Hypothalamic-pituitary-adrenal axis activity in depressive illness. Its relationship to classification.

Serum cortisol response to the 1-mg overnight dexamethasone suppression test was studied in 221 depressed patients and 109 nondepressed psychiatric controls. Nonsuppression distinguished patients with primary unipolar depression (65/146) from patients with secondary unipolar depression (0/42) and nondepressed controls (0/109). Furthermore, nonsuppression distinguished the three familial subtypes of primary unipolar depressive illness: familial pure depressive disease (FPDD; 38/50 patients), sporadic depressive disease (SDD; 24/55 patients), and depression spectrum disease (3/41 patients). Moderate elevations in baseline serum cortisol levels were found in FPDD, SDD, and bipolar depression. Medication did not affect the results. The data suggest that the depressive syndrome is composed of separate illnesses, each of which has a distinctive pattern of hypothalamic-pituitary-adrenal axis activity during the depressed state as well as a specific clinical and familial psychiatric history.

Differentiation of depressive subtypes by insulin insensitivity in the recovered phase.

The glucose response to a standard insulin tolerance test (ITT) has been reported to be blunted in the acute phase of heterogeneous depressive disorders and to be normal in the recovered phase. We studied the glucose response to ITT in the recovered phase depression in patients who had previously been subclassified according to familial and clinical characteristics. All patients with depressive spectrum disease had an adequate glucose response to the ITT, whereas only 40% of patients with familial pure depressive disease and 56% of patients with bipolar illness had an adequate hypoglycemic response. There was also a trend toward a decrease in insulin sensitivity in patients who had been nonsuppressors to dexamethasone when depressed. These findings suggest that the glucose response to ITT may be a useful tool in differentiating among the heterogeneous depressive disorders.

Polysomnographic findings in recently drug-free and clinically remitted depressed patients.

Thirteen patients were examined by sleep polysomnograph (PSG) and the dexamethasone suppression test when clinically depressed and later when clinically remitted for six months and no longer receiving antidepressant medication for two to five weeks. None of the PSG variables (rapid eye movement [REM] latency, total sleep time, stage 1 through 4 times, REM time, and REM densities in periods 1 through 3) was significantly changed between symptomatic depression and symptom remission. While symptomatic, 11 of 13 patients exhibited a reduced REM latency (65 minutes or less). After clinical remission, eight of the 11 continued to exhibit reduced REM latencies, whereas the dexamethasone suppression test tended to show nonsuppression only during clinical depression. These data represent either longer-term (ie, slow to normalize) biologic consequences of a depressive episode or biologic antecedents of clinical depression that may herald a return of the depression in individuals vulnerable to recurrence. Whether PSG abnormalities identify clinically remitted patients who are prone to develop another depressive episode requires longitudinal follow-up studies.

Alprazolam vs amitriptyline in depressions with reduced REM latencies.

This study was designed to compare the antidepressant effects of alprazolam, a triazolobenzodiazepine, with amitriptyline hydrochloride in a group of patients with nonpsychotic, major depressions diagnosed by Research Diagnostic Criteria. A mean rapid eye movement latency of less than 65 minutes was required to enter this study. Dexamethasone suppression tests were conducted before treatment. By strictly applied Research Diagnostic Criteria, 83.6% of the subjects were endogenous, and 34.7% were inpatients. A significantly greater percentage of alprazolam-treated patients responded within the first seven days of treatment. By the end of this six-week trial, alprazolam was associated with significant reductions in Hamilton, Beck, Covi, Raskin, and Carroll Rating scores (pretreatment to posttreatment). However, by the end of treatment the effects of amitriptyline exceeded those of alprazolam on both the Hamilton and Beck scales. These data indicate that alprazolam is not as effective as amitriptyline in major depressions with a shortened rapid eye movement latency.

Which endogenous depressive symptoms relate to REM latency reduction?

In most research dealing with biological abnormalities in depression, the clinical diagnosis of depression is made and the occurrence of a biological abnormality, for example, reduced REM latency, is documented. In this study, that design was reversed; REM latency was used as a grouping variable to assess empirically the "biological" priority of Research Diagnostic Criteria endogenous symptoms. We found that terminal insomnia, pervasive anhedonia, unreactive mood, and appetite loss were most likely to discriminate among "reduced" and "nonreduced" REM latency depressions at various threshold values. Contrary to expectation, diurnal mood variation was found equivalently in all categories of REM latency studied. Implications for clinical decision making based on endogenous symptoms are discussed.

