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Towards an Understanding of Sleep Problems in Childhood Depression: Comment on Robert JJT; Hoffmann RF; Emslie GJ et al. Sex and age differences in sleep macroarchitecture in childhood and adolescent depression
In school-aged children, adolescents, and adults, more than 72% of individuals diagnosed with major depression report co-occurring sleep problems, but little is known about sleep problems in the context of preschool-onset major depressive disorder (PO-MDD). The current study examined the prevalence of various sleep problems in a sample of young children diagnosed with PO-MDD and explored how the treatment of depression, using a modification of parent–child interaction therapy focused on emotional development (PCIT-ED), affects sleep problems. Participants included 229 preschoolers (ages 3–6 years) who met criteria for PO-MDD and participated a single-blind, randomized control trial comparing PCIT-ED to a waitlist control condition. Children were randomly assigned to either PCIT-ED (n = 114) or the waitlist condition (n = 115). Children were assessed at baseline, immediately after PCIT-ED, and 3 months after treatment completion for parent-reported sleep problems across the domains of insomnia, hypersomnia, daytime fatigue, and a total sleep problem index. In our sample, 45% of children had at least one subthreshold sleep problem, 38.4% had at least one threshold sleep problem, and 72.5% had at least one sleep problem (either threshold or subthreshold). Treatment with PCIT-ED significantly reduced sleep problems, including insomnia, daytime fatigue, and total sleep problems, compared to a waitlist condition, even when controlling for child depression. This reduction was maintained at a 3-month follow-up. Sleep problems are a prevalent co-occurring condition with PO-MDD. Interventions such as PCIT-ED that also effectively reduce sleep problems may be particularly beneficial for recovery from PO-MDD.
Clinical trial registration information: a randomized control trial of PCIT-ED for preschool depression; https://clinicaltrials.gov/NCT02076425.
Major depression is a chronic state of depressed mood with significant genetic predisposition. Although a lot of efforts has been tried to localize or associate the genes of major depression, etiological heterogeneity and complexity of this disorder has greatly hold back the use of traditional linkage strategies and candidate gene approaches. Recent advances in high throughput genotyping and microarray techniques have proffered opportunities for comprehensive investigation on genetic alterations and expressions on a scale not previously possible. It has become feasible to find genes with small effect size in major depression using genome-wide association scanning and to identify new pathways or mechanisms of psychopharmacology by the application of functional genomics. In the era of genomic approach to the pathophysiology of major depression, the authors suggest (1) reducing the heterogeneity of major depression by subgrouping the patients according to biological traits such as responses to antidepressant treatments, (2) searching for genes with small effect size using association scanning strategy, genomic control and DNA pooling techniques in genotyping, and (3) developing animal models with genetic vulnerability to major depression by ethylnitrosourea (ENU) mutagenesis technology and efficient behavioral screening tests.
In a prospective study of adolescent depression, adolescents (N = 1,508) were assessed at Time 1 and after 1 year (Time 2) on psychosocial variables hypothesized to be associated with depression. Most psychosocial variables were associated with current (n = 45) depression. Formerly depressed adolescents (n = 217) continued to differ from never depressed controls on many of the psychosocial variables. Many of the depression-related measures also acted as risk factors for future depression (n = 112), especially past depression, current other mental disorders, past suicide attempt, internalizing behavior problems, and physical symptoms. Young women were more likely to be, to become, and to have been depressed. Controlling for the psychosocial variables eliminated the gender difference for current and future but not for past depression.
Data from three samples of adults (Ns = 571, 472, and 989) and a sample of adolescents (N = 1,710) supported the possibility that the prevalence of major depression has been increasing in recent birth cohorts, a phenomenon labeled the age-cohort effect (ACE). A significant ACE for relapse was also found in 1 of the adult samples. In addition, early onset age in the adults (prior to age 25) tended to be associated with relapse. Adults in recent birth cohorts were also found to show an elevated prevalence of other disorders. We examined the power of 4 variables (current mood state, social desirability response bias, labeling, and time interval between the episode and the diagnostic interview) to produce these results without an actual increase in the rate of mental disorder. With 1 exception (labeling), the variables were significantly associated with reports of past episodes of disorder and with birth cohort. Controlling for their influence, however, did not reduce the ACE.
This study examined measures of functional impairment and family relations in a sample of 62 adolescents with major depressive disorder (MDD) and 38 normal controls with no history of psychiatric illness.
Ratings of the following domains were obtained: mother-child relations, father-child relations, spousal relations, sibling relations, peer relations, and school performance. Ratings of each domain for the 3-month period preceding the assessment were derived from information obtained using a semistructured interview administered independently to the adolescents and one of their parents.
Adolescents with MDD were found to have severe difficulties in all areas. Ninety percent of the depressed adolescents had scores greater than 2 SD above the mean of the normal controls on one or more of the domain ratings. In addition, adolescents with difficulties in parent-child relations were more likely than those adolescents without problems in family relations to have difficulties in peer relations and school performance.
The authors discuss the importance of systematically examining psychosocial variables in future studies of the etiology, course, and treatment of MDD in adolescents.
Major depressive disorder (MDD) that arises in adolescence impairs functioning and is associated with suicide risk, but little is known about its continuity into adulthood.
To describe the clinical course of adolescent-onset MDD into adulthood.
Prospective case-control study. Seventy-three subjects had onset of MDD based on systematic clinical assessment during adolescence (Tanner stage III-V) and 37 controls had no evidence of past or current psychiatric disorders, and also were assessed in adolescence (assessment years: 1977-1985). Follow-up was conducted 10 to 15 years after the initial assessment by an independent team without knowledge of initial diagnosis (follow-up years: 1992-1996).
Cases were identified at Columbia Presbyterian Hospital, New York City, NY; controls were recruited from the community.
Suicide and suicide attempts, psychiatric diagnoses, treatment utilization, and social functioning.
Clinical outcomes of adolescent-onset MDD into adulthood compared with control subjects without psychiatric illness include a high rate of suicide (7.7%); a 5-fold increased risk for first suicide attempt; a 2-fold increased risk of MDD, but not other psychiatric disorders; an increased occurrence of psychiatric and medical hospitalization; and impaired functioning in work, social, and family life. Thirty-seven percent of those with adolescent MDD survived without an episode of MDD in adulthood vs 69% of the control participants (relative risk, 2.2 [95% confidence interval, 1.0-4.7; P<.05]).
There is substantial continuity, specificity, morbidity, and potential mortality from suicide into adulthood in adolescent-onset MDD patients. Now that empirically based guides to their treatment are becoming available, early identification and treatment seems warranted.
