Antidepressant response to partial sleep deprivation in unipolar depression is not related to state anxiety

One night of total or partial sleep deprivation (SD) produces a temporary remission in up to 60% of patients with major depression, yet mechanisms remain unclear. We investigated whether the antidepressant effects of SD are caused, even partially, by an improvement in anxiety. As part of a functional magnetic resonance imaging study, 19 unmedicated major depression patients and eight controls completed the Spielberger State/Trait Anxiety Inventory (STAI) (state version) at baseline and sleep-deprived scanning sessions. We found (1) greater anxiety in patients than controls; (2) no baseline or SD STAI difference between responders and nonresponders; (3) no STAI change with SD in any subject group; and (4) no significant correlation between any STAI and Hamilton Depression Rating Scale measures. Our findings did not provide support for an anxiolytic process associated with the antidepressant effects of SD.     

Dopamine receptor D4 is not associated with antidepressant activity of sleep deprivation

Total sleep deprivation (TSD) is an effective treatment for mood disorders which is thought to act through an enhancement in several neurotransmitter pathways including dopaminergic transmission. However, not all patients respond to TSD and genetic factors are likely to play a major role in determining TSD response. The aim of this study is to investigate the influence of dopamine receptor D4 exon 3 (DRD4) variants on TSD antidepressant efficacy in bipolar disorder. One hundred and twenty-four depressed inpatients affected by bipolar disorder (DSM-IV) were treated with repeated cycles of TSD and were typed for DRD4 variants at the third exon using polymerase chain reaction (PCR) techniques. DRD4 variants were not associated with TSD outcome. Consideration of possible stratification effects such as gender, age at onset and duration of illness did not reveal any association either. DRD4 exon 3 variants are not a main factor influencing TSD outcome in bipolar disorder.     

Dopamine receptor D2 and D3 gene variants are not associated with the antidepressant effect of total sleep deprivation in bipolar depression

Total sleep deprivation (TSD) is an effective treatment for mood disorders that is thought to act through an enhancement in several neurotransmitter pathways including dopaminergic transmission. Genetic factors are likely to play a major role in determining individual differences in TSD response. The aim of this study is to investigate the influence of dopamine receptor D3 (DRD3) and dopamine receptor D2 (DRD2) variants on TSD antidepressant efficacy in bipolar disorder. One hundred twenty-four depressed inpatients affected by bipolar disorder (DSM-IV) were treated with TSD and were genotyped for DRD3 first exon Gly/Ser variants and DRD2 codon 311 Ser/Cys variants using polymerase chain reaction techniques. DRD3 and DRD2 variants were not associated with TSD outcome. Consideration of possible stratification effects such as gender, age at onset and duration of illness did not reveal any association either. The tested gene variants are not a main factor influencing TSD outcome in bipolar disorder.     

Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression.

BACKGROUND: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. The aim of the present study was to measure striatal D(2) receptor availability and amphetamine-induced dopamine release in nonpsychotic, unmedicated, unipolar patients during an episode of major depression. METHODS: The striatal equilibrium specific to nonspecific partition coefficient (V(3)") of the D(2) receptor antagonist [(123)I]IBZM was measured with single photon emission computerized tomography before and after amphetamine administration in 9 depressed subjects and 10 matched healthy control subjects. RESULTS: No significant differences were observed in preamphetamine D(2) receptor availability between depressed patients (0.73 +/- 0.08) and control subjects (0.78 +/- 0.10, p =.23). Amphetamine-induced reduction in [(123)I]IBZM V(3)" (DeltaV(3)") was similar in depressed patients (-9.8 +/- 5.5%) and control subjects (-7.8 +/- 2.5%, p =.32). Amphetamine induced a transient improvement in symptomatology in depressed patients, but this improvement did not correlate with [(123)I]IBZM DeltaV(3)". CONCLUSIONS: This study did not replicate previously reported alterations in striatal D(2) receptor density in depressed patients and suggests that stimulant-induced dopamine release is not altered in major depression.     

RGS4 genotype is not associated with antipsychotic medication response in schizophrenia

Summary. The aims of the present study were to compare the allele frequencies of a common single nucleotide polymorphism located upstream of the regulator of G-protein signaling 4 (RGS4) gene (T > G, Rs 951436) in 219 Finnish patients with schizophrenia and in 389 control subjects, to analyze corresponding frequencies between two different subtypes of 93 schizophrenia patients according to their medication response, and to study the effect of this SNP on age at onset in schizophrenia. The RGS4 (T > G, Rs 951436) genotype was not associated with incidence or age at onset in schizophrenia. Neither was the RGS4 genotype associated with medication response with two different subpopulations with schizophrenia.     

