philip gold - Academia.edu (original) (raw)

Papers by philip gold

Research paper thumbnail of The Physiology of Stress and Behavioral Development

Psychology Press, Feb 25, 2014

ABSTRACT

Research paper thumbnail of Mania leading to self-induced subcutaneous emphysema

The American journal of psychiatry, 1983

Research paper thumbnail of Neurotransmitter Metabolism in Anorexia Nervosa

The Psychobiology of Anorexia Nervosa, 1984

Anorexia nervosa is a psychosomatic disorder in which the interplay between psychological and bio... more Anorexia nervosa is a psychosomatic disorder in which the interplay between psychological and biological factors is particularly apparent. The illness appears to develop from a variety of psychosocial and sociocultural stressors, but when the syndrome is fully developed the symptoms are stereotyped. It is possible that, at this point, a characteristic neurobiological syndrome exists, such as occurs in endogenous depression. Evidence to support this hypothesis has developed in recent years. A variety of abnormalities of neuroendocrine function indicate hypothalamic dysfunction in the acute, underweight stages of anorexia nervosa (Vigersky and Loriaux 1977). Various neuroendocrine abnormalities documented in anorexia nervosa include abnormal regulation of growth hormone, gonadotropins, thyrotropin-stimulating hormone, cortisol, defects in urinary concentration or dilution, and failure to regulate core body temperature. Investigators in endocrinology have speculated that these endocrine abnormalities might be secondary to changes in brain neurotransmitter function or metabolism. The dexamethasone suppression test, a biological marker of endogenous depression, is abnormal in many patients with anorexia nervosa (Gerner and Gwirtsman 1981). A large amount of data in animals implicates monoamines, particularly catecholamines and serotonin, in the normal hypothalamic regulation of appetite. A catecholamine hypothesis of the etiology of anorexia nervosa and bulimia has been proposed by Leibowitz (Leibowitz, to be published).

Research paper thumbnail of Re-assessing the catecholamine hypothesis of depression: the case of melancholic depression

Molecular Psychiatry, 2021

The hypothesis that major depression represents a deficiency of norepinephrine (NE) at critical s... more The hypothesis that major depression represents a deficiency of norepinephrine (NE) at critical synapses in the central nervous system has been extremely influential since the mid-1960s. First espoused by Schildkraut [1] and Bunney and Davis [2], the hypothesis was based on the following pharmacological evidence: (i) that imipramine acutely increased NE neurotransmission; (ii) that MAO (monoamine oxidase) inhibitors blocked the metabolism of NE, and hence increased NE neurotransmission; (iii) reserpine, which produced depression, depleted NE from noradrenergic neurons [1, 2]. Though several have questioned the validity of the hypothesis, it has never been definitively challenged. We report here that noradrenergic neurotransmission and locus caeruleus activity is increased rather than decreased in the specific subtype of major depression, melancholia [3–5]. The symptom complex of melancholic depression is compatible with NE hypersecretion in multiple ways [5]. Melancholia contradicts the term depression, in that it is not a state of behavioral and physiological suppression, but rather, often a state of hyperarousal and a tortured sense of worthlessness. NE promotes anxiety and hyperarousal, stimulates corticotropin-releasing hormone (CRH)-mediated hypercortisolism, is neurotoxic promotes insulin resistance, and is an important mediator of bone loss, all of which are relevant to melancholic depression (reviewed in [5]). We found that patients with melancholic depression had increased CSF (cerebrospinal fluid) and plasma levels of NE in samples taken hourly through indwelling lumbar and venous cannula sampled hourly for 30 h [3, 4] (Fig. 1). Plasma cortisol and epinephrine levels were also elevated during the entire 30 h (Fig. 1) [3]. We also found that in both patients and controls, CSF and plasma NE had virtually identical diurnal variations and their diurnal variations were also superimposable with that of plasma cortisol (Fig. 1) [3, 4]. Detrended lag correlations revealed that around-the-clock CSF and plasma NE and plasma cortisol levels were significantly correlated independent of the diurnal rhythm [4]. Not only are CSF and plasma NE levels elevated around-the-clock in depressed patients, but their linkage with the hypercortisolism of melancholia makes it virtually inconceivable that plasma and CSF NE are reduced in depressed patients in the setting sustained elevations in plasma cortisol. This is further supported by the well-known close linkage between the CRH and locus caeruleus/NE systems. Valentino has shown that CRH stimulates the locus caeruleus, while we have shown that NE stimulates CRH release [6]. In addition, it has been found that differential blockade of CRF-evoked behaviors occurs by depletion of NE in rats. Finally, data confirm that CRH engagement of the locus caeruleus-NE system mediates stress-induced anxiety [7]. We also found NE spillover into arterial plasma is also significantly elevated in patients with depression compared to controls at baseline and in response to video-game stress and yohimbine, an alpha-2 noradrenergic antagonist that increases the secretion of plasma NE [3] (Fig. 2). NE spillover into arterial plasma represents the levels of arterial NE corrected for their half-lives via the clearance of NE. This study clearly supports the results of the 30 h studies and strongly support the premise that NE is elevated in patients with melancholic depression. This premise is supported by multiple lines of data showing that multiple tricyclic antidepressant drugs, which are preferentially effective in melancholia. decrease the basal and sensory-evoked firing rates of locus caeruleus * Philip W. Gold philipgold@mail.nih.gov

