The differential influence of life stress on individual symptoms of depression.

OBJECTIVE: Life stress consistently increases the incidence of major depression. Recent evidence has shown that individual symptoms of major depressive disorder (MDD) differ in important dimensions such as their genetic and etiological background, but the impact of stress on individual MDD symptoms is not known. Here, we assess whether stress affects depression symptoms differentially. METHOD: We used the chronic stress of medical internship to examine changes of the nine Diagnostic and Statistical Manual (DSM)-5 criterion symptoms for depression in 3021 interns assessed prior to and throughout internship. RESULTS: All nine depression symptoms increased in response to stress (all P < 0.001), on average by 173%. Symptom increases differed substantially from each other (P < 0.001), with psychomotor problems (289%) and interest loss (217%) showing the largest increases, and suicidal ideation (146%) and sleep problems (52%) the smallest. Symptoms also differed in their severities under stress (P < 0.001): Fatigue, appetite problems and sleep problems were most prevalent; psychomotor problems and suicidal ideation were least prevalent. CONCLUSION: Stress differentially affects the DSM-5 depressive symptoms. Analyses of individual symptoms reveal important insights obfuscated by sum-scores.

Depression is more than the sum score of its parts: individual DSM symptoms have different risk factors.

BACKGROUND: For diagnostic purposes, the nine symptoms that compose the DSM-5 criteria for major depressive disorder (MDD) are assumed to be interchangeable indicators of one underlying disorder, implying that they should all have similar risk factors. The present study investigates this hypothesis, using a population cohort that shifts from low to elevated depression levels. METHOD: We assessed the nine DSM-5 MDD criterion symptoms (using the Patient Health Questionnaire; PHQ-9) and seven depression risk factors (personal and family MDD history, sex, childhood stress, neuroticism, work hours, and stressful life events) in a longitudinal study of medical interns prior to and throughout internship (n = 1289). We tested whether risk factors varied across symptoms, and whether a latent disease model could account for heterogeneity between symptoms. RESULTS: All MDD symptoms increased significantly during residency training. Four risk factors predicted increases in unique subsets of PHQ-9 symptoms over time (depression history, childhood stress, sex, and stressful life events), whereas neuroticism and work hours predicted increases in all symptoms, albeit to varying magnitudes. MDD family history did not predict increases in any symptom. The strong heterogeneity of associations persisted after controlling for a latent depression factor. CONCLUSIONS: The influence of risk factors varies substantially across DSM depression criterion symptoms. As symptoms are etiologically heterogeneous, considering individual symptoms in addition to depression diagnosis might offer important insights obfuscated by symptom sum scores.

The smoke detector principle. Natural selection and the regulation of defensive responses.

Defenses, such as flight, cough, stress, and anxiety, should theoretically be expressed to a degree that is near the optimum needed to protect against a given threat. Many defenses seem, however, to be expressed too readily or too intensely. Furthermore, there are remarkably few untoward effects from using drugs to dampen defensive responses. A signal detection analysis of defense regulation can help to resolve this apparent paradox. When the cost of expressing an all-or-none defense is low compared to the potential harm it protects against, the optimal system will express many false alarms. Defenses with graded responses are expressed to the optimal degree when the marginal cost equals the marginal benefit, a point that may vary considerably from the intuitive optimum. Models based on these principles show that the overresponsiveness of many defenses is only apparent, but they also suggest that, in specific instances, defenses can often be dampened without compromising fitness. The smoke detector principle is an essential foundation for making decisions about when drugs can be used safely to relieve suffering and block defenses.

Group behavioral therapy of obsessive-compulsive disorder: seven vs. twelve-week outcomes.

Previous research has demonstrated that individualized behavioral exposure and response prevention therapy is an effective treatment for Obsessive-Compulsive Disorder. In our prior preliminary report, 7-week group exposure and response prevention therapy was also found effective in reducing obsessions and compulsions. The present report describes a larger sample (N=113) of treatment seeking obsessive-compulsives who received group behavioral therapy. As before, group exposure and response prevention significantly improved ratings of obsessions, compulsions, and depression. These improvements were maintained at 3-month and long-term follow-up. A sub-sample of patients who received 12 weeks of treatment had outcomes at the end of the group and at follow-up that did not significantly differ from those who received 7 weeks of treatment. These results confirm the efficacy of a 7-week behavioral treatment program administered in a group format.

On the difficulty of defining disease: a Darwinian perspective.

