The burden of recurrent depression: causes, consequences, and future prospects.

Depression represents one of the most profound human problems currently facing the global health care system. It is a prevalent clinical condition and is estimated to rival virtually every other known medical illness in burden of disease morbidity early in this millennium. Understanding the chronic nature of this illness is key to the development of a more informed, longitudinal perspective on the diagnosis and treatment of depression. In this report, the morbid impact of depression is reviewed, from the perspectives of illness symptoms, societal impact, and emerging evidence of critical neurobiological consequences of the untreated condition. Reconceptualizing major depression from this longitudinal and multidimensional perspective is crucial to providing an effective response to this critical public health challenge.

The burden of disease for treatment-resistant depression.

Assessing the consequences of specific diseases on global, national, and individual levels is complex. The Global Burden of Disease Study was launched in 1992 to develop objective measures of the burden of disease. Two measures have become widely accepted: disability-adjusted life-years (DALYs) assesses years of life lost due to a disease plus years lived with the disability due to that disease, and years lived with disability (YLDs) is a related measure with greater relevance for diseases that do not routinely produce earlier mortality. When DALYs and YLDs were compared world-wide for 100 disorders, they revealed a huge burden of disease for depression. Indeed, the findings were startling. Neuropsychiatric conditions are by far the world's leader in YLDs, accounting for almost 30%. Unipolar major depressive disorder alone accounted for 11% of global YLDs. The disability of major depressive disorder produces its greatest burden upon women and starts early in life. No separate disability assessments have been compiled for treatment-resistant depression, but of individuals with major depressive disorder, the most severely disabled are those with treatment-resistant depression. The contributions to the morbidity associated with major depressive disorder and treatment-resistant depression include widespread prevalence; relatively early symptom onset; severe underdiagnosis and undertreatment; genetic vulnerabilities and precipitation or accentuation by relatively unavoidable stressors; a longitudinal pattern of frequent recurrences with increasing frequency, severity, and consequences unless treated with maintenance strategies; inadequate prioritization of recurrence prevention among clinicians; and possible suppression of brain neurogenesis, neuronal atrophy, cell death, hippocampal dysfunction, and magnetic resonance imaging changes for those with chronic treatment-resistant depression. Since the patterns of recurrences, cycle acceleration, and increasing severity of treatment-resistant depression are key reasons for its high burden, reducing the burden requires an entire paradigm shift, including emphasis on the prevention of recurrences. Only then will this prevalent, disabling yet treatable disorder lose its ignominious status as a world leader in disease burden.

Insomnia, self-medication, and relapse to alcoholism.

OBJECTIVE: This study was an investigation of the frequencies of insomnia and its self-medication with alcohol in a group of alcoholic patients, as well as the relationship of these variables to alcoholic relapse. METHOD: The subjects were 172 men and women receiving treatment for alcohol dependence. They completed a sleep questionnaire, measures of alcohol problem severity and depression severity, and polysomnography after at least 2 weeks of abstinence. RESULTS: On the basis of eight items from the Sleep Disorders Questionnaire, 61% of the subjects were classified as having symptomatic insomnia during the 6 months before treatment entry. Compared to patients without insomnia, patients with insomnia were more likely to report frequent alcohol use for sleep (55% versus 28%), had significantly worse polysomnographic measures of sleep continuity, and had more severe alcohol dependence and depression. Among 74 alcoholics who were followed a mean of 5 months after treatment, 60% with baseline insomnia versus 30% without baseline insomnia relapsed to any use of alcohol, a significant difference. Insomnia remained a robust predictor of relapse after application of logistic regression analysis to control for other variables. A history of self-medicating insomnia with alcohol did not significantly predict subsequent relapse. CONCLUSIONS: The majority of alcoholic patients entering treatment reported insomnia symptoms. Given the potential link between insomnia and relapse, routine questions about sleep in clinical and research settings are warranted.

Treatment guidelines for depression in pregnancy.

