Michael Feinberg

Diagnosis of endogenous depression ☆: Comparison of clinical, research and neuroendocrine criteria

Eighty-nine depressed outpatients were studied by clinical criteria, Research Diagnostic Criteria (RDC), and the dexamethasone suppression test (DST) of neuroendocrine regulation. A simple outpatient version of the DST, requiring only one blood sample, correctly identified 40% of patients diagnosed clinically as endogenous depression (ED), with a specificity of 98% and a diagnostic confidence of 95%. Differences in age, sex, or severity of symptoms between endogenous and non-endogenous depressives did not account for these results. By comparison, the diagnostic performance of the DST was weaker for the RDC categories Major Depressive Disorder (MDD) and primary MDD. These were less selective and more heterogeneous than the clinical category ED. The clinical diagnoses of ED were supported in 98% of cases by the RDC, but 22% of RDC endogenous MDD diagnoses were not supported by the clinical diagnoses. Abnormal DST results were found only in patients with both the clinical diagnosis of ED and the RDC diagnosis of endogenous MDD. Patients with definite endogenous MDD had a significantly higher frequency of abnormal DST results (42%) than those with probable endogenous MDD (14%), or those with other RDC diagnoses (3%). A significant association was found between positive DST results and a positive family history of depression. These results support other evidence for use of a positive DST result as an external validating criterion for ED. The category MDD contained all cases diagnosed clinically as ED, but was diluted by cases diagnosed clinically as non-endogenous depression who had no neuroendocrine disturbance. The results also confirmed that the endogenous/non-endogenous and primary/secondary classifications of depression are not identical. We conclude: (1) that the DST can be used in the differential diagnosis of depressed outpatients as well as inpatients; (2) that the RDC category primary MDD and the Washington University category primary depression are more heterogeneous and probably less valid than the clinical category ED; (3) that the RDC for endogenous MDD have only moderate validity; (4) that RDC diagnoses cannot substitute for careful clinical diagnoses in research studies; (5) that the best use of the RDC is to support clinical diagnoses, but not to generate diagnoses independently as a free-standing system; (6) that the concept of endogenous or endogenomorphic depression has validity and should be retained in research studies of depression.

The Carroll Rating Scale for Depression

Research studies of depression require a measure of the severity of illness, and various rating scales or inventories have been designed in attempts to meet this need. Ratings by clinicians were introduced first, and these were complemented later by self-rating scales. The performance of these two types of rating has been compared extensively in recent years. Self ratings generally have highly significant overall correlations with clinician ratings, but some significant disagreements have been described. For example, Carroll et al. [5] found that the Hamilton Rating Scale (HAM-D) [11] completed by clinicians was superior to the Zung Self-Rating Depression Scale (SDS) [19] in discriminating global severity of depression across three treatment settings (inpatient, day hospital, general practice). Bailey and Coppen [2] found satisfactory and significant correlations between the HAM-D and the self-rated Beck Depression Inventory (BDI) [4] in only two-thirds of patients: the results in the remaining third were often very divergent. Neither type of rating scale should be used for making a diagnosis of depression [11, 5, 13], although the self-rating scales are often used as screening instruments.

Neuroendocrine dysfunction in genetic subtypes of primary unipolar depression

Disinhibited activity of the hypothalamic-pituitary-adrenocortical (HPA) neuroendocrine system, characterized most specifically by abnormal responses to the dexamethasone suppression test (DST), is observed in 40-50% of patients with endogenous depression. The heterogeneity of endogenous depressives with respect to this neuroendocrine marker is so far unexplained. A recent report from Iowa suggested that genetic factors could account for this heterogeneity, since abnormal DST reponses were found with widely differing frequencies among primary unipolar depressives subtyped by the genetic criteria of Winokur. We studied 14 patients with primary endogenous delusional unipolar depression. Abnormal DST responses were found in 79% of the entire group, and with similar frequencies among each of the Winokur subtypes. In particular, five of six patients (83%) with depression spectrum disease had abnormal DST results. This contrasts with a frequency of 4% reported by the Iowa group. We conclude that disinhibited HPA activity does occur in depression spectrum disease when a delusional endogenous depression is present. Our results and those of the Iowa study could both be consistent with a threshold model of HPA activation. The high frequency of positive DST results in delusional endogenous depressives may be determined by disinhibited central pain mechanisms. Variations in this clinical dimension, combined with variations in threshold for HPA activation by pain mechanisms, could account for the heterogeneity of DST responses among endogenous depressives.

