Peter E. Stokes

Reduced Sensitivity of Lymphocyte Beta-Adrenergic Receptors in Patients with Endogenous Depression and Psychomotor Agitation

It has been suggested that there are altered levels of norepinephrine or other neurotransmitters at functionally important receptors in patients with depressive disorders. This hypothesis is difficult to study in the human central nervous system. However, noradrenergic function can be assessed indirectly with peripheral-blood lymphocytes used as a model of the beta-adrenergic receptor complex. We found that drug-free inpatients with endogenous depression had lower isoproterenol-stimulated cyclic AMP levels in intact lymphocytes than did healthy control subjects (3.9 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01). The density and affinity of beta-adrenergic receptors were similar in controls and depressed subjects (beta-receptor number, 5.4 +/- 0.7 and 5.3 +/- 0.8 fmol per 10(6) cells; binding affinity, 106 +/- 7.6 vs. 99.2 +/- 11.4 pM, respectively). When the depressed patients were subdivided by psychomotor manifestations, binding characteristics were indistinguishable among the subgroups. However, a significant reduction in beta-adrenergic responsiveness was observed in patients with psychomotor agitation, as compared with controls (2.6 +/- 0.5 vs. 7.4 +/- 1.0 pmol per 10(6) cells, P less than 0.01), but not in patients with psychomotor retardation (5.8 +/- 1.1 pmol per 10(6) cells, P less than 0.05). Thus, the desensitization of beta-adrenergic receptors was correlated more closely with the severity of psychomotor agitation than with the overall severity of depression.

Fluoxetine tenth anniversary update: the progress continues.

This tenth anniversary review/update of fluoxetine concentrates on the past 5 years of its clinical application. The mechanism of action of fluoxetine; its metabolism; its efficacy in patients with various diagnostic subgroups of depression, patients with coincident medical disease, children and adolescents with depression, patients with eating disorders, and patients with obsessive-compulsive disorder (OCD); its long-term (maintenance) efficacy; its side effects and toxicity; and pharmacoeconomic considerations are reviewed. Pharmacotherapy is currently the only proven method for treating major depressive disorder that is applicable to all levels of severity of major depressive illness. Since its introduction 10 years ago, fluoxetine has been available to psychiatrists, primary care physicians, and other nonpsychiatric physicians as full-dose effective pharmacotherapy for patients with depression. Fluoxetine has been widely prescribed by physicians knowledgeable in pharmacology and in the treatment of depression because of its proven efficacy (ie, equal to that of tricyclic antidepressants [TCAs]), its ease of administration (with full therapeutic dosing usually starting from day 1), its generally benign side-effect profile, its remarkable safety in over-dose, and its proven effectiveness in the most common depressed patient population--anxious, agitated, depressed patients--as well as in patients with various subtypes and severities of depression. In more recent years it has also proved effective in the treatment of bulimia, an entity for which only limited or inadequate treatment options had been previously available. In OCD, fluoxetine, with its more acceptable side-effect profile and greater ease of dosing, presents a favorable alternative to previous drug therapy and is useful in treating both obsessions and compulsions. Fluoxetine is currently recognized among clinicians as efficacious in treating anxiety disorders and is being used successfully in special depressed populations such as patients with medical comorbidity, elderly patients, adolescents, and children. Rapid discontinuation or missed doses of short-half-life selective serotonin reuptake inhibitors, TCAs, and heterocyclic antidepressants are associated with withdrawal symptoms of a somatic and psychological nature, which cannot only be disruptive, but can also be suggestive of relapse or recurrence of depression. In striking contrast to these short-half-life antidepressants, fluoxetine is rarely associated with such sequelae on sudden discontinuation or missed doses. This preventive effect against withdrawal symptoms on discontinuation of fluoxetine is attributed to the unique extended half-life of this antidepressant. Current studies show that the overall increased effectiveness of fluoxetine in treating depression compensates for its higher cost, compared with older drugs, by reducing the need for physician contact because of increased compliance and less need of titration, and by reducing premature patient discontinuation, thereby yielding fewer relapses, less recurrence, and less reutilization of mental health services.