Depression is a ubiquitous disorder in childbearing women with up to 10% of women experiencing depression in pregnancy. Postpartum depression occurs in 12-16% of pregnancies making it a common complication. Moreover, these illnesses are frequently underdiagnosed in obstetric settings, and a recent report of the Surgeon General's Office confirms that many women do not access services, or receive treatment of inadequate intensity or duration. This paper provides current treatment guidelines to aid in appropriate diagnosis and treatment of depression in pregnancy and postpartum. Review of current literature on psychotropic medication use in pregnancy is also provided.

Serotonin dysregulation in adolescents with major depression: hormone response to meta-chlorophenylpiperazine (mCPP) infusion.

This study examined central serotonin disturbance, as reflected by neuroendocrine hormones, among adolescents with major depression. Prolactin, cortisol, and growth hormone were measured following the infusion of a serotonin agonist, meta-chlorophenylpiperazine (mCPP). Twelve (M=6, F=6) medication-free adolescents with major depression (MDD) were compared with 12 (M=6, F=6) matched normal control subjects, ranging in age from 13 to 17 years. Baseline evaluations and a battery of laboratory tests were completed. mCPP, 0.1 mg/kg i. v., was administered in a placebo-controlled design. Analyses of the neuroendocrine hormones revealed that the depressed group had a higher baseline prolactin level and an augmented prolactin response to mCPP challenge than did the control group. The depressed group experienced a sharper baseline-cortisol decline between 08.00 and 11.00 h, and compared to control subjects they displayed an augmented response to the challenge. The depressed group reported more side effects than the control group during saline infusion, but not during mCPP infusion. Findings suggest that depressed adolescents have an elevated baseline prolactin level, and also experience enhanced prolactin and cortisol responses to the serotonergic challenge. These preliminary findings will be confirmed during our ongoing study.

Extended antidepressant maintenance and discontinuation syndromes.

Unipolar and bipolar depression are episodic, recurrent illnesses for the majority of patients. Because each episode engenders considerable costs for patients, families, and society, prevention of recurrences has high priority. Numerous studies demonstrate that maintenance antidepressants or mood stabilizing medications are efficacious in preventing recurrences. A review of maintenance studies supports the view that all antidepressants perform significantly better than placebo in preventing recurrences of depression--with the stipulation that full antidepressant doses be employed. Earliest studies, conducted two decades ago, evaluated tricyclics (TCAs), heterocyclics, and lithium, while recent studies have focused on selective serotonin reuptake inhibitors (SSRIs). Compliance is essential. Strategies for enhancing compliance include selection of medications with reported safety and few side effects, education of patients and families, referral to patient advocacy groups, and use of new technological compliance aids. Preliminary data suggest that SSRIs are better tolerated than TCAs; fewer patients discontinue these agents due to side effects. Selection criteria for maintenance treatment have not been well determined, but three or more prior episodes is recognized as a relatively strong indicator. Other clinical or genetic criteria have also been suggested. For various reasons, patients may discontinue medications, and when this happens withdrawal phenomena may occur. Withdrawal effects are well documented for all antidepressants and can be profound with TCAs. After stopping some SSRIs, a few withdrawal symptoms may have similarities with those following discontinuation of TCAs, but unique "CNS-like" effects are frequently described, including brief recurrent episodes of dizziness, lightheadedness, vertigo, electric shock-like sensations, and gait instability. These appear to be half-life dependent, with agents with shorter half-lives having more discontinuation symptoms. If antidepressant medications must be discontinued, a gradual taper is preferable, perhaps extending three to six months or longer to prevent discontinuation effects, enable adaptation at the receptor level and allow earlier recognition and treatment of recurrent depressive symptoms.

Sleep-onset rapid eye movement after electroconvulsive therapy is more frequent in patients who respond less well to electroconvulsive therapy.