Free triiodothyronine (T3) and thyroxine (T4) in a group of unipolar depressed patients and normal subjects.

We examined levels of free triiodothyronine (fT3) and free thyroxine (fT4) in serum from a group of 32 patients with unipolar major depression and 46 normal control subjects using the Amerlex (Amersham, Arlington Heights, IL) RIA procedures for these hormones. Free T3 levels were significantly lower (p less than 0.004) in the depressed patients as a group (5.02 +/- 1.01 pmol/L, mean +/- SD) than in the normal control subjects (5.74 +/- 1.23 pmol/L). Free T3 levels were lower (p less than 0.01) in depressed men (5.25 +/- 1.43 pmol/L) when compared with male control subjects (6.46 +/- 1.01 pmol/L). Depressed women (4.78 +/- 0.60 pmol/L) also had lower T3 levels than did the female control subjects (5.09 +/- 1.06 pmol/L), but the difference was not statistically significant. Lower fT3 levels were also observed in melancholic depressed patients when compared with nonmelancholic depressed patients or when compared with normal control subjects. No differences in fT4 were observed between groups in this study.

Dexamethasone response, thyrotropin-releasing hormone stimulation, rapid eye movement latency, and subtypes of depression.

Most prior studies of mood disorders have used a single laboratory test to assist in differential diagnosis, prediction of treatment response, and prediction of relapse. This study compared three laboratory measures in a combined in- and outpatient sample of depressed patients. Dexamethasone suppression test (DST) nonsuppression occurred in 46% of patients with endogenous major depression, in 15% with nonendogenous major depression, and in 56% with bipolar, depressed phase disorder. A blunted thyrotropin-releasing hormone stimulation test (TRH-ST) occurred in 25% of patients with endogenous, 10% with nonendogenous, and 44% with bipolar, depressed phase disorder. Reduced REM latency was found in 65% of endogenous major depressions, in 34% of nonendogenous major depressions, and in 53% of bipolar, depressed phase disorders. Fifty-one percent of those with reduced REM latency also evidenced DST nonsuppression. When the endogenous major depression and bipolar, depressed phase groups were combined, 28% had no laboratory abnormality, whereas 8% evidenced all three. These findings suggest that 1) endogenous/nonendogenous unipolar groups are distinguished by all three laboratory tests; 2) most patients with a blunted TRH-ST also evidence DST nonsuppression; and 3) one half of patients with reduced REM latency evidence DST nonsuppression. Sensitivity is greatest and specificity is lowest for REM latency, followed by the DST and then the TRH-ST.

Polysomnographic findings and dexamethasone nonsuppression in unipolar depression: a replication and extension.

To evaluate the replicability of our previous findings of increased incidence of biological dysregulation in endogenous depression, we have studied a new series of patients with major depressive disorder, unipolar type (n = 103). The subtypes compared were defined by Research Diagnostic Criteria and were endogenous/nonendogenous, primary/secondary, and Winokur's family history classification. As an extension of the research, we evaluated the endogenous subtype more precisely by distinguishing those patients who met criteria for probable endogenous, comparing them to both endogenous and nonendogenous depressed patients. The findings of the replication study were consistent with our earlier report; the incidence of both dexamethasone nonsuppression and reduced rapid eye movement (REM) latency was higher in those with endogenous depression. Findings for each of the other subtypes revealed no differences. The probable endogenous depressed patients were comparable to the nonendogenous depressed patients in all variables measured.

Suicide and the dexamethasone suppression test in unipolar depression.

The authors studied 243 inpatients with unipolar depression who had received DSTs. Of 205 patients with primary depression, the 4 who later committed suicide were among 96 with abnormal DST results; 1 patients with secondary depression committed suicide despite a normal DST result. The authors suggest that hypothalamic-pituitary-adrenal dysfunction is associated with a type of primary depressive illness that is more likely to involve suicide than are other types.

A comparison of the cortisol suppression index and the dexamethasone suppression test.