Research paper thumbnail of The PPARg System in Major Depression: Pathophysiologic and Therapeutic Implications

International Journal of Molecular Sciences, 2021

To an exceptional degree, and through multiple mechanisms, the PPARg system rapidly senses cellul... more To an exceptional degree, and through multiple mechanisms, the PPARg system rapidly senses cellular stress, and functions in the CNS in glial cells, neurons, and cerebrovascular endothelial cell in multiple anti-inflammatory and neuroprotective ways. We now know that depression is associated with neurodegeneration in the subgenual prefrontal cortex and hippocampus, decreased neuroplasticity, and defective neurogenesis. Brain-derived neurotrophic factor (BDNF) is markedly depleted in these areas, and is thought to contribute to the neurodegeneration of the subgenual prefrontal cortex and the hippocampus. The PPARg system strongly increases BDNF levels and activity in these brain areas. The PPARg system promotes both neuroplasticity and neurogenesis, both via effects on BDNF, and through other mechanisms. Ample evidence exists that these brain areas transduce many of the cardinal features of depression, directly or through their projections to sites such as the amygdala and nucleus ac...

Research paper thumbnail of Introduction: The Concept of Stress and Its Historical Development

Advances in Experimental Medicine and Biology, 1988

The terra “stress” has been used, and occasionally abused, by scientists and by the lay public, i... more The terra “stress” has been used, and occasionally abused, by scientists and by the lay public, in almost every single language of the civilized world. Many definitions and meanings have been ascribed either consciously or unconsciously to the word. Nevertheless, despite a lack of general agreement about its meaning, the term has prevailed because it attempts to address a basic principle of Nature, that of maintenance of balance, equilibrium, or harmony in the face of disturbing forces on the one hand and counteracting reestablishing forces on the other. One potential reason for the confusion surrounding the term “stress” is that it has been variously used to describe the disturbing forces, the disturbed balance or disequilibrium, and/or the results of the counteracting, reestablishing forces.

Research paper thumbnail of The Impact of Normal Volunteers on a Psychiatric Research Unit

American Journal of Psychiatry, 1979

Normal subjects were admitted to a psychiatric unit devoted to the study and treatment of affecti... more Normal subjects were admitted to a psychiatric unit devoted to the study and treatment of affective illness. Initially the authors were concerned about the difficulties volunteers might have living with psychiatric patients. However, the volunteers adjusted with relative ease, while the patients' depressive symptoms were exacerbated. Their confrontation with the volunteers "normality" triggered an acute awareness of their underlying sense of failure. This response is analogous to depressed patients' reactions before discharge, when they struggle not only with their special vulnerability to separation and loss but with inevitable challenges to their fragile self-esteem during reintegration into the outside world. The presence of normal volunteers highlighted these issues and led to increased therapeutic work and considerable resolution.

Research paper thumbnail of Hemodynamic and Endocrine Parameters in the Anesthetized Cynomolgus Monkey: A Primate Model

Journal of Medical Primatology, 1984

Hemodynamic and endocrine parameters were determined in nine anesthetized adult male cynomolgus m... more Hemodynamic and endocrine parameters were determined in nine anesthetized adult male cynomolgus monkeys. Simultaneous phasic and mean pressures were measured in the right atrium, pulmonary artery, and abdominal aorta. Intermittent pulmonary artery wedge pressures and mean cardiac output measured by the thermal dilution method were used to calculate stroke volume, systemic vascular resistance, and pulmonary vascular resistance. Plasma adrenocorticotropic hormone (ACTH), cortisol, and plasma renin activity were measured throughout the procedure. Technical aspects, data in the anesthetized monkey, and comparison with previously reported data are presented.

Research paper thumbnail of F171. Ketamine Modulates Kynurenine Pathway in Mood Disorders: A Longitudinal Structural Equation Model

Biological Psychiatry, 2018

Background: Relationship style can influence the patientphysician relationship, adherence to trea... more Background: Relationship style can influence the patientphysician relationship, adherence to treatment recommendations and course of illness. Insecure attachment styles are more prevalent in individuals with mood disorders and has been associated with worse clinical outcomes, whereas a secure attachment is linked to more positive health behaviors, such as greater adherence to health plans and preventive health behaviors. Aim: To examine the prevalence of close relationship/attachment styles in patients with major depression (MDD), bipolar type I (BPI) or bipolar type II (BPII). Methods: 219 participants were recruited from the Mood Disorders Program of the McGill University Health Center in Montreal, Quebec. Mood diagnoses were determined using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). Relationship/attachment styles were assessed using the Experiences in Close Relationships Questionnaire, anxious and avoidant attachment styles were examined. One-way ANOVA and Tukey post-hoc tests were conducted to examine the prevalence of attachment styles within each diagnostic group. Results: The prevalence of anxious attachment differed in the MDD, BPI and BPII groups (F (2, 180) ¼ 5.652, p ¼ .004). There was no difference in prevalence of avoidant attachment style between the groups. Post-testing revealed that the BPII (4.5 ± 1.31) scored significantly higher than the BPI group (3.73 ± 1.25, p ¼ .003). Conclusions: Bipolar type I and type II groups may develop different type of relationships with their treatment team as a consequence of their attachment patterns. Modification of treatment approaches may be warranted.