The response to electroconvulsive therapy (ECT) was monitored with sleep polysomnography studies (SPS) performed pre- and post-ECT, in 25 patients with major depressive disorder (MDD). Patients included in this study met research diagnostic criteria for MDD and had been free of psychotropic medication for at least 10 days before SPS were performed. We compared ECT responders and nonresponders on SPS, demographic, and clinical parameters. Many SPS parameters, regardless of the clinical response, changed significantly with ECT. The presence of delusions was significantly associated with SOREM post-ECT. The presence of sleep-onset REM periods post-ECT was associated with poor response to ECT. SPS performed during a course of ECT may help identify patients at risk of responding less well to this modality of treatment.

Polysomnographic studies in patients referred for ECT: pre-ECT studies.

Forty-one patients referred for electroconvulsive therapy (ECT) were evaluated with a standardized clinical protocol and had polysomnographic studies performed pre-ECT after 10 or more days drug free. Clinical evaluations were performed by blind investigators and included the Research Diagnostic Criteria and the Hamilton Rating Scale for Depression (HRSD). Patients were categorized according to the clinical response. Thirty patients (73%) reached a post-ECT HRSD < or = 10, whereas 21 of them (51.2%) reached a post-ECT HRSD score < or = 6. Sleep-onset rapid eye movement (SOREM) periods were present in 27 (66%) of the patients. Few polysomnographic variables differentiated between excellent responders and patients with residual symptoms. Older patients had significantly more disrupted polysomnographic study parameters. Although present in a significant proportion of patients, baseline SOREM was not a factor in outcome.

Fluoxetine versus phenelzine in atypical depression.

A study was conducted to compare the relative efficacy of fluoxetine and phenelzine in patients with mood-reactive atypical depression. Forty-two patients with atypical depression by the Columbia criteria were studied in a randomized, double-blind treatment study. Following a single-blind placebo lead-in, patients received fluoxetine 20-60 mg/day or phenelzine 45-90 mg/day for 6 weeks. Efficacy was measured by the Hamilton Depression Rating Scale, the Clinical Global Impression (Severity and Improvement) scales, and the Patient Global Impression (Improvement) scale. Of 42 patients randomized, 2 patients never received drugs and 2 phenelzine-treated patients dropped out prior to completion; the remainder completed the 6 weeks of the study. The rates of treatment response did not differ between groups. With a few exceptions (e.g., tremor), phenelzine produced more frequent adverse effects than fluoxetine. It was concluded that fluoxetine is as effective as phenelzine in the treatment of atypical depression, but produces fewer adverse effects and is better tolerated.

Alcohol inhibits lipopolysaccharide-induced tumor necrosis factor alpha gene expression by peripheral blood mononuclear cells as measured by reverse transcriptase PCR in situ hybridization.

We recently showed that alcohol significantly suppressed lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production by whole blood and total mononuclear cells from healthy subjects as measured by bioassay. In the current study, we further examined the effect of alcohol on LPS-induced TNF-alpha gene expression by semiquantitative solution PCR and in situ reverse transcriptase PCR (RT-PCR) hybridization methods. Peripheral blood mononuclear cells were cultured with LPS (10 micrograms/ml) for 4 to 8 h with or without different concentrations of ethanol (0.1, 0.2, and 0.3% [vol/vol]). Total RNA from treated and untreated cultures was extracted and used for solution PCR analysis. Treated and untreated cells were subjected to both conventional in situ hybridization and RT-PCR in situ hybridization. In solution RT-PCR in vitro analysis, alcohol significantly suppressed TNF-specific message. In conventional in situ hybridization, the effect of alcohol on TNF-alpha gene expression was poorly detected. However, when cells were subjected to RT-PCR prior to in situ hybridization, cells treated with alcohol significantly suppressed expression of the message for TNF-alpha. These studies confirm our earlier finding that alcohol suppressed the production of TNF-alpha by LPS-induced whole blood cells and peripheral blood mononuclear cells. Furthermore, these studies also demonstrate that the RT-PCR in situ technique is a powerful tool for detecting and amplifying specific genes in whole cells when limited numbers of cells are available for RNA extraction.