Striatal dopamine D2/D3 receptor availability correlates with individual response characteristics to pain

We studied in healthy humans the contribution of cerebral dopamine D2/D3 receptors to individual differences in response characteristics to painful stimulation. Positron emission tomography was used to measure the dopamine D2/D3 binding potential (D2/D3 BP) with [(11)C]raclopride in the striatum (n = 8) and with [(11)C]FLB 457 in the extrastriatal regions (n = 11). Sensitivity to cutaneous heat pain was assessed by a traditional threshold method and by an analysis based on the signal detection theory which allows the separation of an individual subject's discriminative capacity from the response criterion, i.e. the area under the receiver operating characteristic curve provides a measure of the sensory discriminability (sensory factor) and the response criterion gives an estimate of the subject's response bias or attitude (nonsensory factor). The pain threshold and response criterion were inversely correlated with the D2/D3 BP in the right putamen, whereas the discriminative capacity was not significantly correlated with the D2/D3 BP in any brain region. The correlation of the D2/D3 BP in the putamen with the pain threshold and the subject's response criterion may rather be explained by a dopaminergic effect on nonsensory factors determining the subject's attitude towards pain than by a dopaminergic effect on the subject's discriminative capacity. Alternatively, striatal dopamine D2/D3 receptors could control a modulatory pathway producing a parallel shift in the stimulus-response function for sensory signals, mimicking a change in the subject's response criterion.     

Effect of sleep deprivation on dopamine receptor function in normal subjects

Summary Twenty-four hours sleep deprivation significantly decreased the growth hormone response to the dopamine receptor agonist, apomorphine HCl, in five normal men (0.5 mg s.c.) and one woman (0.75 mg s.c.) but had no effect on basal or post-apomorphine prolactin concentrations. These results suggest that sleep deprivation decreases the sensitivity of certain central dopamine receptors. The relevance of this finding to the antidepressant effect of sleep deprivation is unclear.     

Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression

Several pro-inflammatory cytokines have been implicated in depression and in antidepressant response. This exploratory analysis assessed: 1) the extent to which baseline cytokine levels predicted positive antidepressant response to ketamine; 2) whether ketamine responders experienced acute changes in cytokine levels not observed in non-responders; and 3) whether ketamine lowered levels of pro-inflammatory cytokines, analogous to the impact of other antidepressants. Data from double-blind, placebo-controlled studies of patients with major depressive disorder (MDD) or bipolar disorder (BD) who received a single infusion of sub-anesthetic dose ketamine were used (N = 80). Plasma levels of the eight cytokines were measured at baseline and at 230 min, 1 day, and 3 days post-ketamine. A significant positive correlation was observed between sTNFR1 and severity of depression at baseline. Cytokine changes did not correlate with changes in mood nor predict mood changes associated with ketamine administration. Ketamine significantly increased IL-6 levels and significantly decreased sTNFR1 levels. IL-6 and TNF-α levels were also significantly higher—and sTNFR1 levels were significantly lower—in BD compared to MDD subjects. The functional significance of this difference is unknown. Changes in cytokine levels post-ketamine were not related to antidepressant response, suggesting they are not a primary mechanism involved in ketamine's acute antidepressant effects. Taken together, the results suggest that further study of cytokine levels is warranted to assess their potential role as a surrogate outcome in the rapid antidepressant response paradigm.     

Temporal cortex dopamine D2/3 receptor binding in major depression

The aim of this study was to assess the dopamine function of the temporal cortex in major depressive disorder using [¹²³I]epidepride to image D_2/3 receptor binding sites. Ten major depressives and 10 healthy controls were selected from a general population sample for single-photon emission computed tomography imaging. Among the major depressives there was a strong bilateral correlation between the scores on the 21-item Hamilton Depression Rating Scale and D_2/3 receptor binding. Dopaminergic abnormalities may be present in the temporal cortices of major depressives.     

The C/C genotype of the C957T polymorphism of the dopamine D2 receptor is associated with schizophrenia

The T allele of the human dopamine D2 receptor (DRD2) gene C957T polymorphism is associated with reduced mRNA translation and stability. This results in decreased dopamine induced DRD2 upregulation and decreased in vivo D2 dopamine binding. Conversely, the C allele of the C957T polymorphism is not associated with such changes in mRNA leading to increased DRD2 expression. PET and postmortem binding studies show that schizophrenia is often associated with increased DRD2 availability. We report that on the basis of comparing the frequencies of the C/C and T/T genotypes of 153 patients with schizophrenia and 148 controls that schizophrenia is associated with the C/C genotype. The C957T shows a population attributable risk for schizophrenia of 24% and an attributable risk in those with schizophrenia of 42%. Increased expression of D2 receptors associated with the C allele is likely to be important in the underlying pathophysiology of at least some forms of schizophrenia. Enhanced understanding of schizophrenia afforded by this finding may lead to advances in treatment and prevention.     