Tianeptine enhances while paroxetine inhibits serotonin reuptake into neurons; however, both show an antidepressive action. A subgroup of 38 depressed patients from a drug trial comparing the efficacy of tianeptine with that of paroxetine was studied with regard to their effects on sleep regulation, especially in relation to treatment response. We recorded sleep EEGs at day 7 and day 42 after the start of treatment with either compound, which allows measurement of changes due to the antidepressive medication in relation to the duration of treatment. Spectral analysis of the non-REM sleep EEG revealed a strong decline in the higher sigma frequency range (14-16 Hz) in male treatment responders independent of medication, whereas nonresponders did not show marked changes in this frequency range independent of gender. The patients receiving paroxetine showed less REM sleep and more intermittent wakefulness compared to the patients receiving tianeptine. REM density after 1 week of treatment was a predictor of treatment response in the whole sample. Psychopathological features with regard to the score in single items of the HAMD revealed predictive markers for response, some of which were opposite in the gender groups, especially those related to somatic anxiety. Changes in REM density were inversely correlated to the changes in HAMD in the paroxetine, but not the tianeptine, group. Our data suggest the importance of taking gender into account in the study of the biological effects of drugs. The study further points to the importance of the higher sigma frequency range in the sleep EEG of non-REM sleep and REM density as a marker of treatment response.
Using prospective data, the authors assessed the risk of alcohol-related problems among individuals with self-reported sleep disturbances because of worry.
As part of the Epidemiologic Catchment Area program, a probability sample of Baltimore residents selected by census tracts and households completed a baseline interview in 1981. Between 1993 and 1996, the original Baltimore cohort was traced. Of the 2,633 survivors, a total of 73% were reinterviewed. After excluding individuals with alcohol-related problems or a current or prior history of alcohol abuse and/or dependence at the time of the 1981 interview, the authors identified a cohort of 1,537 individuals who were at risk for problem drinking at the time of the follow-up interview, a median of 12.6 years after the baseline interview. Logistic regression was used to assess the association between sleep disturbance because of worry and the risk for incident reports of alcohol problems.
Survey respondents with sleep disturbances because of worry at the time of the baseline interview had a twofold higher risk for developing an alcohol-related problem, relative to those without these sleep disturbances (odds ratio=2.32, 95% confidence interval [CI]=1.31-4.09), with adjustment for selected demographic and clinical variables. Sleep disturbance because of worry predicted the development of alcohol problems among respondents with lifetime anxiety disorders and lifetime dysphoria (odds ratio=3.82, 95% CI=1.56-9.38, and odds ratio=2.71, 95% CI=1.25-5.91, respectively), but not among those without a history of anxiety disorders or dysphoria.
Sleep disturbances because of worry may increase risk for alcohol-related problems. Risk is highest for those with sleep disturbance and co-occurring anxiety disorders or dysphoria.
The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with 'early-onset' (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case-control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.
The steep decline in slow-wave (delta) electroencephalogram (EEG) intensity across adolescence is a prominent feature of late brain maturation. As a first step in determining whether the adolescent delta decline is similar in both sexes, we compared cross-sectional sleep EEG data from 9- and 12-year-old boys and girls.
All-night EEG recordings, 6 months apart, were conducted on each subject.
EEG was recorded in the subjects' homes.
Thirty-two 9-year-olds and 38 12-year-olds are enrolled in a 4-year longitudinal study of adolescent sleep. There are equal numbers of each sex in both age cohorts.
N/A.
Using ambulatory recorders, EEG was recorded in the subjects' homes on their normal sleep schedule. For each of the 2 semi-annual recording periods, data from the 10 subjects from each age-sex group with the cleanest (fewest artifacts) signals were selected for crosssectional comparisons of visual scoring and EEG variables. All artifact-free 20-second non-rapid eye movement epochs were analyzed with power spectral and period-amplitude analysis.
In the 12-year-old cohort, delta power per minute was 37% higher in boys than girls. The 9-year-old cohort showed no sex difference. A second recording 6 months later produced similar results.
These cross-sectional data indicate that girls begin the steep adolescent decline in slow-wave EEG earlier than boys. We hypothesize that this reflects an earlier onset of adolescent synaptic pruning in females.
Variation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders. The majority of these studies have focused on the functional Val108/158Met polymorphism and yielded conflicting results, with limited studies examining the relationship between other polymorphisms, or haplotypes, and psychiatric illness. We hypothesized that COMT variation may confer a general risk for psychiatric disorders and have genotyped four COMT variants (Val158Met, rs737865, rs165599, and a SNP in the P2 promoter [-278A/G; rs2097603]) in 394 Caucasian cases and 467 controls. Cases included patients with schizophrenia (n = 196), schizoaffective disorder (n = 62), bipolar disorder (n = 82), major depression (n = 30), and patients diagnosed with either psychotic disorder NOS or depressive disorder NOS (n = 24).
SNP rs2097603, the Val/Met variant and SNP rs165599 were significantly associated (p = 0.004; p = 0.05; p = 0.035) with a broad "all affected" diagnosis. Haplotype analysis revealed a potentially protective G-A-A-A haplotype haplotype (-278A/G; rs737865; Val108/158Met; rs165599), which was significantly underrepresented in this group (p = 0.0033) and contained the opposite alleles of the risk haplotype previously described by Shifman et al. Analysis of diagnostic subgroups within the "all affecteds group" showed an association of COMT in patients with psychotic disorders as well as in cases with affective illness although the associated variants differed. The protective haplotype remained significantly underrepresented in most of these subgroups.
Our results support the view that COMT variation provides a weak general predisposition to neuropsychiatric disease including psychotic and affective disorders.
