Clinical and biochemical aspects of depressive disorders: I. Introduction, classification, and research techniques.

The present review focuses on recent data from clinical and animal research concerning the biochemical bases of depressive disorders, diagnosis, and treatment. In addition to integrating these data, problems and future directions in this research are discussed. The review is presented in three parts.

Pituitary hormone responses to meta-chlorophenylpiperazine in panic disorder and healthy control subjects.

The present study reports adrenocorticotropic hormone (ACTH) and prolactin responses after oral administration of 0.25 mg/kg of the serotonin agonist, meta-chlorophenylpiperazine (MCPP), in patients with panic disorder (PD) and in healthy subjects. MCPP blood levels were similar for the two groups, but almost twice as high in males as in females.

Cerebrospinal fluid immunoreactive corticotropin-releasing hormone and adrenocorticotropin secretion in Cushing's disease and major depression: potential clinical implications.

To explore whether possible differences in central nervous system neuromodulators contribute to the differential presentation of affective symptomatology in Cushing's disease and major depression, we examined the levels of immunoreactive CRH and ACTH in the cerebrospinal fluid (CSF) of 11 patients with Cushing's disease, a patient with ectopic ACTH secretion, 34 patients with major depression, and 60 healthy subjects. We elected to measure these peptides not only because both are classically involved in pituitary-adrenal regulation, but also because their primarily arousal-producing and anorexigenic behavioral effects in experimental animals suggest that they may play a role in the symptom complex of depressive syndromes. We also explored whether the CSF levels of these peptides were more helpful in determining the often difficult differential diagnosis between major depression and Cushing's disease than the plasma ACTH response to ovine CRH, a currently used but somewhat insensitive laboratory means of distinguishing these disorders.

Prednisone effects on neurochemistry and behavior. Preliminary findings.

To evaluate the neurochemical, neuroendocrine, and behavioral effects of exogenous corticosteroids in humans, we administered prednisone (80 mg/d orally for 5 days) in a double-blind manner to 12 medically healthy volunteers. Behavioral measures were assessed before, during, and after prednisone administration in all 12 subjects, and cerebrospinal fluid biochemistry was assessed before and during prednisone administration in 9 of the subjects. Prednisone administration was associated with decreases in cerebrospinal fluid levels of corticotropin, norepinephrine, beta-endorphin, beta-lipotropin, and somatostatinlike immunoreactivity.

Effect of topical application of doxycycline on pulp revascularization and periodontal healing in reimplanted monkey incisors.

Maxillary incisors in 47 monkeys, 54 in the experimental group (I) and 117 in the control group (II), were extracted and reimplanted, either immediately or after 30 or 60 min wet or dry storage. Incisors in the experimental group I were additionally kept 5 min in a suspension of 1 mg doxycycline in 20 ml physiologic saline, freshly prepared for each of the 15 animals before reimplantation. The observation time varied from 6 to 8 weeks.

Pulp revascularization in reimplanted immature monkey incisors--predictability and the effect of antibiotic systemic prophylaxis.

In 32 monkeys 105 immature maxillary incisors were extracted and reimplanted either immediately or after 30 or 60 min wet or dry storage. Of the monkeys, 17 (group I) did not receive and 15 (group II) received prophylactic treatment with 4 mg/kg doxycycline before extraction and 2 mg/kg for 5 d after reimplantation. The observation time varied from 6 to 8 weeks.

A review of prehospital care litigation in a large metropolitan EMS system.

A retrospective review of all claims brought against a large, metropolitan emergency medical services (EMS) system related to paramedic-patient encounters during the 12-year period from 1976 through 1987 was undertaken to review and describe the incidence and types of malpractice claims. During this period, EMS units responded to approximately 2 million calls and transported more than 1 million patients. Sixty claims occurred during the incidence study period (1976 through 1985).

In vitro and in vivo effects of the triazolobenzodiazepine alprazolam on hypothalamic-pituitary-adrenal function: pharmacological and clinical implications.

