Philip W. Gold

Clinical and Biochemical Manifestations of Depression

Thousands of studies have been conducted of the functioning of the many neurotransmitter systems in order to explore the biologic basis of major depressive disorder. Instead of reviewing this literature exhaustively, we have attempted to propose a model that accommodates the clinical observation that chronic stress early in life in vulnerable persons predisposes them to major depression with contemporary observations of the potential consequences of repeated central nervous system exposure to effectors of the stress response. This model accords with current clinical judgment that major depression is best treated with a combination of psychopharmacologic agents and psychotherapy. Accordingly, whereas psychopharmacologic intervention may be required to resolve an active episode of major depression and to prevent recurrences, psychotherapy may be equally important to lessen the burden of stress imposed by intense inner conflict and counterproductive defenses.

Mood Disorders in the Medically Ill: Scientific Review and Recommendations

OBJECTIVE The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. DATA SOURCES Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. STUDY SELECTION/DATA EXTRACTION Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. CONCLUSIONS A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Mechanisms of stress: A dynamic overview of hormonal and behavioral homeostasis

Environmental events, both physical and emotional, can produce stress reactions to widely varying degrees. Stress can affect many aspects of physiology, and levels of stress, emotional status, and means of coping with stress can influence health and disease. The stress system consists of brain elements, of which the main components are the corticotropin-releasing hormone (CRH) and locus ceruleus (LC)-norepinephrine (NE)/autonomic systems, as well as their peripheral effectors, the pituitary-adrenal axis and the autonomic system, which function to coordinate the stress response. Activation of the stress system results in behavioral and physical changes which allow the organism to adapt. This system is closely integrated with other central nervous system elements involved in the regulation of behavior and emotion, in addition to the axes responsible for reproduction, growth and immunity. With current trends in stress research which focus on understanding the mechanisms through which the stress-response is adaptive or becomes maladaptive, there is a growing association of stress system dysfunction, characterized by hyperactivity and/or hypoactivity to various pathophysiological states. The purpose of this review is to 1) define the concepts of stress and the stress response from a historical perspective, 2) present a dynamic overview of the biobehavioral mechanisms that participate in the stress response, and 3) examine the consequences of stress on the physiologic and behavioral well-being of the organism by integrating knowledge from apparently disparate fields of science.

Altered Expression of Hypothalamic Neuropeptide mRNAs in Food-Restricted and Food-Deprived Rats

Hypothalamic neuropeptides play a role in appetite and weight regulation. Food restriction for 2 weeks and food deprivation for 4 days were used as models to characterize the effects of weight loss on hypothalamic peptide gene expression in male and female rats. We used in situ hybridization to examine the mRNA levels of hypothalamic peptides which stimulate and inhibit food intake and found selective effects primarily in the arcuate nucleus. Neuropeptide Y (NPY) mRNA was increased and pro-opiomelanocortin (POMC) and galanin (GAL) mRNA were decreased in the hypothalamic arcuate nucleus and corticotropin-releasing hormone (CRH) mRNA was decreased in the hypothalamic paraventricular nucleus in male and female food-restricted and food-deprived rats. Food restriction produced larger changes in peptide mRNA expression than did food deprivation. Changes in NPY, POMC and CRH gene expression induced by food restriction were greater in male than female rats. Elevated NPY and reduced CRH gene expression may be a compensatory physiological response to restore food intake in food-restricted and food-deprived animals. The discrete changes in NPY, POMC, GAL and CRH gene expression in food-restricted and food-deprived animals suggest the involvement of these peptides in abnormal appetitive behavior and weight loss associated with human eating disorders.

Interactions between the Hypothalamic-Pituitary-Adrenal Axis and the Female Reproductive System: Clinical Implications