Wakefulness, NREM sleep, and REM sleep are three distinct states of existence. Each state has characteristic behavioral and physiologic patterns,and each has specific neurophysiologic mechanisms associated with its generation and control. Structures in the brainstem use various neurotransmitters to influence higher brain structures in the midbrain and cortex. The ARAS provides cholinergic, noradrenergic, and glutaminergic stimulation to the thalamus, hypothalamus, and basal forebrain resulting in cholinergic and glutaminergic excitation of the cortex. An active cortex that exhibits a characteristic pattern of desynchronized EEG manifests wakefulness. Various factors affect the need and timing of sleep onset. These factors influence the nucleus tractus solitarius, causing its noradrenergic projections to midbrain and forebrain structures to inhibit activity in the ARAS, resulting inactivation of inhibitory GABAergic thalamocortical projections to the cor-tex. During a state of decreased activation, the cortex exhibits a pattern of synchronized EEG. Transition between NREM sleep and REM sleep is controlled by noradrenergic neurons in the loci coeruleus and serotoninergic neurons in the raphe called REM-off cells and cholinergic neurons in the nucleus reticularis pontis oralis called REM-on cells. Other brain structures are involved in generation and control of REM sleep-related phenomena, such as eye movement and muscle atonia. During wakefulness, there is increased sympathetic tone and decreased parasympathetic tone that maintains most organ systems in a state of action or readiness. During NREM sleep, there is decreased sympathetic tone and increased parasympathetic activity that creates a state of reduced activity. REM sleep is characterized by increased parasympathetic activity and variable sympathetic activity associated with increased activation of certain brain functions. The states of wakefulness and sleep are characterized as stages that are defined by stereotypical EEG, EMG, and EOG patterns. Wakefulness stage has an EEG pattern predominated by the alpha rhythm. With onset of stage 1 sleep, the alpha rhythm attenuates, and an EEG pattern of relatively low voltage and mixed frequency is seen. Progression to stage 2 sleep is defined by the appearance of sleep spindles or K-complexes. Further progression into the deepest sleep stages 3 and 4 is defined by the occurrence of high-amplitude, low-frequency EEG activity. The progression of sleep stages occurs in cycles of 60 to 120 minutes throughout the sleep period. Various circadian environmental and ontologic factors affect the pattern of sleep stage occurrence.
Gene variants exert a complex range of effects on human normal and abnormal behavior. We previously reported the effect of gene variants in serotoninergic and dopaminergic pathways, in a range of clinical features in mood disorders, such as symptomathology, periodicity, social adjustment and treatment response. In this paper we hypothesized that the same gene variants could influence temperamental traits in mood disorders patients. We focused on genes of the serotoninergic and dopaminergic systems (dopamine receptor D4 gene, DRD4; serotonin transporter gene, promoter region SERTPR; tryptophan hydroxylase gene, TPH; monoamine oxidase A gene, MAO-A). Two hundred and seven euthymic subjects, affected by major depressive disorder (n=73) and bipolar disorder (n=134) were assessed by the Cloninger's Temperament and Character Inventory (TCI) and typed using PCR-based analyses. Possible stratification factors such as demographic, clinical and other temperamental factors were also taken into account. We observed that homozygosity for the short SERTPR allele was associated with low novelty-seeking scores (p=0.006) and genotypes containing the DRD4 long allele were marginally associated with low harm avoidance (p=0.05). Finally, the long MAO-A allele was associated with decreased persistence scores among females (p=0.006). Our observation of a pattern of influence on temperamental dimension exerted by serotonergic and dopaminergic genes suggests that the contribution of these polymorphisms to the clinical presentation of mood disorders could be mediated by an influence on personality differences.
The cyclic AMP-response element binding protein (CREB) is an activity-dependent transcription factor important for synaptic plasticity and memory storage. Levels of phosphorylated CREB within the cortex are higher in waking than in sleep, suggesting that CREB plays a role in sleep/wake regulation in mammals. We tested the hypothesis that CREB is critical for sleep/wake regulation by examining behavioral state parameters in mice lacking the alpha and Delta isoforms of CREB. Over 24 h, time spent awake was significantly decreased in CREB alphaDelta mutant mice by approximately 100 min, and time spent in nonrapid eye movement sleep (NREM) sleep was increased correspondingly. Wake and REM sleep periods were shorter in CREB alphaDelta mice, and CREB alphaDelta mice had decreased levels of -activity during wake and REM sleep, consistent with an impairment in the ability to maintain an activated electroencephalogram. These results suggest that the CREB protein contributes to the mechanisms by which wakefulness is maintained and demonstrate that specific genetic alterations in species as diverse as Drosophila and mice produce similar phenotypes in arousal and wakefulness.
The catechol-O-methyltransferase (COMT) gene plays a prominent role in dopaminergic circuits central to drug reward. Allelic variants within the COMT gene are therefore potential candidates for examining interindividual differences in vulnerability to nicotine dependence (ND). We analyzed five single nucleotide polymorphisms (SNPs), including the Val/Met variant (rs4680), which results in a three- to four-fold difference in enzyme activity within COMT, for association with the three ND measures, SQ, HSI, and FTND, in 602 nuclear families of African-American (AA) or European-American (EA) origin. The Val/Met variant showed a significant association with the three ND measures in the pooled and EA samples and with FTND in the AA sample. Haplotype analysis revealed a major protective A-G-T haplotype (frequency 23.6%) for rs740603-rs4680-rs174699 in the AA sample (minimum Z=-3.35; P=0.0005 for FTND), a major protective T-G-T haplotype (frequency 15.2%; minimum Z=-2.92; P=0.003 for FTND) in the EA sample, and a high-risk C-A-T haplotype (frequency 16.9%; minimum Z=3.16; P=0.002 for SQ) in the AA sample for rs933271-rs4680-rs174699. Furthermore, we found that the significant haplotypes within COMT were gender-specific and the significantly associated A-G-T is protective in AA females only, whereas T-G-T is protective in EA males only. Moreover, we found a major high-risk T-A-T haplotype (frequency 56.7%) that showed significant association with the three ND measures in EA males. Further examination of two protective haplotypes, A-G-T in AAs and T-G-T in EAs, indicated that the low COMT enzyme activity Met allele is protective to become nicotine dependent. In summary, our results provide evidence for a role of COMT in the susceptibility to ND and further confirm that its effect is ethnic and gender specific.
The pathophysiology of depression remains enigmatic, although abnormalities in serotonin signaling have been implicated. We
have found that the serotonin 1B receptor [5-hydroxytryptamine (5-HT1B) receptor] interacts with p11. p11 increases localization of 5-HT1B receptors at the cell surface. p11 is increased in rodent brains by antidepressants or electroconvulsive therapy, but decreased
in an animal model of depression and in brain tissue from depressed patients. Overexpression of p11 increases 5-HT1B receptor function in cells and recapitulates certain behaviors seen after antidepressant treatment in mice. p11 knockout
mice exhibit a depression-like phenotype and have reduced responsiveness to 5-HT1B receptor agonists and reduced behavioral reactions to an antidepressant.