We report here a study of the effects of alprazolam on in vivo pituitary-adrenal function in jacketed nonrestrained nonhuman primates and on in vitro CRH release from rat hypothalami and ACTH release from rat dispersed anterior pituicytes. We undertook this study because alprazolam is the only benzodiazepine effective in treating both major depressive and anxiety disorders, and recent data suggest that the hypercortisolism of major depression reflects hypersecretion of CRH. Moreover, the intracerebroventricular administration of CRH can reproduce many of the components of the symptom complex of major depression, including not only hypercortisolism, but also hypothalamic hypogonadism, decreased libido, anorexia, and intense anxiety.

Effects of m-chlorophenylpiperazine in normal subjects: a dose-response study.

m-Chlorophenylpiperazine (MCPP), a direct 5HT receptor agonist, was administered orally to 20 normal subjects in two doses (0.25 and 0.5 mg/kg) in a placebo-controlled design.

Procaine and lidocaine stimulate corticotropin-releasing hormone secretion by explanted rat hypothalami through a sodium conductance-independent mechanism.

We have previously shown that procaine and lidocaine stimulate corticotropin-releasing hormone (CRH) secretion by explanted rat hypothalami. This effect was of interest in light of the fact that both lidocaine and CRH administration to experimental animals can produce kindled seizures which cross-sensitize with electrically kindled seizures, and of recent data suggesting that limbic hyperexcitability, perhaps mediated through CRH, may be involved in the pathophysiology of affective illness. Because a prominent effect of the local anesthetics is to decrease neuronal firing by blocking sodium conductance, we were surprised by the capacity of these agents to cause CRH secretion and pituitary-adrenal activation and wished to further elucidate the possible mechanism(s) of these effects.

Cocaine stimulates rat hypothalamic corticotropin-releasing hormone secretion in vitro.

Acute or chronic cocaine administration exerts multiple behavioral and physiologic effects including stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Pharmacologically, cocaine shares major properties with at least 2 classes of pharmaceuticals. It is a local anesthetic and also a potent psychomotor stimulant.

Meal-related cholecystokinin secretion in eating and affective disorders.

The satiety-inducing effects of centrally and peripherally administered cholecystokinin (CCK) in experimental animals have been well documented. Recently, studies in humans showed that CCK is released into plasma following food ingestion, a phenomenon postulated to promote meal-related satiety. To explore whether abnormal CCK secretion during feeding may be related to pathophysiological mechanisms in disorders associated with appetite abnormalities, we report here studies of the plasma CCK response to a test meal in patients with bulimia nervosa, as well as seasonal (hyperphagic) and melancholic (anorexic) depression.

Stress-responsive neurohormonal systems and the symptom complex of affective illness.

The role of stress in the natural history of major depression has been a subject of intense scrutiny, particularly in light of the 20th century discoveries of some of the biological mediators of stress responses. In this paper we present evidence suggesting the hypothesis that an abnormality in the counterregulation of generalized stress responses underlies critical aspects of the pathophysiology of major depression. In particular, we focus on the role of inadequate glucocorticoid restraint of the central nervous system (CNS) components of the adrenocortical and adrenergic systems, i.

Corticotropin-releasing hormone: from endocrinology to psychobiology.

Corticotropin-releasing hormone (CRH) is a brain neuropeptide which coordinates the endocrine, autonomic and behavioral responses to stress. We review the abnormal response to exogenous CRH in various psychiatric syndromes, including major depression and anorexia nervosa. We also contrast pituitary responses to CRH in patients with depression versus Cushing's disease.

Effects of glucocorticoid antagonism with RU 486 on pituitary-adrenal function in patients with major depression: time-dependent enhancement of plasma ACTH secretion.

Data from our group and others suggest that pituitary-adrenal activation in major depression reflects a defect at or above the hypothalamus which results in the hypersecretion of corticotropin-releasing hormone (CRH); some have suggested, however, that elevated indices of cortisol secretion and lack of suppressibility to dexamethasone may be a manifestation of a primary defect in glucocorticoid receptor activation. We report here a study of early morning pituitary-adrenal responses to the glucocorticoid antagonist RU 486 in patients with major depression and healthy volunteers. Previous data suggested that the response to RU 486 could represent an index of endogenous CRH secretory activity.

