.4% and 34.5%, respectively. By the end of the treatment, a mean decrease in CGI-I score of 1.88 points was obtained (41.14% of reduction; p<0.0001), and 77% of the patients were evaluated as improved (CGI-I score <4). Nervousness was the adverse effect most frequently reported (5.21%), followed by dryness of mouth (4.38%), and insomnia (3.56%). CONCLUSION: The results of this study suggest that the combination strategy with reboxetine appears to be a potentially useful tool in cases of SSRI-resistant depression.     

Preliminary evidence of riluzole efficacy in antidepressant-treated patients with residual depressive symptoms.

BACKGROUND: Excessive glutamatergic neurotransmission may contribute to the pathophysiology of major depressive disorder (MDD). Recent evidence suggests that riluzole and other agents that target glutamate neurotransmission may show antidepressant activity. METHODS: Ten patients with treatment-resistant depression had riluzole added to their ongoing medication regimen for 6 weeks, followed by an optional 6-week continuation phase. Depression and anxiety severity were assessed using the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). Linear mixed models were used to test for a linear trend in HDRS and HARS scores across time with treatment. RESULTS: Subjects' HDRS and HARS scores declined significantly following the initiation of riluzole augmentation therapy. The effect of riluzole was significant at the end of the first week of treatment and persisted for the 12-week duration of the study. CONCLUSIONS: These data suggest that riluzole augmentation produces antidepressant and anxiolytic effects in patients with treatment-resistant depression.     

Foreløbige erfaringer med lobotomia frontalis

Objective: To study the correlation of personality traits measured by the Temperament and Character Inventory (TCI) with the prognosis of major depressive disorder in patients treated with either fluoxetine or short-term psychodynamic psychotherapy in a randomized comparative study. Method: 35 patients with DSM IV-defined major depressive disorder of mild or moderate severity were randomized to receive either short-term psychodynamic psychotherapy or fluoxetine treatment for 16 weeks. Prior to beginning of the therapy, patients were assessed with TCI. The Hamilton Depression Rating Scale (HDRS) was used as the outcome measure completed at the baseline and follow-up at 4 months. Results: In the combined group (n=35), Harm Avoidance was associated with the severity of the depression measured by the HDRS at the baseline (P=0.01) and baseline Self-Directedness with the HDRS at 4 months follow-up (P=0.03). In the fluoxetine treatment group, Reward Dependence (P=0.03), Self-Directedness (P=0.01) and Cooperativeness (P=0.02) at the baseline associated with HDRS at 4 months follow-up. No statistically significant associations between personality traits and depression scores at the follow-up were found in the patients treated with psychotherapy. Conclusion: In this whole cohort of depressive patients, baseline high Self-Directedness predicted higher depression scores after 4 months of treatment. In the fluoxetine treatment group, subjects with high baseline Reward Dependence, Self-Directedness or Cooperativeness were likely more severely depressed at the 4 months follow-up. We suggest that associations between personality traits and remaining depressive symptoms after 4 months treatment with fluoxetine could be caused by the potential differences in the placebo effect.     

Antidepressant effects of selective slow wave sleep deprivation in major depression: a high-density EEG investigation

Sleep deprivation can acutely reverse depressive symptoms in some patients with major depression. Because abnormalities in slow wave sleep are one of the most consistent biological markers of depression, it is plausible that the antidepressant effects of sleep deprivation are due to the effects on slow wave homeostasis. This study tested the prediction that selectively reducing slow waves during sleep (slow wave deprivation; SWD), without disrupting total sleep time, will lead to an acute reduction in depressive symptomatology. As part of a multi-night, cross-over design study, participants with major depression (non-medicated; n = 17) underwent baseline, SWD, and recovery sleep sessions, and were recorded with high-density EEG (hdEEG). During SWD, acoustic stimuli were played to suppress subsequent slow waves, without waking up the participant. The effects of SWD on depressive symptoms were assessed with both self-rated and researcher-administered scales. Participants experienced a significant decrease in depressive symptoms according to both self-rated (p = .007) and researcher-administered (p = .010) scales, while vigilance was unaffected. The reduction in depressive symptoms correlated with the overnight dissipation of fronto-central slow wave activity (SWA) on baseline sleep, the rebound in right frontal all-night SWA on recovery sleep, and the amount of REM sleep on the SWD night. In addition to highlighting the benefits of hdEEG in detecting regional changes in brain activity, these findings suggest that SWD may help to better understand the pathophysiology of depression and may be a useful tool for the neuromodulatory reversal of depressive symptomatology.     

Worsening of delusional depression after sleep deprivation: case reports

Five patients (three bipolars and two unipolars) affected by a major depressive episode with psychotic features were treated with total sleep deprivation (TSD) without concurrent psychotropic medication. After TSD we observed a worsening in psychotic as well as in depressive symptoms as rated on the Dimension of Delusional Experience Rating Scale and on Hamilton Rating Scale for Depression, respectively. TSD is known to markedly enhance the activity of brain monoaminergic pathways. Given the interaction between brain serotonergic and dopaminergic systems in delusional depression, it is possible that an enhancement in dopaminergic activity may be responsible of the symptomatological worsening in delusional depressives observed after TSD.