Several classes of antidepressant drug exist, divided into three broad families, the monoamine reuptake inhibitors, the monoamine oxidase inhibitors and the monoamine receptor antagonists. All these drugs have a common pharmacological effect, to raise the synaptic concentrations of noradrenaline and serotonin. Although different drugs have different relative selectivity for noradrenaline and serotonin systems, these two neurotransmitter pathways work in parallel and in a coherent manner to produce the same final antidepressant response. The lag-time in the onset of action of antidepressants can be explained by the activation of inhibitory autoreceptors on serotonergic and noradrenergic neurones which initially attenuate the effects of antidepressants on synaptic transmitter levels. Over time, these autoreceptors desensitize, allowing the emergence of an overt antidepressant response. This theory has led to the proposition that antagonists at these autoreceptors such as pindolol may be useful adjuncts to antidepressant treatment, in order to hasten the appearance of a clinical response. Evidence for the clinical validity of this idea remains equivocal, however. The use of central monoamine depletion studies has demonstrated that it is elevated synaptic monoamine levels themselves, rather than some downstream postsynaptic changes in, for example, receptor sensitivity, that are responsible for the therapeutic effect of antidepressant drugs. Taken together, the data collected over the last 40 years have allowed the emergence of a unified monoamine hypothesis of antidepressant drug action. Int Clin Psychopharmacol 17 (suppl 1):S1-S12 (C) 2002 Lippincott Williams Wilkins.
The chance discoveries of the first two classes of antidepressant agent, MAOIs and TCAs, both of which act by increasing synaptic concentrations of NA and 5-HT, formed the basis of what became known as the amine theory of depression. Research was then directed towards finding more selective compounds acting at only one monoamine, serotonin. However, it is now being questioned as to whether these selective agents are as effective at treating significant depressive episodes as the drugs with multiple actions. Studies involving depletion of 5-HT or NA have shown that antidepressants which are selective for 5-HT or NA act by parallel independent mechanisms. This suggests that antidepressants which promote both neurotransmitters would possibly have a larger efficacy profile. This idea has found support in the results of Danish studies which compared two SSRIs with clomipramine in two separate studies. Both showed the dual action antidepressant, clomipramine, to give significantly better outcomes in depressed patients. Various new tools are now making it possible to explore the role of the monoamines in more detail. In vivo microdialysis recordings in rats indicate that some selective serotonergic agents do indirectly affect NA levels, suggesting the importance of a dual action, even from 'selective' compounds. Two radio-ligands which selectively label 5-HT re-uptake sites and NA re-uptake sites, respectively, are now being used as tools to locate and quantify the antidepressant re-uptake sites and will allow confirmation of the role of drugs acting on both 5-HT and NA.
The confluence of sleep/wake cycle and circadian rhythm changes that accompany pubertal development and the social and emotional developmental tasks of adolescence may create a period of substantial risk for development of insomnia. Although poor sleep affects cognitive performance and is associated with poor emotional and physical health, epidemiologic studies among adolescents have been limited. In this first epidemiologic study of insomnia defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria in a US sample of adolescents, we estimated lifetime prevalence of insomnia, examined chronicity and onset, and explored the role of pubertal development.
Data come from a random sample of 1014 adolescents who were 13 to 16 years of age, selected from households in a 400000-member health maintenance organization encompassing metropolitan Detroit. Response rate was 71.2%. The main outcome measured was DSM-IV-defined insomnia.
Lifetime prevalence of insomnia was 10.7%. A total of 88% of adolescents with a history of insomnia reported current insomnia. The median age of onset of insomnia was 11. Of those with insomnia, 52.8% had a comorbid psychiatric disorder. In exploratory analyses of insomnia and pubertal development, onset of menses was associated with a 2.75-fold increased risk for insomnia. There was no difference in risk for insomnia among girls before menses onset relative to boys, but a difference emerged after menses onset. In contrast, maturational development was not associated with insomnia in boys.
Insomnia seems to be common and chronic among adolescents. The often found gender difference in risk for insomnia seems to emerge in association with onset of menses.
There are several reported associations between depressive disorders, panic disorder, and obsessive–compulsive disorder (OCD) and a variety of polymorphisms in the monoamine oxidase A (MAOA) gene. Associations have also been reported between the catechol-O-methyltransferase (COMT) gene and both OCD and bipolar depression. However, the role of these markers has not been explored for the personality trait of neuroticism (N), a normally distributed quantitative trait, which is highly genetically correlated with anxiety and depression and may be a vulnerability to either type of disorder. We explored the possible role of MAOA, COMT, and their interaction on N using a selected extremes design. From a sample of 2,085 individuals, each assessed for N by two independent peers rather than using self-report questionnaires, we selected 57 individuals from the top 10% of scores, and 62 individuals from the bottom 10%. Using selected extreme low subjects as the controls, rather than an unselected control group gives roughly twice the power of a standard case-control design. We typed a functional variable number tandem repeat (VNTR) in the MAOA gene promoter, and a functional polymorphism in the coding region of the COMT gene. Two novel alleles in the MAOA VNTR were identified on the basis of their size, and their structure examined by sequencing analysis. We found weak evidence for association with COMT genotype, when the females and males were considered separately, and for MAOA genotype in males only. There was no significant interaction between COMT and MAOA. © 2003 Wiley-Liss, Inc.
Various polymorphisms of the X-chromosomal monoamine oxidase A (MAO-A) gene were investigated for association with affective disorders. However, none of the studied variants could consistently be associated with either major depressive or bipolar affective disorder. Recently, a positive association between panic disorder and a novel functional repeat polymorphism in the MAO-A gene promoter, with the longer alleles being more active, was reported. Since monoaminergic neurotransmission is supposed to play an important role in affective disorders, we investigated a potential association of this polymorphism with major depressive illness in a sample of 146 unrelated patients of German descent and a control group of 101 individuals with a negative life history for affective disorders. Similarly to the recent findings in panic disorder, we observed a significantly increased frequency of genotypes containing only long alleles in female patients with recurrent major depression in comparison with age- and sex-matched controls. Thus, our data suggest that an excess of high-activity MAO-A gene promoter alleles resulting in an elevated MAO-A activity is a risk factor for major depressive disorder in females. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:801–803, 2000. © 2000 Wiley-Liss, Inc.
A previously published model-free linkage analysis of chromosome 2q33-35, highlighted by previous case-control studies and supported by within-family analyses employing the transmission disequilibrium test, revealed evidence of sex-specific linkage of the CREB1-containing region of 2q to unipolar mood disorders among women in 81 recurrent, early-onset, major depressive disorder (RE-MDD) families. Since it has been reported that the LODPAL program from S.A.G.E. v.4.0 used to conduct this previous linkage analysis suffers from an increased type I error rate that is exacerbated by covariates such as sex, we re-analyzed the evidence for this sex-specific linkage result using a simulation approach to estimate the empirical significance of our previous results. The results continue to support sex-specific linkage of the CREB1 region to mood disorders among women from families with RE-MDD. Moreover, these results have been supported by a host of additional published findings that implicate sequence variations in CREB1 in the sex-dependent development of syndromic mood disorders, as well as related clinical features and disorders.