Life events and depression in children with pervasive developmental disorders.

To determine the role of life events in the occurrence of depression in children with pervasive developmental disorders (PDD), we compared 11 patients (DSM-III-R; 9 male; 2 female; M age: 11.0 years; M full-scale IQ: 75.3) with PDD and depression, with an age- and sex-matched control group of patients with PDD without depression (DSM-III-R; 9 male; 2 female; M age: 9.8 years; M full-scale IQ: 60.6). Information was collected about the occurrence of unpleasant life events in the 12 months prior to the onset of depression. Depressed children experienced significantly more life events in the 12 months prior to the onset of depression. Exit events such as bereavement were more common in the depressed group. Findings suggest that, as in the general population, significant life events, particularly those with a negative impact, may contribute to the occurrence of depression in children with PDD. Future studies should explore the role of both biologic factors and environmental stressors in the onset of depression in this population.

Selective inhibition by alcohol and cortisol of natural killer cell activity of lymphocytes from cord blood.

1. The immunosuppressive effects of drugs such as alcohol or hormones such as cortisol may be age-related. To test this hypothesis, the authors investigated the in vitro effects of ethanol (EtOH) and cortisol on Natural Killer (NK) cell activity of lymphocytes from normal cord blood in comparison with that of lymphocytes from normal adult peripheral blood. 2. K562, an erythroleukemia cell line, was used as a target in a 4 hr 51Cr release assay. 3. Ethanol at 0.3% (V/V) and cortisol at 0.05, 0.1 and 0.2 microgram/ml concentrations, added directly to a mixture of effector and target cells significantly suppressed the NK activity of cord blood lymphocytes in a dose dependent fashion, whereas similar concentrations of either EtOH or cortisol did not manifest significant immunoregulatory effects on NK cell activity of normal adult lymphocytes. 4. Pre-treatment of the target with either EtOH or cortisol for 4 hours did not affect cytotoxicity. Inhibition of cytotoxicity was also not due to direct toxicity of effector cells because lymphocytes treated with either EtOH or cortisol showed normal 51Cr release and their viability was comparable to that of untreated control cells. 5. This suggests a selective inhibitory effect of EtOH and cortisol on NK activity of neonatal lymphocytes that may be of clinical significance.

Shortened REM latency PostECT is associated with rapid recurrence of depressive symptomatology.

Electroconvulsive therapy (ECT) is highly effective in the treatment of major depressive disorder (MDD). The 1-year relapse rates are reported to be high and in the 30%-60% range, however. To test whether polysomnography (PS) can identify patients with a propensity for relapse we studied 20 patients, responders to a course of ECT, with PS studies. All patients met baseline diagnostic criteria for MDD, were treated with ECT following standardized protocols, had PS studies performed after the course of ECT in a medication-free state, received maintenance antidepressants postECT, and were followed periodically with phone interviews. The recurrence of depressive symptoms was determined at 3 months and 6 months after discharge. Fifty-five percent of the patients were symptomatic when evaluated 6 months after the ECT. Sleep Onset rapid eye movement (REM) periods were identified in 55% of the patients. As a group, patients who had experienced a recurrence of depressive symptoms by 6 months after discharge, had significantly shorter REM latencies after the course of ECT. A shorter REM latency after ECT identified patients who at six months demonstrated significant depressive symptomatology. Shortened REM latency after ECT in patients with MDD appears to be a correlate of vulnerability for relapse.

Suppression of tumor necrosis factor production by alcohol in lipopolysaccharide-stimulated culture.