Research paper thumbnail of A Major Role for the Lateral Habenula in Depressive Illness: Physiologic and Molecular Mechanisms

Frontiers in Psychiatry, 2019

Emerging preclinical and clinical evidence indicate that the lateral habenula plays a major role ... more Emerging preclinical and clinical evidence indicate that the lateral habenula plays a major role in the pathophysiology of depressive illness. Aberrant increases in neuronal activity in the lateral habenula, an anti-reward center, signals down-regulation of brainstem dopaminergic and serotonergic firing, leading to anhedonia, helplessness, excessive focus on negative experiences, and, hence, depressive symptomatology. The lateral habenula has distinctive regulatory adaptive role to stress regulation in part due to its bidirectional connectivity with the hypothalamic-pituitary-adrenal (HPA) axis. In addition, studies show that increased lateral habenula activity affects components of sleep regulation including slow wave activity and rapid eye movement (REM), both disrupted in depressive illness. Lack of perceived reward experienced during the adverse outcomes also precipitates lateral habenula firing, while outcomes that meet or exceed expectations decrease lateral habenula firing and, in turn, increase midbrain dopaminergic and serotonergic neurotransmission. The ability to update expectations of the environment based on rewards and aversive stimuli reflects a potentially important survival mechanism relevant to the capacity to adapt to changing circumstances. What if one lives in a continuously aversive and invalidating environment or under the conditions of chronic stress? If there is a propensity of the habenula to release many burst discharges over time, an individual could habitually come to perceive the world as perpetually disappointing. Conceivably, the lateral habenula could learn to expect an adverse outcome systematically and communicate it more easily. Thus, if the lateral habenula fires more frequently, it may lead to a state of continuous disappointment and hopelessness, akin to depression. Furthermore, postmortem studies reveal that the size of the lateral habenula and total number of neurons are decreased in patients who had depressive illness. Novel research in the field shows that ketamine induces rapid and sustained antidepressant effect. Intriguingly, recent preclinical animal models show that ketamine abolishes N-methyl-D-aspartate receptor (NMDAR)-dependent lateral habenula bursting activity, leading to rapid resolution of depressive symptoms.

Research paper thumbnail of Altered expression of type 2 CRH receptor mRNA in the VMH by glucocorticoids and starvation

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1998

In the rat, high-dose corticosterone (Cort) administration, the hypercortisolism of starvation, a... more In the rat, high-dose corticosterone (Cort) administration, the hypercortisolism of starvation, and adrenalectomy are all associated with decreased food intake and weight loss. We report here a study of the effects of high-dose Cort administration, starvation, and adrenalectomy on two peripheral hormones known to influence food intake and energy use, insulin and leptin. We also studied the impact of these interventions on the levels of type 2 corticotropin-releasing hormone receptor (CRHR-2) mRNA in the hypothalamic paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH). The VMH is classically referred to as the satiety center because electrical stimulation of the VMH leads to inhibition of food intake, whereas CRHR-2 are thought to transduce the profound anorexogenic effects of CRH or its related peptide urocortin. Starvation and adrenalectomy each lowered plasma insulin and leptin levels and were associated with decrements in CRHR-2 mRNA levels in the VMH. Cort administ...

Research paper thumbnail of Basic and Clinical Studies with Corticotropin-Releasing Hormone

Psychiatric Clinics of North America, 1988

Research paper thumbnail of Hormonal and metabolic responses to exercise across time of day and menstrual cycle phase

Journal of Applied Physiology, 1997

Galliven, E. A., A. Singh, D. Michelson, S. Bina, P. W. Gold, and P. A. Deuster. Hormonal and met... more Galliven, E. A., A. Singh, D. Michelson, S. Bina, P. W. Gold, and P. A. Deuster. Hormonal and metabolic responses to exercise across time of day and menstrual cycle phase. J. Appl. Physiol. 83(6): 1822–1831, 1997.—Two studies, each utilizing short-term treadmill exercise of a different intensity, assessed the metabolic and hormonal responses of women to exercise in the morning (AM) and late afternoon (PM). In study 1, plasma concentrations of growth hormone, arginine vasopressin, catecholamines, adrenocorticotropic hormone, cortisol, lactate, and glucose were measured before, during, and after high-intensity exercise (90% maximal O2 uptake) in the AM and PM. In study 2, plasma concentrations of adrenocorticotropic hormone, cortisol, lactate, and glucose were measured before, during, and after moderate-intensity exercise (70% maximal O2 uptake) in the AM and PM in the follicular ( days 3–9), midcycle ( days 10–16), and luteal ( days 18–26) phases of the menstrual cycle. The results o...