Symptom frequency and severity were compared in two sequential clinically referred samples of 95 children and 92 adolescents, aged 6 to 18 years, all medically healthy, assessed with the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present Episode, who met unmodified Research Diagnostic Criteria for major depressive disorder (MDD). There were no significant differences between the two groups in the majority of depressive symptoms. However, prepubertal children had greater depressed appearance, somatic complaints, psychomotor agitation, separation anxiety, phobias, and hallucinations, whereas adolescents had greater anhedonia, hopelessness, hypersomnia, weight change, use of alcohol and illicit drugs, and lethality of suicide attempt, but not severity of suicidal ideation or intent. Adolescents with a duration of the depressive episode of two years or greater had significantly higher rates of suicidal ideation and intent, lethality, and number of suicide attempts than youngsters with depressive episodes of shorter duration. A principal components factor analysis of psychiatric symptoms was carried out in all 296 youngsters evaluated during the same period who met DSM-III criteria for any Axis I diagnosis. The majority had an affective disorder. Factors were quite similar for both adolescents and children and included an "endogenous" and an "anxious" factor, as in many studies of adult depression. In addition, three other factors were found: negative cognitions, appetite and weight changes, and a conduct factor. Suicidal ideation was a component of both the negative cognitions factor and the conduct factor.(ABSTRACT TRUNCATED AT 250 WORDS)
This paper presents retrospective and prospective data regarding time course parameters of major depressive disorder (MDD) in community adolescents (14 to 18 years old): time to onset and recovery and, among those who recovered, time to recurrence.
Diagnostic interviews were conducted with 1,508 randomly selected high school students. Three hundred sixty-two had experienced at least one past or current episode of MDD.
Mean age at onset of first episode was 14.9 (SD = 2.8). Early MDD onset was associated with female gender and suicidal ideation. MDD episode duration ranged from 2 to 520 weeks, with a mean of 26.4 weeks (SE = 3.3) and a median of 8.0 weeks. Longer episodes were observed in those whose depression occurred early (at or before age 15), whose depression had been accompanied by suicidal ideation, and for whom treatment was sought. Of the adolescents who recovered, 5% relapsed within 6 months, 12% within 1 year, and approximately 33% within 4 years. Shorter time to recurrence was associated with prior suicidal ideation and attempt and with later first onset.
Risk of MDD is low in childhood, increasing substantially with adolescence. The majority of episodes in community adolescents are relatively brief, although the risk of recurrence is substantial. Suicidal behaviors are important mediators of episode duration and of recurrence.
It is known from animal experiments that the regulation of REM and Non-REM sleep is governed by cholinergic and serotonergic/adrenergic neurons in the brain stem. Cholinergic neurons in the gigantocellular field of the tegmentum seem to be responsible for the triggering and maintenance of REM sleep. These findings are of special interest for interpreting abnormalities of REM sleep in depression. Psychiatric sleep research in the last two decades has demonstrated that an early onset of REM sleep and heightened REM density frequently occurs in patients suffering from depression. Extrapolating from animal data on REM sleep regulation, the premature onset of REM sleep in depression may be interpreted as the consequence of a central nervous cholinergic overactivity or muscarinic supersensitivity. In our experimental work we have tested assumptions of the so-called reciprocal interaction model of NonREM and REM sleep by cholinergic/anticholinergic stimulation strategies of sleep in healthy subjects. Furthermore, the impact of cholinergic stimulation on sleep in depression, healthy control subjects and other psychopathological conditions was investigated. These studies demonstrated that the most pronounced REM sleep response to cholinergic stimulation occurred in depression.
The enzyme which has come to be known as monoamine oxidase was discovered in liver over 60 years ago as tyramine oxidase (Hare, 1928). Almost 10 years later, Blaschko et al. (1957a,b) established that epinephrine, norepinephrine and dopamine were also substrates for this enzyme. Zeller (1938) distinguished monoamine oxidase as different from several other amine oxidases, such as diamine oxidase. Although it was generally assumed that catecholamines were metabolized by MAO, this was not established until isotopically labelled epinephrine and an MAO inhibitor became available. Schayer (1951) found that after administration of N-methyl-14C-epinephrine, only about 50% of the radioactivity appeared in the urine, whereas when the 14C label was incorporated into the β-position on the side chain, almost all of the radioactivity could be recovered. One year later, Zeller et al. (1952) discovered that isonicotinic acid hydrazide (iproniazid) inhibited MAO. When animals pretreated with the MAO inhibitor were administered N-methyl-14C-epinephrine, almost all of the radioactivity was recovered (Schayer et al., 1955), indicating that the enzyme was responsible for the metabolism of about half of the administered catecholamine. Schayer et al. (1952, 1953) had found that five urinary metabolite products of β-labelled-14C-norepinephrine could be separated by paper chromatography, but the chemical structures of these compounds were not known.
Armstrong et al. (1957) showed that 3-methoxy-4-hydroxymandelic acid (vanillyl mandelic acid, VMA) was the major metabolite of norepinephrine and Shaw et al. (1957) demonstrated that large amounts of homovanillic acid (HVA) were excreted in urine after administration of 3,4-dihydroxy-phenylalanine (DOPA). These observations led Axelrod to examine the possibility that O-methylation might precede deamination and to his discovery of catechol-O-methyl transferase (Axelrod, 1957, 1959). At that time it became apparent that there were two possible routes for metabolism of norepinephrine to VMA — either deamination followed by O-methylation or O-methylation and subsequent deamination. The relative roles of these two pathways in terminating the physiological actions of catecholamines then became a focus of attention. Biochemical methods were used to access directly the relative importance of the two metabolic pathways. Physiological methods, based on the effects of drugs which alter metabolism of the catecholamine, were used to examine the role of MAO and COMT in terminating the actions of administered or endogenously released catecholamines.
Sleep measures were obtained in 16 depressed and 21 control adolescents following 1 week of adherence to a uniformly imposed and strictly enforced sleep/wake schedule. Three nights of baseline electroencephalographic (EEG) sleep on the same 10:00 PM to 7:00 AM schedule revealed prolonged sleep latency and reduced rapid eye movement (REM) latency in the depressed adolescents. Following baseline measures, sleep was restricted for 2 nights (10:00 PM-4:00 AM) and measures of recovery sleep were obtained showing further sleep latency differences. There was no evidence for delta sleep changes or sleep continuity differences in depressed adolescents. These results suggest that control over sleep/wake schedules is an important methodological issue in adolescent sleep studies. Furthermore, the findings are consistent with a larger body of evidence indicating that dysregulation near sleep onset represents a primary psychobiological change in early-onset depression.
