Bernard J. Carroll

Urinary free Cortisol excretion in depression

Urinary free cortisol (UFC) excretion was determined in 60 depressed inpatients and in 35 psychiatric inpatients with other disorders. The depressed patients had high daily UFC values, while the other patients excreted normal amounts. Over 40% of the depressed patients had UFC excretions in the range seen in Cushings disease, while only 6% of the other patients excreted such high amounts of cortisol. Age and sex differences did not account for the results. Among the depressed patients those with depressive neuroses excreted less than unipolar or bipolar depressives. Following treatment, more normal UFC excretion was found in depressed patients. The estimation of UFC and its clinical utility are discussed in detail. UFC determination is a simple and informative indicator of adrenal cortical activation and its application to psychoendocrine studies is recommended.

Premenstrual tension syndrome: The development of research diagnostic criteria and new rating scales

Research diagnostic criteria for premenstrual tension syndrome (PMTS) are developed using data collected from a study of 42 women who were suffering from severe PMTS but were well at other times. Two specific scales are also devised for rating the severity of PMTS, a 36‐item self‐report questionnaire and a 10‐item scale for use by therapist/researcher. It is proposed that after further evaluation and validation, these instruments may permit more useful comparisons of data on the etiology and treatment of this disorder.

Resistance to Suppression by Dexamethasone of Plasma 11-O.H.C.S. Levels in Severe Depressive Illness

Use of the midnight dexamethasone suppression test showed that the plasma 11-hydroxycorticosteroid (11-O.H.C.S.) level did not undergo its normal reduction in 14 out of 27 patients with severe depression. Resistance to dexamethasone suppression correlated with the clinical rating of the severity of depression, while recovery from depression was associated with return of normal responsiveness to dexamethasone. The explanation of these findings is unknown.

Cerebrospinal fluid and plasma free cortisol concentrations in depression

Cerebrospinal fluid (CSF) cortisol levels were examined in a total group of 65 patients. Those who were not depressed (ND), and those suffering from depressive neuroses (DN) had marginally elevated values. Patients with unipolar depression (UD) and bipolar depression (BD) had levels twice as high as the ND and DN patients. Psychotic UD and BD patients had the highest values, three to four times as high as the ND and DN subjects. A significant reduction of CSF cortisol levels was observed following treatment and recovery. Manic patients had moderately elevated CSF cortisol values. The CSF results were in good agreement with plasma total cortisol levels and with urinary free cortisol excretion. Age and sex effects were not responsible for the observed differences; similar results were found in patient subgroups studied in Australia and in the United States. Preliminary equilibrium dialysis data are presented for plasma and CSF cortisol binding. CSF cortisol was 20% bound and 80% free. Plasma free cortisol levels were in good agreement with CSF free cortisol values. Depressed patients have increased tissue and central nervous system (CNS) exposure to free, physiologically active glucocorticoids. The appearance of severe depressive symptoms which manifest a diurnal rhythm may be determined in part by excesssve CNS exposure to glucocorticoids.

Pathophysiology of hypercortisolism in depression

Objective:  The mechanisms mediating hypercortisolemia in depression remain controversial. Adopting the biomarker strategy, we studied adrenocorticotropin (ACTH) and cortisol dynamics in hypercortisolemic and non‐hypercortisolemic depressed in‐patients, and in normal volunteers.

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.

Issues for DSM-5: Whither Melancholia? The Case for Its Classification as a Distinct Mood Disorder

Melancholia, a syndrome with a long history and distinctly specific psychopathological features, is inadequately differentiated from major depression by the DSM-IV specifier. It is neglected in clinical assessment (e.g., in STAR*D [1]) and treatment selection (e.g., in the Texas Medication Algorithm Project [2]). Nevertheless, it possesses a distinctive biological homogeneity in clinical experience and laboratory test markers, and it is differentially responsive to specific treatment interventions. It therefore deserves recognition as a separate identifiable mood disorder. Melancholia has been variously described as “endogenous,” “endogenomorphic,” “autonomous,” “type A,” “psychotic,” and “typical” depression (3–6). In contrast to the current DSM criteria for the melancholia specifier (features of which are often shared with major depression), it has characteristic clinical features (5–7).

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.

MRI correlates of Suicide attempt history in unipolar depression

BACKGROUND Suicide represents a major health problem in the United States, and prediction of suicide attempts is difficult. No structural neuroimaging studies have been done to specifically examine findings in patients who have attempted suicide. The objective of this study was to compare MRI findings in unipolar patients with and without a history of a suicide attempt. METHODS In this post hoc analysis, 20 unipolar subjects with a history of a suicide attempt were matched by age and gender to unipolar subjects without a history of an attempt. Subjects were also matched on parameters such as cardiovascular history, electroconvulsive treatment history, and history of psychosis. Subjects with a history of any neurologic condition were excluded. There were no significant differences in age of onset of depression, number of episodes of depression, and Hamilton Depression scores between the two groups. T2-weighted magnetic resonance imaging (MRI) scans were rated using the Coffey and Boyko rating scales. RESULTS Unipolar patients with a history of a suicide attempt demonstrated significantly more subcortical gray matter hyperintensities compared with patients without such a history. CONCLUSIONS Patients with abnormal MRI findings may be at higher risk for mood disorders and suicide attempts because of disruption of critical neuroanatomic pathways. Gray matter hyperintensities in the basal ganglia may be especially associated with risk for suicide attempts.

Monoamine mediation of the morphine-induced activation of mice

1 . The dose‐response relationship for hyperactivity in grouped mice following the injection of morphine sulphate has been established. 2 . The activation response can be modified by drugs which affect either catecholamines or indoleamines. 3 . The monoamine precursors l‐DOPA and 5‐hydroxytryptophan potentiate the response. 4 . The monoamine synthesis inhibitors α‐methyl‐p‐tyrosine and p‐chlorophenylalanine reduce the response. 5 . Inhibition of monoamine oxidase activity by pargyline caused a great increase in the response. The simultaneous administration of reserpine resulted in a further potentiation. 6 . Reserpine blocked the response whenever it was given alone, either before, with or after the injection of morphine. 7 . Blockade of α‐adrenoceptors with phentolamine or phenoxybenzamine reduced the response. 8 . Blockade of tryptaminergic receptors with methysergide or cinanserin also antagonized the response. 9 . The major tranquillizers haloperidol and chlorpromazine reduced the response. Haloperidol was especially effective in this regard. 10 . The tricyclic antidepressant drug imipramine potentiated the response. 11 . The morphine antagonist nalorphine completely prevented the response. 12 . The anticholinergic agent atropine and the antihistaminic drug mepyramine did not affect the response. 13 . We conclude that dopamine, noradrenaline and 5‐hydroxytryptamine are all involved in the normal activation response of grouped mice to morphine, with dopaminergic mechanisms being of primary importance.