Research paper thumbnail of Marked differences in functioning of the hypothalamicpituitary-adrenal axis between groups of men

Journal of Applied Physiology, 1997

Petrides, John S., Philip W. Gold, Gregory P. Mueller, Anita Singh, Costas Stratakis, George P. C... more Petrides, John S., Philip W. Gold, Gregory P. Mueller, Anita Singh, Costas Stratakis, George P. Chrousos, and Patricia A. Deuster.Marked differences in functioning of the hypothalamic-pituitary-adrenal axis between groups of men. J. Appl. Physiol. 82(6): 1979–1988, 1997.—To compare profiles of hypothalamic-pituitary-adrenal (HPA) responsiveness, healthy, moderately trained men ( n = 15) were classified as high ( n = 7) or low responders ( n = 8) on the basis of plasma adrenocorticotropic hormone (ACTH) responses to strenuous treadmill exercise 4 h after 4 mg of dexamethasone (Dex). These groups were then evaluated to compare 1) HPA and growth hormone responses to exercise at 90% maximal oxygen uptake 4 h after placebo, Dex (4 mg), and hydrocortisone (100 mg); 2) pituitary-adrenal responses to infusion of arginine vasopressin (AVP); 3) plasma cortisol after a Dex suppression test (1 mg); and 4) behavioral characteristics. In comparison to low responders, high responders exhibited sig...

Research paper thumbnail of Eating behavior in bulimia nervosa: multiple meal analyses

The American Journal of Clinical Nutrition, 1994

Ten bulimic individuals were admitted to an inpatient unit and for 7 consecutive days eating beha... more Ten bulimic individuals were admitted to an inpatient unit and for 7 consecutive days eating behavior was observed and recorded. Age, sex, and weight-matched control subjects (n = 10) were admitted to the same unit for 4 d. All food and fluid intake, frequency ofbinge eating and purging, and ratings of appetite and mood before and after eating were recorded every 24 h. Bulimic patients demonstrated chaotic eating patterns that varied within as well as between individuals. Total daily energy intake was significantly higher for bulimic patients (41982 ± 1 13 U; 10 034 ± 2701 kcal) than for control subjects (8050 ± 0427 U; 1924 ± 102 kcal). On average, patients binged 1.6 times, purged three times, and ate one snack or meal without purging daily. Macronutnient analyses of intake revealed significantly less energy from protein and more energy from fat in bulimic patients compared with control subjects. Some improvement of mood was noted after binges, the magnitude of which was greatest after purging.

Research paper thumbnail of Food selection and intake of obese women with binge-eating disorder

The American Journal of Clinical Nutrition, 1992

Research paper thumbnail of Young adult's attachment style as a partial mediator between maternal functioning and young adult offsprings' functioning

Journal of affective disorders, May 1, 2018

The quality of our early attachment relationships with primary caregivers is carried forward to n... more The quality of our early attachment relationships with primary caregivers is carried forward to new developmental domains, including interpersonal contexts in adulthood. One of the factors that can disrupt early attachment is maternal depression, which may be associated with less responsive care and may impede the development of a secure attachment. Moreover, this disruption in secure attachment may act as a mechanism by which offspring of depressed mothers are more likely to experience their own psychopathology. In this study we predicted that attachment anxiety and avoidance would mediate the relationship between maternal depression diagnosis and functional impairment predicting young adult offspring's functional impairment. This study utilized longitudinal data from 98 families with clinically diagnosed depressed and well mothers, and two of their young adult children, an older and younger sibling (N = 123, Female = 75, Mage = 22.09, SD = 2.57). Mother's and young adult c...

Research paper thumbnail of Supression of plasma cortisol in depressed patients by acute intravenous methadone infusion

American Journal of Psychiatry, 1980

1. Am J Psychiatry. 1980 Jul;137(7):862-3. Supression of plasma cortisol in depressed patients by... more 1. Am J Psychiatry. 1980 Jul;137(7):862-3. Supression of plasma cortisol in depressed patients by acute intravenous methadone infusion. Gold PW, Extein I, Pickar D, Rebar R, Ross R, Goodwin FK. PMID: 7386677 [PubMed - indexed for MEDLINE]. MeSH Terms. ...

Research paper thumbnail of Prospective assessment of menstrually related mood disorders

American Journal of Psychiatry, 1984

For prospective longitudinal confirmation of menstrually related mood changes, the authors select... more For prospective longitudinal confirmation of menstrually related mood changes, the authors selected a 100-mm visual analogue scale for twice-daily self-rating of mood. The advantages of this method are simplicity; increased compliance; ease of graphic presentation, allowing evaluation of severity and relationship to menstruation; and greater uniformity among studies of menstrually related syndromes. In a preliminary application of this measure to 20 women with self-diagnosed premenstrual syndrome, eight (40%) had a mean depression rating during the week before menstruation that was 30% higher than during the week after cessation of menstruation.

Research paper thumbnail of CSF oxytocin in anorexia nervosa and bulimia nervosa: clinical and pathophysiologic considerations

American Journal of Psychiatry, 1990

Oxytocin is a hypothalamic neuropeptide with both centrally and peripherally directed pathways. D... more Oxytocin is a hypothalamic neuropeptide with both centrally and peripherally directed pathways. Data from experimental animals indicate that oxytocin impairs consolidation of aversively conditioned behaviors and is released after feeding or experimental gastric distension. The authors report that the mean CSF oxytocin level of five underweight women with restricting anorexia, but not 12 underweight bulimic anorexic women or 35 normal-weight women with bulimia nervosa, was significantly lower than the level of 11 control subjects. Restricting anorexic patients' low CSF oxytocin levels may reflect their persistently low food intake, and this behavior may exacerbate their tendency for perseverative preoccupation with adverse consequences of food intake.