Dr. George P. Chrousos (Developmental Endocrinology Branch, National Institute of Child Health and Human Development [NICHD], National Institutes of Health [NIH], Bethesda, Maryland): Ancient physicians knew of the adverse effects of stress on the reproductive system [1, 2]. In the 5th century BCE, Hippocrates of Cos explained the impotence and infertility of the Scythians, nomadic tribes living in what is now southern Ukraine, as a result of their rough lives. About the men, he wrote, From the cold and tiredness they forget their sexual drive and their desire to come into union with the other sex; about the women, he stated, nor is their menstrual discharge such as it should be, but scanty and at too long intervals. About 500 years later, Soranos of Ephesus published the following differential diagnosis of amenorrhea in his pioneering treatise on gynecology and perinatology: Of those who do not menstruate, some have no ailment and it is physiological for them not to menstruate, either because of their age, as in those too young or too old, or because they are pregnant, or barren singers and athletes. Others, however, do not menstruate because of a disease of the uterus or of the rest of the body, for example when subjected to under-nourishment, great emaciation and wasting or to the accumulation of fatty flesh, or cachexia, or fevers and long ailment. The hypothalamic-pituitary-adrenal axis, together with the arousal and autonomic nervous systems, constitutes the stress system (Figure 1). This system is activated during stress and produces the clinical phenomenology of what Hans Selye described as the stress syndrome [3]. Indeed, during stress, several changes take place in the central nervous system and periphery of mammals, changes that help preserve the individual and the species. These include the mobilizing of adaptive behaviors and peripheral functions and the inhibiting of biologically costly behaviors and vegetative functions, such as reproduction, feeding, and growth. Figure 1. Interactions of the reproductive system with the hypothalamic-pituitary-adrenal axis and locus ceruleus-norepinephrine system (LC/NE). middle right The principal molecular regulators of the hypothalamic-pituitary-adrenal axis are corticotropin-releasing hormone (CRH), a 41-amino acid peptide, and the nonapeptide arginine-vasopressin, both of which are secreted by parvicellular neurons of the paraventricular nucleus of the hypothalamus into the hypophyseal portal system [3]. There, they synergistically stimulate pituitary adrenocorticotropic hormone (ACTH) secretion and, consequently, cortisol secretion by the adrenal cortex. The noradrenergic brainstem neurons that regulate the central arousal (locus ceruleus) and systemic sympathetic-adrenomedullary systems are innervated and stimulated by and reciprocally innervate and stimulate the parvicellular hypothalamic CRH and arginine-vasopressin neurons of the paraventricular nucleus. The female reproductive system is regulated by the hypothalamic-pituitary-ovarian axis (Figure 1). Neurons that secrete gonadotropin-releasing hormone in the preoptic and arcuate nucleus areas of the hypothalamus secrete into the hypophyseal portal system and stimulate the production of follicle-stimulating and luteinizing hormones, which then activate the ovary to secrete estradiol and progesterone [4]. In addition to acting on their other target tissues (other components of the central nervous system, uterus, genitalia, and skin), both of the gonadal steroids and another ovarian hormone, inhibin, exert negative feedback effects on the secretion of follicle-stimulating and luteinizing hormones. An excellent example of the effect of stress on the female reproductive system is so-called stress-induced or functional hypothalamic amenorrhea [5, 6]. Indeed, the prevalence of sustained secondary amenorrhea in normal young women is about 2%. This rate increases markedly in proportion to chronic stress, all the way up to 100% in prisoners before execution. Thus, if severe enough, stress can completely inhibit the female reproductive system. During her reproductive years, a normal woman is exposed to a monthly fluctuation of circulating estradiol and progesterone that may affect her behavior, mood, and immune and other functions. Indeed, epidemiologic data underscore the effect of gonadal function on nonreproductive female processes [7, 8]. Thus, suicide attempts and allergic bronchial asthma attacks correlate with the phase of the menstrual cycle, with fourfold increases in prevalence seen when the plasma estradiol level is at its lowest (that is, in the late luteal and menstruation phases) [9, 10]. Other studies have suggested that the period of peak estradiol secretion in the state immediately before ovulation is associated with elevations in mood, a phenomenon that might contribute to fecundity. Hypothalamic-Pituitary-Adrenal Axis and the Female Reproductive System Dr. David Torpy (Developmental Endocrinology Branch, NICHD, NIH): The hypothalamic-pituitary-adrenal axis, when activated by stress, has an inhibitory effect on the reproductive system; teleologically, this makes sense (Figure 1; Table 1). Indeed, the hypothalamic CRH neurons innervate and inhibit directly or indirectly, through proopiomelanocortin neurons, the hypothalamic control center of the gonadal axis [11]. In addition, glucocorticoids secreted from the adrenal cortex act at the levels of the hypothalamic, pituitary, gonadal, and end-target tissues to suppress the gonadal axis. On the other hand, estradiol exerts a negative, although indirect, effect on the activity of the gonadotropin-releasing hormone neuron, which has no detectable estrogen receptor [12]. Table 1. Interactions between the Stress System and the Female Reproductive System* The interaction between the hypothalamic-pituitary-adrenal and gonadal axes at the level of the hypothalamus was directly examined in rhesus monkeys [13]. Insulin-induced hypoglycemia caused an increase in cortisol levels and a decrease in plasma luteinizing hormone levels associated with reduced electrical activity measured directly at the gonadotropin-releasing hormone neuron. When a CRH antagonist was given intracerebroventricularly, the effect of insulin hypoglycemia on electrical activity at the gonadotropin-releasing hormone pulse generator was greatly attenuated; this finding suggests that CRH has a direct effect on the hypothalamic neurons that secrete gonadotropin-releasing hormone. Glucocorticoids inhibit gonadal axis function at the hypothalamic, pituitary, and uterine levels [14-16]. Sakakura and colleagues studied women who had received prednisolone for various indications for 1.5 to 5 months in daily doses ranging from 10 mg to 40 mg [15]. All of these women had menstrual disturbances associated with glucocorticoid treatment, and the investigators found that prednisolone reduced the peak luteinizing hormone response to intravenous gonadotropin-releasing hormone by about 60%. This suggests an inhibitory effect of glucocorticoids on the pituitary gonadotroph. Glucocorticoids also inhibit estradiol-stimulated uterine growth [16]. In one placebo-controlled experiment done in rats, dexamethasone and estradiol were administered for 5 days. Estradiol alone produced the expected increase in uterine weight; this increase was significantly attenuated by daily coadministration of dexamethasone, the effect of which may be partly explained by the reduced intracellular estrogen receptor concentrations measured in this experiment. Most likely, however, glucocorticoid receptor-mediated inhibition of the c-fos/c-jun transcription factor by protein-protein interaction is primarily responsible for this inhibition [17]; this factor is used in the signal transduction pathways of many growth factors and is directly or indirectly stimulated by estrogen [18]. Estrogen, which is derived principally from the ovaries, stimulates the hypothalamic-pituitary-adrenal axis (Figure 1). This had been suspected on the basis of sex differences in hypothalamic-pituitary-adrenal axis responses to stimuli in both animals and humans [19]. Compared with controls, pregnant women and women receiving high-dose estrogen therapy had elevated levels of free cortisol in both morning and evening plasma samples [20]. In addition, hypothalamic-pituitary-adrenal axis responsiveness is greater in women than in men. When ACTH and cortisol responses to ovine CRH were compared in 24 men and 19 women [21], the ACTH peak response was significantly greater in women and the cortisol response was characteristically prolonged in response to higher peak ACTH levels. Estrogen can induce hyperresponsiveness of the hypothalamic-pituitary-adrenal axis to stimuli in normal men; thus, this effect seems to be due to estrogen rather than to other factors specific to female physiology [22]. Recently, estradiol patches were given to normal men who were then subjected to a psychosocial stressor-unprepared public speaking-for 15 minutes. Cortisol and ACTH responses were greater in the estradiol recipients than in the placebo recipients. Similarly, the plasma norepinephrine response in these men was augmented by estrogen, possibly because of the stimulation of CRH neurons (which innervate and stimulate central noradrenergic neurons) or because of direct effects on the production or metabolism of norepinephrine [23, 24]. Estrogen stimulation of the hypothalamic-pituitary-adrenal axis may be exerted through interaction of the ligand-activated estrogen receptor with specific DNA sequences, the estrogen-responsive elements, in the promoter of the human CRH gene [25, 26]. Estrogen may exert some of its physiologic negative feedback effect on the reproductive axis through a subpopulation of CRH and proopiomelanocortin neurons that inhibit gonadotropin-releasing hormone and, hence, follicle-stimulating hormone and luteinizing hormone secretion. Evidence from studies in