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.     

Delta sleep ratio as a predictor of sleep deprivation response in major depression.

The fast but short-lasting improvement of depressive symptoms by sleep deprivation (SD) in about 60% of patients with a major depressive disorder is well established, but the mechanisms of action are still not clear. Recent studies suggest that changes in non rapid eye movement (NREM) sleep, especially in slow wave activity (SWA), could be associated with the therapeutic outcome of SD. In the current study, spectral analysis of NREM sleep EEG directly prior to SD was performed to determine if automatically derived sleep parameters predict SD response. Sixteen pair matched and drug free patients with a major depressive disorder, 8 SD responders and 8 non-responders (response criterion: 50% reduction on the 6-item HAMD score), were included. Average EEG spectral power was calculated for the whole night before SD and for single NREM episodes. While whole-night averages of spectral power did not differ significantly between subgroups, SD responders showed a steady decrease of SWA across successive NREM episodes, whereas in non-responders an increase from the first to the second episode was observed. The different distribution of SWA was significantly expressed in the delta sleep ratio (quotient of SWA in the first to the second NREM episode). In conclusion, a high delta sleep ratio is a positive predictor for SD response. Referred to psycho- and pharmacotherapeutic results it is hypothesized that low and high values of the delta sleep ratio characterize subgroups of depressed patients with different neurobiological alterations, which could be relevant for further scientific and therapeutic approaches.     

Blunted prolactin response to fentanyl in depression. Normalizing effect of partial sleep deprivation

There is some evidence that sleep deprivation (SD) might exert its antidepressant properties by involving endogenous opioid mechanisms. The authors investigated the effects of mu-receptor agonist administration on prolactin release in depressed patients before and after partial SD. Medication-free female depressed inpatients (N=18) were participating in two fentanyl challenge tests after partial SD and undisturbed sleep, 3 days apart in random order. Healthy volunteer women (N=10) were enrolled after full night sleep as comparison subjects. Five of them had placebo trials. Participants were given an intravenous injection of 0.1 mg/70 kg fentanyl at 9:00 AM. The prolactin secretory response to the opiate agonist was investigated for 1 h with serial blood sampling. After a night of undisturbed sleep, fentanyl administration prompted increases in plasma prolactin concentrations with blunted responses found in the depressed group. Following partial SD, the stimulated prolactin secretion of depressed patients increased significantly and was comparable to the response of comparison subjects. These findings suggest that SD acts via an opioid/dopamine-related mechanism. An alternative explanation, based on serotonin involvement is addressed in the discussion.     

Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers

Decreased dopaminergic function has been postulated to underlie cocaine addiction. To examine the possibility that dysfunction of brain regions subserved by the dopamine system could promote cocaine self-administration, positron emission tomography and a dual-tracer approach was used to examine dopamine D₂ receptor availability and regional brain glucose metabolism in cocaine abusers. When compared to normal controls, cocaine abusers showed significant decreases in dopamine D₂ receptor availability which persisted 3-4 months after detoxification. Decreases in dopamine D₂ receptor availability were associated with decreased metabolism in several regions of the frontal of these brain areas which are involved in the channeling of drive and affect could lead to loss of control resulting in compulsive drug-taking behavior. © 1993 Wiley-Liss, Inc.     

多巴胺D3受体基因多态性与精神分裂症初发期患者抗精神病药疗效关系的研究

目的　探讨多巴胺D3 受体 (DRD3)基因多态性与精神分裂症初发期患者精神症状严重度和抗精神病药疗效是否相关。方法　对 10 9例精神分裂症初发期患者分别进行利培酮治疗 [4 3例 ,3～ 5mg/d ,平均 ( 4 0± 0 5 )mg/d]和氯丙嗪治疗 [6 6例 ,15 0～ 6 0 0mg/d ,平均 ( 339± 87)mg/d],疗程 10周。采用聚合酶链反应 限制性片段长度多态性技术检测其中 10 8例患者 (男 5 2例 ,女 5 6例 )DRD3基因ser9gly多态性。采用阳性和阴性症状量表 (PANSS)评定患者治疗前和治疗第 10周末的精神症状 ,并分析基因型及其他临床指标与PANSS分值和减分率的关系。结果　DRD3ser9gly基因型在各患者组分布频率均符合Hardy Weinberg定律 (P >0 0 5 ) ;基因型在治疗显效和未显著进步组分布频率的差异有显著性 ( χ2 =6 4 4 ,ν=2 ,P <0 0 5 ) ;各基因型亚组临床指标的差异均无显著性 (均P >0 0 5 ) ;基因型与患者治疗前PANSS总分及治疗第 10周末PANSS总减分率、阳性症状减分率的差异均有显著性(均P <0 0 5 )。结论　DRD3基因ser9gly功能多态性可能是精神分裂症初发期患者精神症状严重程度和抗精神病药疗效 (尤其对阳性症状疗效 )的遗传影响因子。     