Research paper thumbnail of The Physiology of Stress and Behavioral Development

Psychology Press, Feb 25, 2014

ABSTRACT

Research paper thumbnail of Mania leading to self-induced subcutaneous emphysema

The American journal of psychiatry, 1983

Research paper thumbnail of Neurotransmitter Metabolism in Anorexia Nervosa

The Psychobiology of Anorexia Nervosa, 1984

Anorexia nervosa is a psychosomatic disorder in which the interplay between psychological and bio... more Anorexia nervosa is a psychosomatic disorder in which the interplay between psychological and biological factors is particularly apparent. The illness appears to develop from a variety of psychosocial and sociocultural stressors, but when the syndrome is fully developed the symptoms are stereotyped. It is possible that, at this point, a characteristic neurobiological syndrome exists, such as occurs in endogenous depression. Evidence to support this hypothesis has developed in recent years. A variety of abnormalities of neuroendocrine function indicate hypothalamic dysfunction in the acute, underweight stages of anorexia nervosa (Vigersky and Loriaux 1977). Various neuroendocrine abnormalities documented in anorexia nervosa include abnormal regulation of growth hormone, gonadotropins, thyrotropin-stimulating hormone, cortisol, defects in urinary concentration or dilution, and failure to regulate core body temperature. Investigators in endocrinology have speculated that these endocrine abnormalities might be secondary to changes in brain neurotransmitter function or metabolism. The dexamethasone suppression test, a biological marker of endogenous depression, is abnormal in many patients with anorexia nervosa (Gerner and Gwirtsman 1981). A large amount of data in animals implicates monoamines, particularly catecholamines and serotonin, in the normal hypothalamic regulation of appetite. A catecholamine hypothesis of the etiology of anorexia nervosa and bulimia has been proposed by Leibowitz (Leibowitz, to be published).

Research paper thumbnail of Re-assessing the catecholamine hypothesis of depression: the case of melancholic depression

Molecular Psychiatry, 2021

The hypothesis that major depression represents a deficiency of norepinephrine (NE) at critical s... more The hypothesis that major depression represents a deficiency of norepinephrine (NE) at critical synapses in the central nervous system has been extremely influential since the mid-1960s. First espoused by Schildkraut [1] and Bunney and Davis [2], the hypothesis was based on the following pharmacological evidence: (i) that imipramine acutely increased NE neurotransmission; (ii) that MAO (monoamine oxidase) inhibitors blocked the metabolism of NE, and hence increased NE neurotransmission; (iii) reserpine, which produced depression, depleted NE from noradrenergic neurons [1, 2]. Though several have questioned the validity of the hypothesis, it has never been definitively challenged. We report here that noradrenergic neurotransmission and locus caeruleus activity is increased rather than decreased in the specific subtype of major depression, melancholia [3–5]. The symptom complex of melancholic depression is compatible with NE hypersecretion in multiple ways [5]. Melancholia contradicts the term depression, in that it is not a state of behavioral and physiological suppression, but rather, often a state of hyperarousal and a tortured sense of worthlessness. NE promotes anxiety and hyperarousal, stimulates corticotropin-releasing hormone (CRH)-mediated hypercortisolism, is neurotoxic promotes insulin resistance, and is an important mediator of bone loss, all of which are relevant to melancholic depression (reviewed in [5]). We found that patients with melancholic depression had increased CSF (cerebrospinal fluid) and plasma levels of NE in samples taken hourly through indwelling lumbar and venous cannula sampled hourly for 30 h [3, 4] (Fig. 1). Plasma cortisol and epinephrine levels were also elevated during the entire 30 h (Fig. 1) [3]. We also found that in both patients and controls, CSF and plasma NE had virtually identical diurnal variations and their diurnal variations were also superimposable with that of plasma cortisol (Fig. 1) [3, 4]. Detrended lag correlations revealed that around-the-clock CSF and plasma NE and plasma cortisol levels were significantly correlated independent of the diurnal rhythm [4]. Not only are CSF and plasma NE levels elevated around-the-clock in depressed patients, but their linkage with the hypercortisolism of melancholia makes it virtually inconceivable that plasma and CSF NE are reduced in depressed patients in the setting sustained elevations in plasma cortisol. This is further supported by the well-known close linkage between the CRH and locus caeruleus/NE systems. Valentino has shown that CRH stimulates the locus caeruleus, while we have shown that NE stimulates CRH release [6]. In addition, it has been found that differential blockade of CRF-evoked behaviors occurs by depletion of NE in rats. Finally, data confirm that CRH engagement of the locus caeruleus-NE system mediates stress-induced anxiety [7]. We also found NE spillover into arterial plasma is also significantly elevated in patients with depression compared to controls at baseline and in response to video-game stress and yohimbine, an alpha-2 noradrenergic antagonist that increases the secretion of plasma NE [3] (Fig. 2). NE spillover into arterial plasma represents the levels of arterial NE corrected for their half-lives via the clearance of NE. This study clearly supports the results of the 30 h studies and strongly support the premise that NE is elevated in patients with melancholic depression. This premise is supported by multiple lines of data showing that multiple tricyclic antidepressant drugs, which are preferentially effective in melancholia. decrease the basal and sensory-evoked firing rates of locus caeruleus * Philip W. Gold philipgold@mail.nih.gov