Acute hypothalamic-pituitary-adrenal responses to the stress of treadmill exercise. Physiologic adaptations to physical training

To study the effects of physical conditioning on the hypothalamic-pituitary-adrenal axis, we examined the plasma ACTH, cortisol, and lactate responses in sedentary subjects, moderately trained runners, and highly trained runners to graded levels of treadmill exercise (50, 70, and 90 percent of maximal oxygen uptake) and to intravenous ovine corticotropin-releasing hormone (1 microgram per kilogram of body weight). Basal evening concentrations of ACTH and cortisol, but not of lactate, were elevated in highly trained runners as compared with sedentary subjects and moderately trained runners. Exercise-stimulated ACTH, cortisol, and lactate responses were similar in all groups and were proportional to the exercise intensity employed. These responses, however, were attenuated in the trained subjects when plotted against applied absolute workload. Only the highly trained group had diminished responses of ACTH and cortisol to ovine corticotropin-releasing hormone, consistent with sustained hypercortisolism. We conclude that physical conditioning is associated with a reduction in pituitary-adrenal activation in response to a given workload. Alterations of the hypothalamic-pituitary-adrenal axis consistent with mild hypercortisolism and similar to findings in depression and anorexia nervosa were found only in highly trained runners. Whether these alterations represent an adaptive change to the daily stress of strenuous exercise or a marker of a specific personality profile in highly trained athletes is unknown.