Most attempts to craft a definition of disease seem to have tackled two tasks simultaneously: 1) trying to create a series of inclusion and exclusion criteria that correspond to medical usage of the word disease and 2) using this definition to understand the essence of what disease is. The first task has been somewhat accomplished, but cannot reach closure because the concept of "disease" is based on a prototype, not a logical category. The second task cannot be accomplished by deduction, but only by understanding how the body works and what each component is for, in evolutionary detail. An evolutionary view of the origins of the body and its vulnerabilities that result in disease provides an objective foundation for recognizing pathology. Our social definition of disease will remain contentious, however, because values vary, and because the label "disease" changes judgments about the moral status of people with various conditions, and their rights to medical and social resources.

Persistent respiratory irregularity in patients with panic disorder.

BACKGROUND: Dysregulated respiratory control may play a role in the pathophysiology of panic disorder. This could be due to abnormalities in brain stem respiratory nuclei or to dysregulation at higher brain levels. Results from previous studies using the doxapram model of panic have yielded an unclear picture. A brief cognitive manipulation reduced doxapram-induced hyperventilation in patients, suggesting that higher level inputs can substantially alter their respiratory patterns. However, respiratory abnormalities persisted, including a striking irregularity in breathing patterns. METHODS: To directly study respiratory irregularity, breath-by-breath records of tidal volume (V(t)) and frequency (f) from previously studied subjects were obtained. Irregularity was quantified using von Neumann's statistic and calculation of "sigh" frequency in 16 patients and 16 matched control subjects. Half of each group received a standard introduction to the study and half received a cognitive intervention designed to reduce anxiety/distress responses to the doxapram injection. RESULTS: Patients had significantly greater V(t) irregularity relative to control subjects. Neither the cognitive intervention nor doxapram-induced hyperventilation produced significant changes in V(t) irregularity. The V(t) irregularity was attributable to a sighing pattern of breathing that was characteristic of panic patients but not control subjects. Patients also had somewhat elevated f irregularity relative to control subjects. CONCLUSIONS: The irregular breathing patterns in panic patients appear to be intrinsic and stable, uninfluenced by induced hyperventilation or cognitive manipulation. Further study of V(t) irregularity and sighs are warranted in efforts to localize dysregulated neural circuits in panic to brain stem or midbrain levels.

Is depression an adaptation?

Many functions have been suggested for low mood or depression, including communicating a need for help, signaling yielding in a hierarchy conflict, fostering disengagement from commitments to unreachable goals, and regulating patterns of investment. A more comprehensive evolutionary explanation may emerge from attempts to identify how the characteristics of low mood increase an organism's ability to cope with the adaptive challenges characteristic of unpropitious situations in which effort to pursue a major goal will likely result in danger, loss, bodily damage, or wasted effort. In such situations, pessimism and lack of motivation may give a fitness advantage by inhibiting certain actions, especially futile or dangerous challenges to dominant figures, actions in the absence of a crucial resource or a viable plan, efforts that would damage the body, and actions that would disrupt a currently unsatisfactory major life enterprise when it might recover or the alternative is likely to be even worse. These hypotheses are consistent with considerable evidence and suggest specific tests.

Marital quality and psychological adjustment to widowhood among older adults: a longitudinal analysis.

OBJECTIVES: This study examined whether psychological adjustment to widowhood is affected by three aspects of marital quality--warmth, conflict, and instrumental dependence-assessed prior to the loss. METHODS: The Changing Lives of Older Couples (CLOC) is a prospective study of a two-stage area probability sample of 1,532 married individuals aged 65 and older. The CLOC includes baseline data on marital quality and mental health and data on grief, anxiety, and depression collected 6, 18, and 48 months after spousal loss. RESULTS: Widowhood was associated with elevated anxiety among those who were highly dependent on their spouses and lower levels of anxiety among those who were not dependent on their spouses. Levels of yearning were lower for widowed persons whose relationships were conflicted at baseline and higher for those reporting high levels of marital closeness and dependence on their spouses. Women who relied on their husbands for instrumental support had significantly higher levels of yearning than men who depended on their wives. DISCUSSION: The findings contradict the widespread belief that grief is more severe if the marriage was conflicted and suggest a more complex relationship between bereavement and characteristics of the marriage.

Natural selection, mental modules and intelligence.

The question of whether intelligence is one trait or many has exercised several generations of researchers, but no consensus is in sight. Evolutionary psychology, with its emphasis on domain-specific mental modules, seems to offer hope for advancing understanding of this question. We know that the mind has been shaped by natural selection to maximize reproductive success. This tells us what the mind must do--it must solve the adaptive problems that the organism confronts. However, whether this functional capacity is manifest in congruent anatomic, physiological, genetic, cognitive or psychometric structures is another matter. Examination of how natural selection shaped other mechanisms suggests that knowing functional demands provides only modest guidance as to the structure of mechanisms. None the less, it remains simultaneously clear that these mechanisms are not entirely general, but have been shaped to cope with specific challenges. Our metaphors for the mind, whether as a digital computer or a Swiss army knife, are misleading because computers and tools are products of intelligent design. In contrast, minds are products of natural selection whose intertwined components are products of incorporated genetic mutations whose effects are widespread and constrained by historical precedents. Our tendencies to describe the structure of the mind in terms of discrete components make it difficult for us to comprehend the mind as a mind. One antidote may be to minimize metaphorical descriptions of postulated structures of mind and focus instead on its function.