Research paper thumbnail of The PPARg System in Major Depression: Pathophysiologic and Therapeutic Implications

International Journal of Molecular Sciences, 2021

To an exceptional degree, and through multiple mechanisms, the PPARg system rapidly senses cellul... more To an exceptional degree, and through multiple mechanisms, the PPARg system rapidly senses cellular stress, and functions in the CNS in glial cells, neurons, and cerebrovascular endothelial cell in multiple anti-inflammatory and neuroprotective ways. We now know that depression is associated with neurodegeneration in the subgenual prefrontal cortex and hippocampus, decreased neuroplasticity, and defective neurogenesis. Brain-derived neurotrophic factor (BDNF) is markedly depleted in these areas, and is thought to contribute to the neurodegeneration of the subgenual prefrontal cortex and the hippocampus. The PPARg system strongly increases BDNF levels and activity in these brain areas. The PPARg system promotes both neuroplasticity and neurogenesis, both via effects on BDNF, and through other mechanisms. Ample evidence exists that these brain areas transduce many of the cardinal features of depression, directly or through their projections to sites such as the amygdala and nucleus ac...

Research paper thumbnail of Introduction: The Concept of Stress and Its Historical Development

Advances in Experimental Medicine and Biology, 1988

The terra “stress” has been used, and occasionally abused, by scientists and by the lay public, i... more The terra “stress” has been used, and occasionally abused, by scientists and by the lay public, in almost every single language of the civilized world. Many definitions and meanings have been ascribed either consciously or unconsciously to the word. Nevertheless, despite a lack of general agreement about its meaning, the term has prevailed because it attempts to address a basic principle of Nature, that of maintenance of balance, equilibrium, or harmony in the face of disturbing forces on the one hand and counteracting reestablishing forces on the other. One potential reason for the confusion surrounding the term “stress” is that it has been variously used to describe the disturbing forces, the disturbed balance or disequilibrium, and/or the results of the counteracting, reestablishing forces.

Research paper thumbnail of The Impact of Normal Volunteers on a Psychiatric Research Unit

American Journal of Psychiatry, 1979

Normal subjects were admitted to a psychiatric unit devoted to the study and treatment of affecti... more Normal subjects were admitted to a psychiatric unit devoted to the study and treatment of affective illness. Initially the authors were concerned about the difficulties volunteers might have living with psychiatric patients. However, the volunteers adjusted with relative ease, while the patients' depressive symptoms were exacerbated. Their confrontation with the volunteers "normality" triggered an acute awareness of their underlying sense of failure. This response is analogous to depressed patients' reactions before discharge, when they struggle not only with their special vulnerability to separation and loss but with inevitable challenges to their fragile self-esteem during reintegration into the outside world. The presence of normal volunteers highlighted these issues and led to increased therapeutic work and considerable resolution.

Research paper thumbnail of Hemodynamic and Endocrine Parameters in the Anesthetized Cynomolgus Monkey: A Primate Model

Journal of Medical Primatology, 1984

Hemodynamic and endocrine parameters were determined in nine anesthetized adult male cynomolgus m... more Hemodynamic and endocrine parameters were determined in nine anesthetized adult male cynomolgus monkeys. Simultaneous phasic and mean pressures were measured in the right atrium, pulmonary artery, and abdominal aorta. Intermittent pulmonary artery wedge pressures and mean cardiac output measured by the thermal dilution method were used to calculate stroke volume, systemic vascular resistance, and pulmonary vascular resistance. Plasma adrenocorticotropic hormone (ACTH), cortisol, and plasma renin activity were measured throughout the procedure. Technical aspects, data in the anesthetized monkey, and comparison with previously reported data are presented.

Research paper thumbnail of F171. Ketamine Modulates Kynurenine Pathway in Mood Disorders: A Longitudinal Structural Equation Model

Biological Psychiatry, 2018

Background: Relationship style can influence the patientphysician relationship, adherence to trea... more Background: Relationship style can influence the patientphysician relationship, adherence to treatment recommendations and course of illness. Insecure attachment styles are more prevalent in individuals with mood disorders and has been associated with worse clinical outcomes, whereas a secure attachment is linked to more positive health behaviors, such as greater adherence to health plans and preventive health behaviors. Aim: To examine the prevalence of close relationship/attachment styles in patients with major depression (MDD), bipolar type I (BPI) or bipolar type II (BPII). Methods: 219 participants were recruited from the Mood Disorders Program of the McGill University Health Center in Montreal, Quebec. Mood diagnoses were determined using the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). Relationship/attachment styles were assessed using the Experiences in Close Relationships Questionnaire, anxious and avoidant attachment styles were examined. One-way ANOVA and Tukey post-hoc tests were conducted to examine the prevalence of attachment styles within each diagnostic group. Results: The prevalence of anxious attachment differed in the MDD, BPI and BPII groups (F (2, 180) ¼ 5.652, p ¼ .004). There was no difference in prevalence of avoidant attachment style between the groups. Post-testing revealed that the BPII (4.5 ± 1.31) scored significantly higher than the BPI group (3.73 ± 1.25, p ¼ .003). Conclusions: Bipolar type I and type II groups may develop different type of relationships with their treatment team as a consequence of their attachment patterns. Modification of treatment approaches may be warranted.