To qualitatively review the literature of the past decade covering the epidemiology, clinical characteristics, natural course, biology, and other correlates of early-onset major depressive disorder (MDD) and dysthymic disorder (DD).
A computerized search for articles published during the past 10 years was made and selected studies are presented.
Early-onset MDD and DD are frequent, recurrent, and familial disorders that tend to continue into adulthood, and they are frequently accompanied by other psychiatric disorders. These disorders are usually associated with poor psychosocial and academic outcome and increased risk for substance abuse, bipolar disorder, and suicide. In addition, DD increases the risk for MDD. There is a secular increase in the prevalence of MDD, and it appears that MDD is occurring at an earlier age in successive cohorts. Several genetic, familial, demographic, psychosocial, cognitive, and biological correlates of onset and course of early-onset depression have been identified. Few studies, however, have examined the combined effects of these correlates.
Considerable advances have been made in our knowledge of early-onset depression. Nevertheless, further research is needed in understanding the pathogenesis of childhood mood disorders. Toward this end, studies aimed at elucidating mechanisms and interrelationships among the different domains of risk factors are needed.
In this article we summarize our current understanding of depression in older (14-18 years old) adolescents based on our program of research (the Oregon Adolescent Depression Project). Specifically, we address the following factors regarding adolescent depression: (a) phenomenology (e.g., occurrence of specific symptoms, gender and age effects, community versus clinic samples); (b) epidemiology (e.g., prevalence, incidence, duration, onset age); (c) comorbidity with other mental and physical disorders; (d) psychosocial characteristics associated with being, becoming, and having been depressed; (e) recommended methods of assessment and screening; and (f) the efficacy of a treatment intervention developed for adolescent depression, the Adolescent Coping With Depression course. We conclude by providing a set of summary statements and recommendations for clinicians.
The present article reviews direct and indirect evidence of the effects of sex steroids on different aspects of sleep. It begins with a review of what is known about the effects of steroid hormones on sleep and on central nervous system processes related to sleep, such as the GABA-ergic system, in animals. It continues with a review of the effects of exogenous hormones on human sleep and a review of studies comparing sleep during hypogonadal states secondary to surgical or natural menopause. The article proceeds to review the data on the effects of the menstrual cycle on both subjective and objective aspects of sleep and circadian temperature and melatonin rhythms in samples of healthy women, women with premenstrual dysphoric disorder, and women with primary insomnia. Then, the article reviews gender differences in sleep during depression and raises the possibility that sex steroids moderate these differences. Finally, the article concludes with a discussion of the implications of the data reviewed for basic clinical, and methodological aspects of sleep research.
Cholinergic neurons have been implicated in depression and in the disorders of REM sleep in depression. We examined a common A-> T 1890 polymorphism in the 3' UTR of the cholinergic muscarinic receptor 2 (CHRM2) gene. There was a significant increase in the frequency of 11 homozygotes in 126 women with major depression (43.7%) compared to 304 women without major depression (25.7%), P =.001. There was no increase in the frequency of 11 homozygotes in 52 men with depression (26.9%) compared to 278 men without depression (27.7%). Regression analysis, scoring subjects with the 11 genotype as 1, and those with other genotypes as 0, showed that in women r(2) =.030, F = 13.37, P =.0003. By contrast, in men r(2) =.00001, F = 0.002, P =.96. These results are consistent with a gender-specific role of the CHRM2 gene in depression in women.
Abnormalities in brain monoamine oxidase A activity have been implicated in the pathogenesis of depressive illness and suicidal behavior. The present investigation was to determine whether there is an association between MAO-A gene polymorphism and depressed suicide. The EcoRV polymorphism in MAO-A gene with alleles associated with enzyme activity was studied in postmortem brain samples from 44 depressed suicide victims and 92 control subjects of the same ethnic background. We have found significant differences in genotype/allele distribution between depressed suicide victims and controls in males (p = 0.012) but not in females or the total sample. The odds ratio (OR) for the high activity-related allele of the MAO-A gene associated with depressed suicide in males was 3.1. Our finding suggests that MAO-A may be a susceptibility gene in depressed male suicide victims. The results thus provide further evidence that genetic factors can modulate risk for depression, suicide or both by influencing monoaminergic activity in sexually dimorphic manner.
Depression is a common disorder that impacts on all aspects of a person's life. For the past 10 years, clinicians have focused on serotonin in their treatment of depression. This is largely due to the growing acceptance of the efficacy and safety of the selective serotonin reuptake inhibitors (SSRIs) in comparison with older tricyclic antidepressants (TCAs). However, evidence for a role of noradrenaline in depression has been accumulating for some time, beginning with the discovery that drugs which either caused or alleviated depression acted to alter noradrenaline metabolism. Until recently, the role of noradrenaline in depression was predicted from clinical experience with noradrenergic TCAs (desipramine, nortriptyline and protriptyline) and selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, milnacipran). The licensing of reboxetine, a selective noradrenaline reuptake inhibitor now allows the role of noradrenaline in depression to be investigated directly. This review presents key data from the literature that support a role for noradrenaline in depression taking into account neurophysiology, psychopharmacology and clinical trial data.
There are several converging reasons to focus on sleep regulation in relation to healthy adolescent development: (a) Sleep appears to be particularly important during periods of brain maturation; (b) there are substantial biological and psychosocial changes in sleep and circadian regulation exist across pubertal development; (c) interactions between physical and psychosocial domains can lead to dramatic alterations in sleep patterns and habits during adolescence; (d) increasing evidence that many adolescents frequently obtain insufficient sleep exists; (e) there is mounting evidence that sleep deprivation has its greatest negative effects on the control of behavior, emotion, and attention, a regulatory interface that is critical in the development of social and academic competence, and psychiatric disorders; (f) the most obvious direct health consequences of insufficient sleep are high-risk behaviors associated with substance abuse and automobile accidents; (g) substantial evidence for bidirectional effects between sleep and behavioral/emotional regulation exists. Although the past decade has seen research progress in these areas, there continue to be major gaps in existing knowledge and a paucity of well-controlled studies to guide specific health policy decisions and recommendations regarding sleep in adolescence. In particular, there is need for improved understanding of the acute and chronic effects of inadequate sleep in adolescents, guidelines for defining adequate sleep in adolescents, and a better delineation of the links among sleep, behavior, and affect regulation. Finally, this paper briefly examines one specific application of this knowledge area regarding early starting times among some high schools.