Cervical dystonia is associated with a polymorphism in the dopamine (D5) receptor gene

The objective was to assess whether polymorphisms in the dopamine receptor and transporter genes are associated with development of primary cervical dystonia. A case-control allelic association study is described of 100 patients with cervical dystonia and 100 controls using polymorphisms within D1-5 receptor and dopamine transporter genes. No significant association was found between patient and control allele frequencies for polymorphisms in genes for the D1 to 4 receptors and dopamine transporter. Significant associations, however, were found for alleles 2 and 6 of the D5 receptor microsatellite. Carriage of allele 2 was associated with cervical dystonia, whereas allele 6 was overrepresented in the control group, implying a possible protective effect. The association with allele 6 remained significant after Bonferroni correction. In conclusion, the finding of a significant association with an allele in the D5 receptor gene in patients with cervical dystonia may indicate a pathogenic role of this gene (or neighbouring genes). Further studies are required to confirm this finding and to assess whether these alleles are part of distinct haplotypes associated with other polymorphisms imparting a functional effect on the D5 receptor.     

Challenging the sleep homeostat: sleep in depression is not premature aging

ObjectivesThe close relationship between major depression and sleep disturbances led to the hypothesis of a deficiency in homeostatic sleep pressure in depression (S-deficiency hypothesis). Many observed changes of sleep characteristics in depression are also present in healthy aging, leading to the premise that sleep in depression resembles premature aging. In this study, we aimed at quantifying the homeostatic sleep–wake regulation in young women with major depression and healthy young and older controls under high sleep pressure conditions.MethodsAfter an 8-h baseline night nine depressed women, eight healthy young, and eight healthy older women underwent a 40-h sustained wakefulness protocol followed by a recovery night under constant routine conditions. Polysomnographic recordings were carried out continuously. Sleep parameters as well as the time course of EEG slow-wave activity (SWA) (EEG spectra range: 0.75–4.5 Hz), as a marker of homeostatic sleep pressure, were analyzed during the recovery night.ResultsYoung depressed women exhibited higher absolute mean SWA levels and a stronger response to sleep deprivation, particularly in frontal brain regions. In contrast, healthy older women exhibited not only attenuated SWA values compared to the other two groups, but also an absence of the frontal SWA predominance.ConclusionsHomeostatic sleep regulation and sleep architecture in young depressed women are not equal to premature aging. Moreover, our findings demonstrate that young moderately depressed women exhibit no deficiency in the sleep homeostatic process S as predicted by the S-deficiency hypothesis, but, rather, live on an elevated level of homeostatic sleep pressure.     

Wake-up stroke is not associated with obstructive sleep apnea

Objective/BackgroundObstructive sleep apnea is a risk factor for stroke. This study sought to assess the relationship between obstructive sleep apnea (OSA) and wake-up strokes (WUS), that is, stroke symptoms that are first noted upon awakening from sleep.Patients/methodsIn this analysis, 837 Brain Attack Surveillance in Corpus Christi (BASIC) project participants completed an interview to ascertain stroke onset during sleep (WUS) versus wakefulness (non-wake-up stroke, non-WUS). A subset of 316 participants underwent a home sleep apnea test (HSAT) shortly after ischemic stroke to assess for OSA. Regression models were used to test the association between OSA and WUS, stratified by sex.ResultsOf 837 participants who completed the interview, 251 (30%) reported WUS. Among participants who underwent an HSAT, there was no significant difference in OSA severity [respiratory event index (REI)] among participants with WUS [median REI 17, interquartile range (IQR) 10, 29] versus non-WUS (median REI 18, IQR 9, 30; p = 0.73). OSA severity was not associated with increased odds of WUS among men [unadjusted odds ratio (OR) 1.011, 95% confidence interval (95% CI) 0.995, 1.027] or women (unadjusted OR 0.987, 95% CI 0.959, 1.015). These results remained unchanged after adjustment for age, congestive heart failure, body mass index, and pre-stroke depression in men (adjusted OR 1.011, 95% CI 0.994, 1.028) and women (adjusted OR 0.988, 95% CI 0.959, 1.018).ConclusionsAlthough OSA is a risk factor for stroke, the onset of stroke during sleep is not associated with OSA in this large, population-based stroke cohort.