Many studies have shown that alcohol consumption is associated with alteration in immune responses and increased incidence of infection in the host. Tumor necrosis factor (TNF) is a potent soluble mediator of immunoregulation and inflammation, and plays a very important role in host's defenses against infection and tumor. We propose that one of the mechanisms of alcohol-mediated immunosuppression may be due to a defect in the synthesis and release of the TNF. To determine this, we studied the direct effect of alcohol on lipopolysaccharide (LPS)-induced TNF production by whole blood and total mononuclear cell from normal subjects. Aliquots of blood samples (1 ml) or ficoll-hypaque separated total mononuclear cells (1 x 10(6)/ml) were cultured with different concentrations of either ethanol or acetaldehyde in the presence or absence of LPS for 4 hr at 37 degrees C. Plasma samples and culture supernatants were assayed for TNF levels in a bioassay using a TNF-sensitive WEHI 164 subclone 13 cell line. LPS at 10 micrograms/ml produced a maximal level of TNF compared with lower (1 micrograms/ml) or higher concentration (50 micrograms/ml) of LPS. Kinetics studies showed that an incubation time of 4 hr with LPS produced a maximum level of TNF production by blood. Alcohol, as low as 0.1% concentration, produced significant suppression of LPS-induced TNF production by whole blood, whereas alcohol at 0.2 and 0.3% concentrations were required to produce a significant suppression of TNF production by separated mononuclear cells. Anti-TNF-alpha antibodies significantly neutralized the LPS-induced TNF that suggests that blood monocytes may be the primary source of TNF production.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical characteristics of patients with concurrent major depressive disorder and panic disorder.

OBJECTIVE: This study was designed to test the hypothesis that patients with both major depressive disorder and panic disorder exhibit more clinical symptoms and have a more protracted course of illness than patients with major depressive disorder only. METHOD: The authors compared standardized clinical evaluations (from Schedule for Affective Disorders and Schizophrenia interviews) of 119 patients with major depressive disorder only and 57 patients with major depressive disorder and concurrent panic disorder. Clinical and demographic variables were included. RESULTS: The patients with both disorders reported symptoms of major depressive disorder earlier in life and also required treatment and hospital admission earlier in life. Many clinical features during the index episode were significantly more severe in the patients with both disorders. A logistic regression identified a "panic index" consisting of the symptoms of somatic anxiety, phobia, indecisiveness, and feelings of inadequacy. Scores on this index allowed proper classification of patients to either of the two diagnostic groups with high reliability. CONCLUSIONS: In major depressive disorder, the presence of panic disorder is suggestive of a more severe and precocious form of illness.

Selective effect of alcohol on cellular immune responses of lymphocytes from AIDS patients.

In this study we examined the in vitro effects of alcohol on the proliferative responses of lymphocytes from healthy donors and AIDS patients to a recombinant fusion peptide, env-gag, corresponding to portions of the gp41 envelope (env) and internal core (gag) proteins of HIV. The effects of alcohol (ETOH) on the natural killer (NK) cell activities of lymphocytes from healthy donors and patients with AIDS were also investigated. Peripheral blood mononuclear cells from both normal donors and AIDS patients produced significant levels of lymphocyte proliferative responses to the HIV env-gag peptide; however, these responses were significantly higher in patients with AIDS, showing the specificity of the response. The env-gag-induced proliferative responses of lymphocytes from normal subjects were significantly suppressed when cultures contained only higher levels of ETOH (0.2% and 0.3%), whereas ETOH even at a lower level (0.1%) produced significant suppression of the env-gag-induced proliferation of lymphocytes only from AIDS patients. Direct addition of ETOH at concentrations of 0.1%, 0.2%, and 0.3% to cultures of lymphocytes from normal donors and NK target cells did not produce significant suppression of NK cell activities. However, ETOH at concentrations of 0.2% and 0.3% significantly suppressed the NK activities of lymphocytes from AIDS patients, and the suppressive effect was observed at all E:T cell ratios examined. Control peptide from the Escherichia coli expression vector did not produce any significant effect on lymphocyte proliferative responses or NK activity of both normal donors and AIDS patients.(ABSTRACT TRUNCATED AT 250 WORDS)