The serotoninergic system is involved in the regulation of sleep and wakefulness, its activity being at maximum during the awake state and minimum during sleep. In particular, the production of rapid eye movement (REM) sleep depends on the decrease of serotoninergic tone in brain stem structures. Thus, serotoninergic compounds which increase this tone (such as antidepressants) induce inhibition of REM sleep. Depression is associated with a functional decrease of serotoninergic neurotransmission and with specific alterations of sleep, notably insomnia. Paradoxically, even though they complain of sleep loss, depressed patients exhibit significant mood improvement after one night of sleep deprivation. This antidepressant effect can be accounted for by the same serotoninergic mechanisms as those described for pharmacological treatments. Indeed, the therapeutic action of antidepressants such as selective serotonin reuptake inhibitors is thought to depend directly on the enhancement of central serotoninergic neurotransmission. Such enhancement is achieved through desensitization of serotoninergic autoreceptors, which results from chronic treatment with these compounds. Sleep deprivation also induces an activation of serotoninergic neurons due to prolonged wakefulness, and leads to similar serotoninergic adaptive processes. The common neurobiological mechanisms resulting from pharmacological antidepressant treatment and sleep deprivation suggest that sleep loss in some insomniac or in depressed patients might be an endogenous compensatory process which would be therapeutical rather than pathological. This proposal should open the way to new strategies in the treatment of depression.
The main purpose of the present study was to calculate percentile curves for total sleep duration per 24 hours, for nighttime and for daytime sleep duration from early infancy to late adolescence to illustrate the developmental course and age-specific variability of these variables among subjects.
A total of 493 subjects from the Zurich Longitudinal Studies were followed using structured sleep-related questionnaires at 1, 3, 6, 9, 12, 18, and 24 months after birth and then at annual intervals until 16 years of age. Gaussian percentiles for ages 3 months to 16 years were calculated for total sleep duration (time in bed) and nighttime and daytime sleep duration. The mean sleep duration for ages 1 to 16 years was estimated by generalized additive models based on the loess smoother; a cohort effect also had to be included. The standard deviation (SD) was estimated from the loess smoothed absolute residuals from the mean curve. For ages 3, 6, and 9 months, an alternative approach with a simple model linear in age was used. For age 1 month, empirical percentiles were calculated.
Total sleep duration decreased from an average of 14.2 hours (SD: 1.9 hours) at 6 months of age to an average of 8.1 hours (SD: 0.8 hours) at 16 years of age. The variance showed the same declining trend: the interquartile range at 6 months after birth was 2.5 hours, whereas at 16 years of age, it was only 1.0 hours. Total sleep duration decreased across the studied cohorts (1974-1993) because of increasingly later bedtime but unchanged wake time across decades. Consolidation of nocturnal sleep occurred during the first 12 months after birth with a decreasing trend of daytime sleep. This resulted in a small increase of nighttime sleep duration by 1 year of age (mean 11.0 +/- 1.1 hours at 1 month to 11.7 +/- 1.0 hours at 1 year of age). The most prominent decline in napping habits occurred between 1.5 years of age (96.4% of all children) and 4 years of age (35.4%).
Percentile curves provide valuable information on developmental course and age-specific variability of sleep duration for the health care professional who deals with sleep problems in pediatric practice.
Chronic insomnia afflicts approximately 5-10% of the adult population in Western industrialized countries. Insomnia may be secondary, i.e. triggered and/or maintained by psychiatric/organic illnesses, the intake of prescribed/illicit drugs or alcohol, or by a combination of these factors. Insomnia can also occur as primary insomnia, caused by a psychophysiological hyperarousal process. In the present review a literature search was undertaken to identify longitudinal epidemiological studies which investigate the question whether primary insomnia at baseline predicts the development of depression at follow-up measurements.
MEDLINE search for the medical subject headings insomnia and depression; identification of longitudinal epidemiological studies with at least two measurement points 1 year apart measuring insomnia and depression and indicating explicit criteria for both disorders.
Eight relevant epidemiological studies were identified. Almost unambiguously insomnia at baseline significantly predicted an increased depression risk at follow-up 1-3 years later.
As insomniac symptoms alone seem to be of predictive value for the development of depression in the succeeding years, it would be worthwhile to investigate if early adequate treatment is able to prevent psychiatric sequelae of primary insomnia.
Few longitudinal studies have attempted to identify risk factors in mid-adolescence for subsequent depression in young adulthood. Mid-adolescence is a critical developmental phase for studying vulnerability to depression due to high incidence and prevalence of depression.
In a longitudinal study, following an urban Finnish community cohort (761 males and 887 females) from age 16, mid-adolescent risk factors for depression at age 22 years were studied. Data were collected by a questionnaire at school at age 16, and by a postal questionnaire at age 22.
Of the females 116 (13%) and of the males 69 (9%) had depression (S-BDI) in young adulthood. In multivariate analyses baseline depressive symptoms, low self-esteem, dissatisfaction with academic achievement, problems with the law, poor atmosphere at home and having no close friends predicted subsequent depression. Risk factors for males included more 'externalizing' aspects, for females more 'internalizing' factors.
Mid-adolescence is an important age to study risk for depression, and self-reported perceptions of psychosocial well-being have predictive value. Preventive efforts can be selectively targeted at adolescents who have been exposed to identifiable risk factors.
To examine the prevalence and correlates of sleep problems in Japanese adolescents.
The survey was designed as a cross-sectional sampling. The targets of the survey were junior and senior high schools throughout Japan. Sample schools were selected by stratified cluster sampling. Self-reported anonymous questionnaires were sent to sample schools for all students to fill out.
A total of 107,907 adolescents responded, and 106,297 questionnaires were subjected to analysis.
The overall prevalences of sleep problems in the month preceding the questionnaire were difficulty initiating sleep (boys: 15.3%, girls: 16.0%); nocturnal sleep duration less than 6 hours (boys: 28.7%, girls: 32.6%); excessive daytime sleepiness (boys: 33.3%, girls: 39.2%), and subjectively insufficient sleep (boys: 38.1%, girls: 39.0%). Multiple logistic regression analysis showed that female sex, being a senior high-school student, and having an unhealthy lifestyle (psychological stress, smoking, and drinking alcohol) were risk factors for sleep problems.
Self-reported sleep problems in Japanese adolescents were common and were associated with multiple factors. There is a need for health education directed at solving sleep problems in Japanese adolescents.