Proximate and evolutionary studies of anxiety, stress and depression: synergy at the interface.

While enormous progress has been made in unraveling the proximate physiological mechanisms that account for anxiety, stress, and low mood, these states continue to give rise to considerable conceptual confusion. This is, in part, because proximate studies have neither been adequately distinguished from, nor integrated with, evolutionary explanations for the adaptive functions of anxiety, stress, and mood. A complete biological explanation that incorporates both proximate and evolutionary explanations will be of great value to better define the border between normal and pathological, to help to explain why pathological anxiety and depression are so common, and to provide a much-needed basis for sensible decisions about when different pharmacological manipulations are likely to be helpful or harmful. Ideally, evolutionary considerations should provide a conceptual framework within which the biological significance of the proximate mechanisms can be better understood, and the proximate findings should provide tests of evolutionary hypotheses. Studies at the interface between evolutionary and proximate explanations will be difficult, but important to better understand individual differences in vulnerability and the etiology of diseases that result from dysregulation of anxiety and mood.

Effect of alcohol on social phobic anxiety.

OBJECTIVE: Previous research has demonstrated a greater-than-expected association between social phobia and alcohol use disorders. The purpose of this study was to test the hypothesis that drinking alcohol reduces social phobic anxiety. METHOD: Treatment-seeking individuals with social phobia (N = 40) were asked to give two impromptu speeches. Twenty subjects received a placebo alcoholic drink before both speeches, and 20 subjects received a placebo before the first speech, followed by a moderate dose of alcohol before the second speech. Subjective anxiety ratings, heart rate, and cognitions related to social anxiety were used as measures of anxiety. RESULTS: Repeated measures analyses of variance yielded no significant differences in anxiety (subjective, physiological, cognitive) between the alcohol and placebo groups. Current and past drinking habits did not significantly alter the effect of alcohol on anxiety. The belief that one received alcohol was significantly related to levels of subjective anxiety and negative cognitions. CONCLUSIONS: Alcohol does not directly reduce social phobic anxiety. The belief that one received alcohol may reduce social anxiety.

Anxiety and cardiovascular reactivity in the Tecumseh population.

OBJECTIVE: Increased cardiovascular reactivity has been proposed to be a critical mediator in the development of hypertension and cardiovascular disease. The personality factors associated with cardiovascular reactivity are still subject to debate. The studies reported here were undertaken to examine the relationship between trait anxiety and cardiovascular stress reactivity in a community-based sample (Tecumseh). DESIGN AND METHODS: All studies were carried out in an outpatient setting. Cardiovascular reactivity to isometric handgrip and mental arithmetic was assessed and recorded by automatic blood pressure monitoring in 832 subjects aged 19-41 years. Spielberger trait and state anxiety measures were collected immediately before the stressors were applied. RESULTS: No differences in baseline heart rate, systolic or diastolic blood pressure were observed across anxiety categories. There was a clear negative correlation between trait anxiety and cardiovascular reactivity to mental arithmetic. The pattern was less clear in response to isometric handgrip. CONCLUSIONS: These results suggest that individuals with high trait anxiety demonstrate reduced cardiovascular reactivity while those with low trait anxiety demonstrate increased reactivity, whereas the opposite might have been expected.

Defense mechanism changes in successfully treated patients with obsessive-compulsive disorder.

OBJECTIVE: Changes in defense mechanisms after treatment of patients with obsessive-compulsive disorder (OCD) were measured by using an established rating scale. METHOD: Before and after 7-week group behavior therapy, 17 patients with DSM-III-R OCD were assessed with the Defense Style Questionnaire, Yale-Brown Obsessive Compulsive Scale, and Beck Depression Inventory. RESULTS: After behavior therapy the patients evidenced significant decreases in Yale-Brown Obsessive Compulsive Scale scores and significant increases in the use of more adaptive defense mechanisms. There were no significant changes in three maladaptive defense mechanism categories. The improvement in adaptive defenses was independently linked to improvement both in OCD and in depression. CONCLUSIONS: Personality as defined by defense mechanisms may be more amenable to brief behavioral treatment than previously thought. The permanence of these changes must be further assessed.