Pituitary-adrenal function in depressed patients: Resistance to dexamethasone suppression

Abstract Hypothalamic-pituitary-adrenocortical function is activated by physical stress and anxiety. This laboratory and others have reported elevated plasma cortisol levels in depressed patients. We report here the response to 48 hr and overnight dexamethasone suppression tests in markedly depressed patients. In twenty-seven 48-hr tests, 0·5 mg dexamethasone was given orally every 6 hr for 8 doses (4 mg total). 0900 plasma cortisol level was determined after 24 and 48 hr. In 55 overnight tests, 1, 2, or 8 mg dexamethasone was given at 2300 hr and 0900 plasma sampled 10 hr later. Seventy-four % of patients showed marked resistance to suppression in the 48 hr tests (second 0900 plasma > 5 μg/ 100 ml). Eighteen of 22 patients did not suppress to

Specificity of mixed affective states: clinical comparison of dysphoric mania and agitated depression

To investigate the clinical specificity of mixed affective states, we compared clinical characteristics of mixed (dysphoric) manics to those of agitated depressed patients. The subjects were inpatients studied in the NIMH Clinical Research Branch Collaborative Study on the Psychobiology of Depression, Biological Studies. Behavior and symptom ratings for depressive and manic symptoms were obtained during a 15-day placebo washout period. Patients with agitated depression were compared to those in acute manic episodes with and without prominent depressive symptoms. Mania ratings clearly distinguished agitated depressed from mixed manic patients. Concerning depression and general psychopathology, mixed manics had more severe agitation, hostility and cognitive impairment than did agitated depressed patients. Depressed mood and anxiety did not differ significantly between the two groups. Nurse ratings for depression and anxiety, based on ward behavior, were similar for mixed manics and agitated depressed patients, while physician-interview rated depression and anxiety were higher in agitated depressed patients. These data support the existence of superimposed depressive and manic syndromes in mixed manics.

Neuropsychologic effects of lithium discontinuation.

This study investigated the effects of blind lithium discontinuation and resumption on measures of cognition, creativity, and fine motor performance in 46 lithium-maintained euthymic outpatients. Scores on memory measures, tests of tapping speed, and associative productivity all improved significantly during the time off of lithium. In an effort to further explain these results, analyses were undertaken with six possible intervening variables: age, sex, lithium concentration in plasma, thyroid function, duration of lithium maintenance, and depressive symptoms. Significant group and interactive effects are reported and discussed. A multiple regression analysis suggested that lithium has a greater neuropsychologic effect in younger, less-depressed patients having higher lithium concentrations in plasma.

A Multi-Vantaged Approach to Measurement of Behavioral and Affect States for Clinical and Psychobiological Research:

The development of methods based on the “multivantaged” assessment of behavioral, affect, and cognitive constructs in patients with affective disorders, is reponed. The state and outcome constructs were derived for application in clinical and psychobiological studies, particularly those aimed at testing biobehavioral hypotheses and the evaluation of the effects of drugs. The development of the constructs is based on the combining of scales from established measures which assess the patient in the interview, on the ward, from his self-report, and from a new vantage, through video methodology. Psychometric analyses primarily from data from the NIMH Collaborative Study of the Psychobiology of Depression describe the assembling of the 11 state constructs, and the estimation of their reliabilities, their interrelationships, and their validities. The methods are shown to be capable of characterizing pathologic and “normal” affects, social and expressive behaviors, and impairments in the cognitive and somatic spheres. They differentiated such diverse groups as depressives, manics, and normals, and such behaviorally similar depressive types as the unipolar and bipolar. Preliminary evidence is reported which indicates differential sensitivity to the effects of tricyclic drugs

Insulin Tolerance Test: human growth hormone response and insulin resistance in primary unipolar depressed, bipolar depressed and control subjects