We investigated whether the genetic variants of the MAO-A gene were associated with major depression and/or the clusters of depressive symptoms. The EcoRV and the uVNTR polymorphisms were studied in a population of 191 patients with major depression and 233 control subjects. The EcoRV polymorphism was found to be associated with depression in males but not in females. Haplotype analysis revealed that one of the haplotypes (EcoRV2-uVNTR1) was significantly more frequent among male patients than male controls. Among the HAMD symptom clusters, insomnia scores were significantly higher in male patients carrying allele 2 of the EcoRV polymorphism. These data suggest that the EcoRV and uVNTR polymorphisms may be involved in the pathogenesis of major depression and associated with insomnia in depressed patients.
There is considerable research evidence suggesting that sleep is biologically linked to mood disorders in adults. However, polysomographic and neuroendocrine studies in children and adolescents have not found consistent changes in sleep architecture paralleling adult major depression. This review provides a detailed description of sleep research that has been conducted in early-onset affective disorders, uncovers the potential limitations of the available data, and formulates future research directions in this important subject.
Puberty is a dynamic period of physical growth, sexual maturation, and psychosocial achievement that generally begins between age 8 and 14 years. The age of onset varies as a function of sex, ethnicity, health status, genetics, nutrition, and activity level. Puberty is initiated by hormonal changes triggered by the hypothalamus. Children with variants of normal pubertal development--both early and late puberty--are common in pediatric practice. Recognizing when variations are normal and when referral for further evaluation is indicated is an important skill.
Adolescence is a time of change that can be both exciting and stressful. In this review, we focus on the central role that disturbed sleep and daytime sleepiness occupies in interactions involving substance abuse and negative health, social, and emotional outcomes. As a means of improving sleep and lowering risk for recidivism of substance abuse, we developed and implemented a six-session group treatment to treat sleep disturbances in adolescents who have received treatment for substance abuse. The components of the treatment are stimulus control instructions, use of bright light to regularize sleep, sleep hygiene education, cognitive therapy, and Mindfulness-Based Stress Reduction. Preliminary evidence indicates that participants who completed four or more sessions in the treatment program showed improved sleep and that improving sleep may lead to a reduction in substance abuse problems at the 12-month follow-up.
Many hormones play important roles in both pubertal development and sleep regulation. Because of the possible consequences of impaired sleep, including impaired health and cognition, it is important to examine whether an association between pubertal stage and sleep exists. The aim of this analysis is to examine the association between sleep and adolescent growth and developmental stage in a large sample of adolescents ages 12-16 years from a nationally representative longitudinal study. This analysis used the public-use data set of the National Longitudinal Study of Adolescent Health, an extensive survey of health and behavior among adolescents in the United States. The study included two interviews approximately 1 year apart. Pubertal development, sleep variables, and height are self-reported. Pubertal development scores were calculated by summing responses to three questions for each sex. The sleep variables include sleep duration, frequent insomnia (once/week or more), frequently waking tired (once/week or more), and insufficient sleep. The results indicate a sex difference in the association between sleep problems and pubertal development. Among females, there was a significant increase in sleep problems with increasing pubertal development score, but not among males. The negative association between sleep duration and pubertal development score, however, was significant in both males and females. There is no association between sleep duration and height velocity (inches/year) in this sample. The results, which are based on a large sample size, warrant further examination with more objective measures into the association between sleep and growth and development among adolescents.
Children with major depressive disorder (MDD) often complain of sleep disturbances; however, polysomnographic studies have failed to find objective evidence of these disturbances. This article examines subjective sleep reports of children with MDD and healthy controls focusing on comparing subjective and objective sleep measures.
Fifty-one subjects with MDD and 42 healthy subjects, 8-17 years old, participated in a comprehensive psychobiologic study including three nights of EEG sleep recording. Each morning, subjects completed a post-sleep form subjectively rating their sleep, which was then compared with their polysomnographic studies.
Depressed subjects reported significantly worse sleep on four scales: subjective sleep quality, perceived number of awakenings, estimated minutes awake, and perceived ease of waking. In contrast to these subjective complaints, objective EEG measures indicated no evidence of disturbed sleep in the depressed sample compared to controls. Furthermore, exploratory analyses focusing on the subset of depressed subjects with the greatest subjective sleep disturbance showed, paradoxically, significantly better sleep in terms of the number of EEG awakenings and objective disturbances.
Despite clinical evidence of subjective sleep complaints in depressed children, our EEG measures showed little evidence to indicate an objective basis for these perceptions. These findings raise provocative questions regarding the nature of sleep complaints associated with early-onset depression.
Of all the psychiatric disorders associated with insomnia, depression is the most common. It has been estimated that 90% of patients with depression complain about sleep quality. Since the first reports of short rapid eye movement (REM) latency in depressed patients and of the effect of sleep deprivation on depression in the 1970s, numerous sleep studies have provided extensive observations and theoretical hypotheses concerning the etiology and pathophysiology of depression. The aim of this review is to summarize knowledge regarding the relationships between sleep and depression.
MEDLINE and PsycINFO searches of the literature published in English or French between 1964 and 2005 that examined the relationships between sleep disturbance and depression were conducted. Search terms used were depression, depressive disorder, affective disorder, mood disorders, seasonal affective disorder, sleep, sleep disorders, insomnia, REM, polysomnography, sleep deprivation, electroencephalography, PET, SPECT, and fMRI.
Two hundred five papers were identified and selected and then integrated into the following categories: sleep architecture, antidepressive therapies, age- and gender-associated differences, functional imaging results, and sleep-related hypotheses explaining the pathophysiology of depression.
Numerous studies provide findings indicating the remarkable relationship between sleep alterations and depression. Although the existing hypotheses are not likely to explain all aspects of the sleep alterations in depression, each may be worth being maintained for refinements of pathophysiologic models of depression as new data accumulate. Further research taking into account the heterogeneity of depressive disorder and linking the different areas of research is needed to develop more comprehensive theoretical models and new therapies for depression.
In this review of the last 5 years' developments in research into depression we focus on recent advances and current controversies. We cover epidemiology and basic science as well as the treatment of depression in adults in all its forms. Depression in , as well as in has been covered in recent Seminars in The Lancet. Depression in adulthood remains a very common and under-treated condition, resulting in a high degree of disability. Increasingly detailed knowledge about impairment of information processing in depression is being supplemented by quantitative studies of the brain processes underlying these impairments. Most patients improve with present treatments. The mechanisms of action of antidepressants are not fully understood; the hypothesis that reversing hippocampal cell loss in depression may be their active principle is a fascinating new development. Moral panic about the claim that antidepressant serotonin reuptake inhibitors cause patients to commit suicide and become addicted to their medication may have disconcerted the public and members of the medical profession. We will try to describe the considerable effort that has gone into collecting evidence to enlighten this debate.