Research paper thumbnail of A Major Role for the Lateral Habenula in Depressive Illness: Physiologic and Molecular Mechanisms

Frontiers in Psychiatry, 2019

Emerging preclinical and clinical evidence indicate that the lateral habenula plays a major role ... more Emerging preclinical and clinical evidence indicate that the lateral habenula plays a major role in the pathophysiology of depressive illness. Aberrant increases in neuronal activity in the lateral habenula, an anti-reward center, signals down-regulation of brainstem dopaminergic and serotonergic firing, leading to anhedonia, helplessness, excessive focus on negative experiences, and, hence, depressive symptomatology. The lateral habenula has distinctive regulatory adaptive role to stress regulation in part due to its bidirectional connectivity with the hypothalamic-pituitary-adrenal (HPA) axis. In addition, studies show that increased lateral habenula activity affects components of sleep regulation including slow wave activity and rapid eye movement (REM), both disrupted in depressive illness. Lack of perceived reward experienced during the adverse outcomes also precipitates lateral habenula firing, while outcomes that meet or exceed expectations decrease lateral habenula firing and, in turn, increase midbrain dopaminergic and serotonergic neurotransmission. The ability to update expectations of the environment based on rewards and aversive stimuli reflects a potentially important survival mechanism relevant to the capacity to adapt to changing circumstances. What if one lives in a continuously aversive and invalidating environment or under the conditions of chronic stress? If there is a propensity of the habenula to release many burst discharges over time, an individual could habitually come to perceive the world as perpetually disappointing. Conceivably, the lateral habenula could learn to expect an adverse outcome systematically and communicate it more easily. Thus, if the lateral habenula fires more frequently, it may lead to a state of continuous disappointment and hopelessness, akin to depression. Furthermore, postmortem studies reveal that the size of the lateral habenula and total number of neurons are decreased in patients who had depressive illness. Novel research in the field shows that ketamine induces rapid and sustained antidepressant effect. Intriguingly, recent preclinical animal models show that ketamine abolishes N-methyl-D-aspartate receptor (NMDAR)-dependent lateral habenula bursting activity, leading to rapid resolution of depressive symptoms.

Research paper thumbnail of Altered expression of type 2 CRH receptor mRNA in the VMH by glucocorticoids and starvation

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 1998

In the rat, high-dose corticosterone (Cort) administration, the hypercortisolism of starvation, a... more In the rat, high-dose corticosterone (Cort) administration, the hypercortisolism of starvation, and adrenalectomy are all associated with decreased food intake and weight loss. We report here a study of the effects of high-dose Cort administration, starvation, and adrenalectomy on two peripheral hormones known to influence food intake and energy use, insulin and leptin. We also studied the impact of these interventions on the levels of type 2 corticotropin-releasing hormone receptor (CRHR-2) mRNA in the hypothalamic paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH). The VMH is classically referred to as the satiety center because electrical stimulation of the VMH leads to inhibition of food intake, whereas CRHR-2 are thought to transduce the profound anorexogenic effects of CRH or its related peptide urocortin. Starvation and adrenalectomy each lowered plasma insulin and leptin levels and were associated with decrements in CRHR-2 mRNA levels in the VMH. Cort administ...

Research paper thumbnail of Basic and Clinical Studies with Corticotropin-Releasing Hormone

Psychiatric Clinics of North America, 1988

Research paper thumbnail of Hormonal and metabolic responses to exercise across time of day and menstrual cycle phase

Journal of Applied Physiology, 1997

Galliven, E. A., A. Singh, D. Michelson, S. Bina, P. W. Gold, and P. A. Deuster. Hormonal and met... more Galliven, E. A., A. Singh, D. Michelson, S. Bina, P. W. Gold, and P. A. Deuster. Hormonal and metabolic responses to exercise across time of day and menstrual cycle phase. J. Appl. Physiol. 83(6): 1822–1831, 1997.—Two studies, each utilizing short-term treadmill exercise of a different intensity, assessed the metabolic and hormonal responses of women to exercise in the morning (AM) and late afternoon (PM). In study 1, plasma concentrations of growth hormone, arginine vasopressin, catecholamines, adrenocorticotropic hormone, cortisol, lactate, and glucose were measured before, during, and after high-intensity exercise (90% maximal O2 uptake) in the AM and PM. In study 2, plasma concentrations of adrenocorticotropic hormone, cortisol, lactate, and glucose were measured before, during, and after moderate-intensity exercise (70% maximal O2 uptake) in the AM and PM in the follicular ( days 3–9), midcycle ( days 10–16), and luteal ( days 18–26) phases of the menstrual cycle. The results o...