Suicide, neuroendocrine dysfunction and CSF 5-HIAA concentrations in depression

ABSTRACT Disinhibition of the hypothalamic-pituitary-adrenal (HPA) neuroendocrine system is characterized by high CSF cortisol concentrations and abnormal dexamethasone suppression test (DST) results. These two variables are strongly correlated. Abnormal DST results are strongly associated with serious suicidal behavior in melancholic patients. Low CSF 5-HIAA concentrations are dissociated from abnormal DST results. Thus the neuroendocrine disturbance and the neurotransmitter disturbance appear to be unrelated biochemical markers in depressed patients. Since there is evidence that both markers may predict suicide behavior, however, further studies of each marker in the same patients should be performed.

Clinical correlates of sleep onset rem periods in depression

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Dexamethasone suppression test and selection of antidepressant medications

Endogenous depressives with abnormal dexamethasone suppression tests (DSTs) respond better to somatic antidepressant treatments than those with normal DSTs. Whether the DST also aids in the selection of specific antidepressants has not been determined. A pilot report suggested that patients with abnormal DSTs might be noradrenaline-deficient and respond preferentially to imipramine or desipramine, whereas those with normal DSTs might be serotonin-deficient and respond best to amitriptyline or clomipramine. Attempting to replicate this observation, we studied 26 patients diagnosed with Research Diagnostic Criteria as major depressive disorder, endogenous subtype, and with DSM-III as having melancholia. All were drug-free during baseline evaluation. All had abnormal DST results, with post-dexamethasone plasma cortisol levels exceeding 5 microgram/dl. We treated subjects with either imipramine or amitriptyline and compared clinical response with weekly Hamilton Depression Rating Scales, completed by raters blind to both DST results and the research question. Thereapeutic plasma levels were documented. We found no significant differences in treatment response between the subgroups. Twenty of the 26 subjects did well. The imipramine-treatment group failed to have either earlier response or better final outcome. These data fail to replicate suggestions that DST results assist in the selection of either imipramine or amitriptyline.

Simultaneous panic and depressive disorders: Clinical and sleep EEG correlates

Panic and depressive symptoms occur simultaneously in many depressed patients. To study the frequency of this association and to determine whether patients with simultaneous panic and major depression differed from those with only major depressive disorder (MDD) in clinical features and in sleep electroencephalographic (EEG) variables, we evaluated a total sample of 336 patients with MDD. Fifty-eight (17%) had both panic and MDD; 50 had complete data and were matched for age and severity of illness with other patients having only MDD. Patients with simultaneous panic and depression had significantly higher ratings for psychic and somatic anxiety, and rapid eye movement (REM) latencies approximating normal values. Patients with only MDD (without panic disorder) rated significantly higher in guilt feelings and had shorter REM latencies. Our results suggest that the simultaneous occurrence of panic and depression is relatively frequent, is accompanied by differences in sleep EEG variables, and may have implications for treatment.

The effect of amphetamine on plasma cortisol in patients with endogenous and non-endogenous depression

Abstract Amphetamine sulphate (0.1 mg/kg, i.v.) produced no consistent change in plasma cortisol levels in 21 depressed patients. Seven patients with endogenous depression (melancholia) were matched with seven patients with non-endogenous depression; there was no difference in the cortisol response to amphetamine between these two groups.

Serial Monitoring of Antidepressant Response to Electroconvulsive Therapy with Sleep EEG Recordings and Dexamethasone Suppression Tests

The study of the biological correlates of major depressive disorder (MDD) has received great impetus in recent years. Electroencephalographic (EEG) sleep measurements and the Dexamethasone Suppression Test (DST) have been among the most studied and productive of these biological correlates. Commonly described EEG sleep abnormalities in MDD include shortened rapid eye movement (REM) latency, increased REM density, decreased delta sleep, decreased sleep efficiency, and decreased total sleep time (Kupfer and Thase 1983; Gillin et al. 1984). With EEG sleep measurements, used individually or through discriminant analysis, the sensitivity, specificity, and diagnostic confidence for primary endogenous depression ranges from 61% to 90%, 80% to 100%, and 83% to 100%, respectively (Kupfer and Thase 1983). Similar findings have been described for the DST in MDD (Carroll et al. 1981). Thus, both the sleep EEG and the DST can be used to support the

Inferential statistical methods for strengthening the interpretation of laboratory test results

Laboratory test results for the diagnosis of psychiatric illness usually are reported descriptively despite the ready availability of appropriate inferential statistics. A tests sensitivity, specificity, and diagnostic confidence are conditional probabilities. Confidence intervals may be calculated for these probabilities in any given study. Statistical tests for comparing the results of several studies use techniques for planned and posterior comparisons applied to contingency tables. These established statistical methods aid in the interpretation of laboratory test findings.