Basic and clinical studies with corticotropin-releasing hormone. Implications for a possible role in panic disorder.

We have presented several lines of circumstantial evidence suggesting a possible role for CRH in the panic disorder syndrome. Such a role has by no means been demonstrated and is indeed challenged by several lines of contradictory data. Critical evaluation of this hypothesis must await further basic research on the role of hypothalamic and extrahypothalamic CRH in stress-mediated phenomena and on their interrelationships.

The oCRH stimulation test before and after clinical recovery from depression.

A substantial body of data suggests that excessive cortisol secretion in depression may result from a dysregulation at several sites within the hypothalamic-pituitary-adrenocortical (HPA) axis. These alterations in regulatory mechanisms are thought to be the result of a hypothalamic 'overdrive' of corticotropin-releasing hormone (CRH). Previous studies have demonstrated a diminished adrenocorticotropin (ACTH) secretory response, as well as a heightened adrenocortical responsiveness after ovine-CRH administration in depressed patients.

Salivary cortisol: a practical method for evaluation of adrenal function.

Salivary cortisol represents a simple, noninvasive, stress-free measure that can greatly facilitate the longitudinal study of hypothalamic-pituitary-adrenal axis activity in patients with psychiatric disorders. By means of a slight modification of a commercially available radioimmunoassay kit, we studied the stability of salivary cortisol under different conditions, as well as the relationship between plasma and salivary cortisol under basal circadian conditions and following stimulation (CRH) and suppression (dexamethasone). We observed that salivary cortisol was quite stable at room temperature without centrifugation and that salivary and plasma cortisol values were highly correlated.

Alterations in immunocompetence during stress, bereavement, and depression: focus on neuroendocrine regulation.

There is now clear evidence that stress, bereavement, and depression can compromise specific components of the immunologic apparatus. The first part of this paper gives an overview of fundamental immunology and is followed by a review of the patterns, possible causes, and potential clinical implications of abnormal immunoregulation. After a discussion of the immunomodulating properties of glucocorticoids, the authors conclude with an overview of the many factors that mediate the complex interdependence between immunologic function, the brain, and neuroendocrine regulation.

Intravenous procaine as a probe of limbic system activity in psychiatric patients and normal controls.

Evidence from animal and human studies suggests that procaine hydrochloride may selectively activate limbic system structures and suppress neocortical structures. We administered a series of intravenous bolus doses of procaine hydrochloride to 31 subjects (7 with affective disorders, 17 with borderline personality disorder, and 7 healthy normal volunteers). Dose-related cognitive and sensory distortions and illusions were observed; affective experiences ranged widely from euphoric to dysphoric.

Pituitary and adrenocortical responses to the ovine corticotropin releasing hormone in depressed patients and healthy volunteers.

It has been suggested that limbic system-hypothalamic "overdrive" may be the underlying mechanism causing an augmented secretion of corticotropin releasing hormone (CRH), heightened adrenocortical responsiveness to corticotropin (adrenocorticotropic hormone) (ACTH), and alteration in cortisol feedback regulatory mechanisms as demonstrated by the dexamethasone suppression test. We examined pituitary and adrenocortical responses after morning administration of ovine CRH (oCRH) in 26 depressed patients and 11 healthy volunteers. Basal plasma ACTH concentrations were similar in both groups, whereas patients had a significantly diminished cumulative ACTH response after administration of oCRH.

Corticotropin releasing hormone: relevance to normal physiology and to the pathophysiology and differential diagnosis of hypercortisolism and adrenal insufficiency.

CRH is a 41 amino acid peptide first isolated from ovine and subsequently from rat and human hypothalami. We have conducted a series of clinical studies with oCRH and hCRH in volunteers and patients with various disorders of hypothalamic-pituitary-adrenal function. In volunteers, it was demonstrated that hCRH administration produced ACTH and cortisol responses which closely mimic naturalistically occurring secretory episodes.