Preliminary data from the National Institute of Mental Health-Clinical Research Branch Collaborative Program on the Psychobiology of Depression dealing with the human growth hormone (hGH) response to the Insulin Tolerance Test (ITT) during the pre-treatment (drug-free) period of the study are presented in this paper. Data are reported for 54 unipolar depressed, 21 bipolar depressed, and 40 normal control subjects, who represent approximately 50% of the final subject sample to be studied. In this population the unipolar depressed subjects showed a significantly greater resistance to insulin-induced hypoglycaemia than bipolar and control subjects. After applying the inclusion/exclusion criteria necessary to interpret hGH responses accurately, the data from only 54 subjects were acceptable. Mean peak hGH concentrations were not significantly different among the three groups. There was, however, a significant difference in the distributions of the hGH peak response, with the bipolar depressed population demonstrating greater variability in response than unipolar and control populations. These findings are discussed as they relate to previous reports and theoretical considerations.

Depressive mania versus agitated depression: Biogenic amine and hypothalamic-pituitary-adrenocortical function

The existence of mixed affective states challenges the idea of specific biological abnormalities in depression and mania. We compared biogenic amines and hypothalamic-pituitary-adrenocortical (HPA) function in mixed manic (n = 8), pure manic (n = 11), agitated bipolar depressed (n = 20), and nonagitated bipolar depressed (n = 27) inpatients (Research Diagnostic Criteria). Mixed manics met Research Diagnostic Criteria for primary manic episodes and also met criteria for major depressive episodes except for duration. The norepinephrine metabolite methoxyhydroxy phenthylene glycol (MHPG) was higher in cerebrospinal fluid from mixed manic than from agitated depressed patients, consistent with differences previously reported between the overall samples of depressed and manic patients. Similarly, patients in a mixed state had higher urinary excretion of norepinephrine (NE) and elevated output of NE relative to its metabolites. HPA activity was similar in mixed manic and agitated depressed patients. These data suggest that mixed manics combine certain biological abnormalities considered to be characteristic of mania and of depression.

Adrenocortical hyperactivity in depression: Effects of agitation, delusions, melancholia, and other illness variables

In an attempt to determine the relative contributions to adrenocortical hyperactivity in depression of agitation, delusions, and melancholic subtype, we measured cortisol levels before and after dexamethasone in 93 unipolar major depressed inpatients. Stepwise multiple regression showed that agitation predicted 22% of the variance in a.m. cortisol level after dexamethasone. Addition of the variables melancholia and delusionality to the regression model accounted for 27% and 34%, respectively, of the variance in the same cortisol variable. Age, illness severity, and weight loss added no further significant predictive value. Age, weight loss, and illness severity did affect cortisol levels when examined separately from the other variables. Rate of nonsuppression on the dexamethasone suppression test (DST) differed between the nonmelancholic major depressive group and any other group with melancholia. These results suggest why some discrepancies may exist between studies of the DST in delusional depression and indicate that agitation merits careful assessment in future studies of DST response.

Stress, depression, and mania: relationship between perceived role of stressful events and clinical and biochemical characteristics

We investigated the perceived role of stressful events in episodes of major affective disorder in patients studied in the NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression (Biological Studies). Using items from the Schedule for Affective Disorders and Schizophrenia (SADS), episodes were divided into environment‐sensitive (high perceived role of stressful events) and autonomous (minimal or no perceived role of stressful events). Patients with environment‐sensitive episodes had fewer previous episodes and a longer index episode. The groups did not differ with respect to age, gender, education, socioeconomic group, diagnosis, severity of illness, or eventual response to treatment. Unipolar depressed patients with environment‐sensitive episodes had lower CSF 5‐HIAA than those with autonomous episodes. Among bipolar depressed patients, those with autonomous episodes had elevated excretion of O‐methylated catecholamine metabolites and of epinephrine, while those with environment‐sensitive episodes had normal excretion of cate‐cholamines and metabolites. Manic subjects with environment‐sensitive episodes had elevated norepinephrine excretion, while this was normal in manics with autonomous episodes. Relationships between environmental sensitivity of affective episodes and neurotransmitter function therefore appear to be related to the type of episode.;