Research paper thumbnail of Marked differences in functioning of the hypothalamicpituitary-adrenal axis between groups of men

Journal of Applied Physiology, 1997

Petrides, John S., Philip W. Gold, Gregory P. Mueller, Anita Singh, Costas Stratakis, George P. C... more Petrides, John S., Philip W. Gold, Gregory P. Mueller, Anita Singh, Costas Stratakis, George P. Chrousos, and Patricia A. Deuster.Marked differences in functioning of the hypothalamic-pituitary-adrenal axis between groups of men. J. Appl. Physiol. 82(6): 1979–1988, 1997.—To compare profiles of hypothalamic-pituitary-adrenal (HPA) responsiveness, healthy, moderately trained men ( n = 15) were classified as high ( n = 7) or low responders ( n = 8) on the basis of plasma adrenocorticotropic hormone (ACTH) responses to strenuous treadmill exercise 4 h after 4 mg of dexamethasone (Dex). These groups were then evaluated to compare 1) HPA and growth hormone responses to exercise at 90% maximal oxygen uptake 4 h after placebo, Dex (4 mg), and hydrocortisone (100 mg); 2) pituitary-adrenal responses to infusion of arginine vasopressin (AVP); 3) plasma cortisol after a Dex suppression test (1 mg); and 4) behavioral characteristics. In comparison to low responders, high responders exhibited sig...

Research paper thumbnail of Eating behavior in bulimia nervosa: multiple meal analyses

The American Journal of Clinical Nutrition, 1994

Ten bulimic individuals were admitted to an inpatient unit and for 7 consecutive days eating beha... more Ten bulimic individuals were admitted to an inpatient unit and for 7 consecutive days eating behavior was observed and recorded. Age, sex, and weight-matched control subjects (n = 10) were admitted to the same unit for 4 d. All food and fluid intake, frequency ofbinge eating and purging, and ratings of appetite and mood before and after eating were recorded every 24 h. Bulimic patients demonstrated chaotic eating patterns that varied within as well as between individuals. Total daily energy intake was significantly higher for bulimic patients (41982 ± 1 13 U; 10 034 ± 2701 kcal) than for control subjects (8050 ± 0427 U; 1924 ± 102 kcal). On average, patients binged 1.6 times, purged three times, and ate one snack or meal without purging daily. Macronutnient analyses of intake revealed significantly less energy from protein and more energy from fat in bulimic patients compared with control subjects. Some improvement of mood was noted after binges, the magnitude of which was greatest after purging.

Research paper thumbnail of Food selection and intake of obese women with binge-eating disorder

The American Journal of Clinical Nutrition, 1992

Research paper thumbnail of Young adult's attachment style as a partial mediator between maternal functioning and young adult offsprings' functioning

Journal of affective disorders, May 1, 2018

The quality of our early attachment relationships with primary caregivers is carried forward to n... more The quality of our early attachment relationships with primary caregivers is carried forward to new developmental domains, including interpersonal contexts in adulthood. One of the factors that can disrupt early attachment is maternal depression, which may be associated with less responsive care and may impede the development of a secure attachment. Moreover, this disruption in secure attachment may act as a mechanism by which offspring of depressed mothers are more likely to experience their own psychopathology. In this study we predicted that attachment anxiety and avoidance would mediate the relationship between maternal depression diagnosis and functional impairment predicting young adult offspring's functional impairment. This study utilized longitudinal data from 98 families with clinically diagnosed depressed and well mothers, and two of their young adult children, an older and younger sibling (N = 123, Female = 75, Mage = 22.09, SD = 2.57). Mother's and young adult c...

Research paper thumbnail of Supression of plasma cortisol in depressed patients by acute intravenous methadone infusion

American Journal of Psychiatry, 1980

1. Am J Psychiatry. 1980 Jul;137(7):862-3. Supression of plasma cortisol in depressed patients by... more 1. Am J Psychiatry. 1980 Jul;137(7):862-3. Supression of plasma cortisol in depressed patients by acute intravenous methadone infusion. Gold PW, Extein I, Pickar D, Rebar R, Ross R, Goodwin FK. PMID: 7386677 [PubMed - indexed for MEDLINE]. MeSH Terms. ...

Research paper thumbnail of Prospective assessment of menstrually related mood disorders

American Journal of Psychiatry, 1984

For prospective longitudinal confirmation of menstrually related mood changes, the authors select... more For prospective longitudinal confirmation of menstrually related mood changes, the authors selected a 100-mm visual analogue scale for twice-daily self-rating of mood. The advantages of this method are simplicity; increased compliance; ease of graphic presentation, allowing evaluation of severity and relationship to menstruation; and greater uniformity among studies of menstrually related syndromes. In a preliminary application of this measure to 20 women with self-diagnosed premenstrual syndrome, eight (40%) had a mean depression rating during the week before menstruation that was 30% higher than during the week after cessation of menstruation.

Research paper thumbnail of CSF oxytocin in anorexia nervosa and bulimia nervosa: clinical and pathophysiologic considerations

American Journal of Psychiatry, 1990

Oxytocin is a hypothalamic neuropeptide with both centrally and peripherally directed pathways. D... more Oxytocin is a hypothalamic neuropeptide with both centrally and peripherally directed pathways. Data from experimental animals indicate that oxytocin impairs consolidation of aversively conditioned behaviors and is released after feeding or experimental gastric distension. The authors report that the mean CSF oxytocin level of five underweight women with restricting anorexia, but not 12 underweight bulimic anorexic women or 35 normal-weight women with bulimia nervosa, was significantly lower than the level of 11 control subjects. Restricting anorexic patients' low CSF oxytocin levels may reflect their persistently low food intake, and this behavior may exacerbate their tendency for perseverative preoccupation with adverse consequences of food intake.