Bone Mineral Density in Women with Depression

BACKGROUND Depression is associated with alterations in behavior and neuroendocrine systems that are risk factors for decreased bone mineral density. This study was undertaken to determine whether women with past or current major depression have demonstrable decreases in bone density. METHODS We measured bone mineral density at the hip, spine, and radius in 24 women with past or current major depression and 24 normal women matched for age, body-mass index, menopausal status, and race, using dual-energy x-ray absorptiometry. We also evaluated cortisol and growth hormone secretion, bone metabolism, and vitamin D-receptor alleles. RESULTS As compared with the normal women, the mean (+/-SD) bone density in the women with past or current depression was 6.5 percent lower at the spine (1.00+/-0.15 vs. 1.07+/-0.09 g per square centimeter, P=0.02), 13.6 percent lower at the femoral neck (0.76+/-0.11 vs. 0.88+/-0.11 g per square centimeter, P<0.001), 13.6 percent lower at Wards triangle (0.70+/-0.14 vs. 0.81+/-0.13 g per square centimeter, P<0.001), and 10.8 percent lower at the trochanter (0.66+/-0.11 vs. 0.74+/-0.08 g per square centimeter, P<0.001). In addition, women with past or current depression had higher urinary cortisol excretion (71+/-29 vs. 51+/-19 micrograms per day [196+/-80 vs. 141+/-52 nmol per day], P=0.006), lower serum osteocalcin concentration (P=0.04), and lower urinary excretion of deoxypyridinoline (P=0.02). CONCLUSIONS Past or current depression in women is associated with decreased bone mineral density.

Abnormal hypothalamic-pituitary-adrenal function in anorexia nervosa: pathophysiologic mechanisms in underweight and weight-corrected patients

To study the pathophysiology of hypercortisolism in patients with anorexia nervosa, we examined plasma ACTH and cortisol responses to ovine corticotropin-releasing hormone before and after correction of weight loss. We also studied patients with bulimia whose weight was normal, since this disorder has been suspected to be a variant of anorexia nervosa. Before their weight loss was corrected, the anorexic patients had marked hypercortisolism but normal basal plasma ACTH. The hypercortisolism was associated with a marked reduction in the plasma ACTH response to corticotropin-releasing hormone. When these patients were studied three to four weeks after their body weight had been restored to normal, the hypercortisolism had resolved but the abnormal response to corticotropin-releasing hormone remained unchanged. On the other hand, at least six months after correction of weight loss their responses were normal. The bulimic patients whose weight was normal also had a normal response to corticotropin-releasing hormone. We conclude that in underweight anorexics, the pituitary responds appropriately to corticotropin-releasing hormone, being restrained in its response by the elevated levels of cortisol. This suggests that hypercortisolism in anorexics reflects a defect at or above the hypothalamus. The return to eucortisolism soon after correction of the weight loss indicates resolution of this central defect despite persistence of abnormalities in adrenal function.

The Stress Response and the Regulation of Inflammatory Disease

The molecular and biochemical bases for interactions between the immune and central nervous systems are described. Immune cytokines not only activate immune function but also recruit central stress-responsive neurotransmitter systems in the modulation of the immune response and in the activation of behaviors that may be adaptive during injury or inflammation. Peripherally generated cytokines, such as interleukin-1, signal hypothalamic corticotropin-releasing hormone (CRH) neurons to activate pituitary-adrenal counter-regulation of inflammation through the potent antiinflammatory effects of glucocorticoids. Corticotropin-releasing hormone not only activates the pituitary-adrenal axis but also sets in motion a coordinated series of behavioral and physiologic responses, suggesting that the central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. The pathophysiologic perturbation of this feedback loop, through various mechanisms, results in the development of inflammatory syndromes, such as rheumatoid arthritis, and behavioral syndromes, such as depression. Thus, diseases characterized by both inflammatory and emotional disturbances may derive from common alterations in specific central nervous system pathways (for example, the CRH system). In addition, disruptions of this communication by genetic, infectious, toxic, or pharmacologic means can influence the susceptibility to disorders associated with both behavioral and inflammatory components and potentially alter their natural history. These concepts suggest that neuropharmacologic agents that stimulate hypothalamic CRH might potentially be adjunctive therapy for illnesses traditionally viewed as inflammatory or autoimmune.

Induction of corticotropin-releasing hormone gene expression by glucocorticoids: implication for understanding the states of fear and anxiety and allostatic load.

Evidence supports the idea of two distinct corticotropin-releasing hormone (CRH) systems in the brain: one which is constrained by glucocorticoids and the other which is not. It is this latter system that includes two primary sites (central nucleus of the amygdala and the lateral bed nucleus of the stria terminalis) in which the regulation of CRH gene expression can be disassociated from that of the paraventricular nucleus of the hypothalamus. It is this other system that we think is linked to fear and anxiety and to clinical syndromes (excessively shy fearful children, melancholic depression, post-traumatic stress disorder and self-administration of psychotropic drugs). The excess glucocorticoids and CRH, and the state of anticipatory anxiety, contribute to allostatic load, a new term that refers to the wear and tear on the body and brain arising from attempts to adapt to adversity.