Psychoactive drug use in evolutionary perspective.

Pure psychoactive drugs and direct routes of administration are evolutionarily novel features of our environment. They are inherently pathogenic because they bypass adaptive information processing systems and act directly on ancient brain mechanisms that control emotion and behavior. Drugs that induce positive emotions give a false signal of a fitness benefit. This signal hijacks incentive mechanisms of "liking" and "wanting," and can result in continued use of drugs that no longer bring pleasure. Drugs that block negative emotions can impair useful defenses, although there are several reasons why their use is often safe nonetheless. A deeper understanding of the evolutionary origins and functions of the emotions and their neural mechanisms is needed as a basis for decisions about the use of psychoactive drugs.

Childhood adversity and vulnerability to mood and anxiety disorders.

Based upon epidemiological surveys, adverse childhood events are proposed to be risk factors for adult depressive and anxiety disorders. However, the extent to which these events are seen in clinical patient populations is less clear. We examined the prevalence of a number of proposed risk factors for depression in 650 patients with mood and anxiety disorders at the time of presentation for treatment in an outpatient subspecialty clinic. Emotional abuse, physical abuse, or sexual abuse (childhood adversity) was found in approximately 35% of patients with major depression and panic disorder, was more common in women than men, and was associated with an earlier onset of symptoms. Childhood adversity was also strongly associated with marital discord/divorce, and psychopathology in a parent, suggesting family discord predisposes to childhood abuse. Furthermore, the association of childhood abuse with parental mental illness suggests that genetic and environmental factors are difficult to separate as etiological factors in vulnerability.

Platelet alpha 2-adrenoreceptors, catecholamines, hemodynamic variables, and anxiety in panic patients and their asymptomatic relatives.

The objectives of this study were to a) replicate our prior finding of a decreased number (Bmax) of platelet alpha 2-adrenoreceptors in panic disorder, b) determine if binding is also decreased in asymptomatic first-degree relatives of panic patients (known to be at increased risk for developing panic), and c) evaluate the effect of treatment on the presumptive decrease in binding (i.e., is the decrease a state or a trait marker for panic?). Panic patients had clonidine and yohimbine platelet-binding assays, symptom ratings, and measurement of lying and standing plasma epinephrine, norepinephrine, systolic and diastolic blood pressure, and heart rate before treatment, after approximately 2 months of medication (fluoxetine, tricyclics, or alprazolam) and/or cognitive behavioral treatment, and after symptom remission while drug free; normal subjects had determinations of the same measures at approximately the same time intervals. Relatives of both groups had one determination only of all measures. Tritiated clonidine binding was decreased and lying heart rate was increased in patients before treatment. Magnitude of binding decrease was correlated with symptom severity and standing norepinephrine. No binding abnormality was seen in first-degree relatives of patients. Treatment increased clonidine binding in patients. Both patients and relatives of patients showed significantly increased standing plasma norepinephrine in comparison to controls. There is a state-related decrease in binding, associated with symptom severity and norepinephrine, in panic disorder. Abnormal reactivity of norepinephrine to standing might be a marker for increased likelihood of panic development in individuals at risk.

Respiratory psychophysiology and anxiety: cognitive intervention in the doxapram model of panic.

UNLABELLED: The goals of this study were to: a) confirm prior evidence that the respiratory stimulant doxapram induces panic attacks and produces excessive hyperventilation in patients with panic disorder and b) explore the impact of cognitive mediators on symptom and respiratory responses. METHOD: Thirty-two subjects (16 patients and 16 controls) received doxapram (0.5 mg/kg) and placebo infusions while symptom, respiratory, and heart rate responses were monitored. Subjects were randomly assigned to receive either a standard introduction or a cognitive intervention designed to reduce the panic responses of panic patients to laboratory challenges. RESULTS: Doxapram was a potent and specific panicogenic agent, inducing panic in 75% of patients and 12.5% of controls. Compared with controls, patients also showed a greater decrease in end tidal carbon dioxide (CO2) and greater increases in minute ventilation, respiratory frequency, and heart rate. The cognitive intervention substantially attenuated the excessive hyperventilatory response of patients but did not fully normalize their breathing patterns. Tidal volume was the only respiratory measure not significantly altered by the cognitive intervention. CONCLUSIONS: In patients with panic disorder, doxapram (0.5 mg/kg) triggers panic attacks about as potently as 7% CO2 and more potently than 5% CO2 or lactate. Psychological factors can modulate the appearance of ventilatory abnormalities in panic patients, but persistent respiratory disturbances were still seen. Psychological factors and respiratory physiology both appear to be important phenomena in laboratory panic.