The cortisol suppression index (CSI) (the ratio of pre- to postdexamethasone serum cortisol concentrations) was compared to the dexamethasone suppression test (DST) in endogenously depressed DST suppressors (N = 20) and nonsuppressors (N = 21) and in normal controls (N = 23). The 8 a.m. CSI detected 17.1% and 31.7% of endogenous depressives at the 4.0 and 6.0 thresholds; for the 4 p.m. CSI, rates were 48.8% and 65.9%. The 4 p.m. CSI produced 17.4% and 39.1% false positives in normal controls at the two thresholds, whereas the false positive rate for the DST was 4.3%. These data suggest that the CSI is not as specific as the standard DST for the detection of endogenous depression.

The dexamethasone suppression test in patients with mood disorders.

BACKGROUND: This study was undertaken to (1) determine whether the endogenous/nonendogenous mood disorder dichotomy is validated by the dexamethasone suppression test (DST); (2) determine whether other subtyping schemes (unipolar/bipolar, DSM-III melancholic/nonmelancholic, Winokur's family history subtypes) relate to the DST; (3) evaluate the relative contributions of symptom severity, weight loss, and other factors to DST status; and (4) assess the relative sensitivity of various post-dexamethasone cortisol determinations in the detection of dexamethasone nonsuppression. METHOD: 487 consecutive adult inpatients (N = 131) and outpatients (N = 356) with unipolar (N = 422) or bipolar disorder (N = 65) underwent the 1.0-mg DST. Nonsuppression was defined as at least one post-dexamethasone cortisol measurement > 4.0 micrograms/dL. RESULTS: Nonsuppression occurred in 27% of all patients with major depression and 43% of all bipolar depressed phase patients. For outpatients, dexamethasone nonsuppression occurred in 35.2% of subjects with endogenous (unipolar + bipolar; N = 145) and 9.0% of those with nonendogenous (unipolar only; N = 211) depressions (single 4 p.m. post-dexamethasone cortisol). For inpatients, dexamethasone nonsuppression was found in 61.5% of subjects with endogenous (N = 104) and 18.5% of those with nonendogenous (N = 27) depressions (three post-dexamethasone cortisol determinations). For the inpatient and outpatient sample together, the DST had a sensitivity of 46.2% and a specificity of 89.9% in differentiating endogenous from nonendogenous major depressive episodes. Weight loss, gender, and symptom severity added little to the endogenous/nonendogenous dichotomy. The Research Diagnostic Criteria (RDC) primary/secondary and Winokur and colleagues' family history subtypes for unipolar depression were not strongly validated by the DST. The 4 p.m. and 11 p.m. samples together detected 91.0% of those inpatients with abnormal three-sample DST results. The 8 a.m. sample alone detected 30% of those, the 4 p.m. sample alone detected 67%, and the 11 p.m. sample alone detected 62%. CONCLUSION: The RDC endogenous/nonendogenous dichotomy was validated by the DST.

Relationships among the TRH, REM latency, and dexamethasone suppression tests: preliminary findings.

The DST and TRH stimulation test (TRHST) were administered to 68 depressed in- and outpatients; 28 subjects also received 2 nights of sleep EEG. Results indicated that (1) the TRHST differentiated RDC endogenous from nonendogenous unipolar subtypes at the 5 but not the 7 IuU/ml threshold, (2) neither order nor timing of DST and TRHST testing affected TRHST response, (3) the TRHST detected subjects not identified by the DST, and (4) REM latency detected some patients (23%) not identified by either the TRHST or DST.

Alprazolam in bipolar-I depressions.

In an open-label study of alprazolam in five bipolar-I depressed patients, three patients remitted completely, one failed to respond, and one responded transiently, based on the Hamilton Rating Scale and Beck Depression Inventory scores. Further studies of alprazolam as an antidepressant are warranted.

Plasma GABA in affective illness. A preliminary investigation.

Plasma levels of gamma-aminobutyric acid (GABA) were determined in 34 clinically symptomatic patients with diagnosis of affective disorder and in 20 normal controls. Lowest levels were found in patients with familial pure depressive disease and in depression spectrum disease, while levels of patients with sporadic depressive disease, though significantly lower than control, were not as low. Plasma GABA levels in secondary depression and in bipolar depression were similar to control. Bipolar manic patients had plasma GABA levels that were significantly higher than control values.

Dexamethasone suppression test response in major depression: stability across hospitalizations.

In the course of several studies of hypothalamic-pituitary-adrenal axis activity in depression, 43 patients presented on separate admissions with definite depression and, on both admissions, received dexamethasone suppression tests (DSTs). DST results were discordant across admissions in 21% of cases; among patients who were nonsuppressors on either admission, results were discordant in 40.9%. The correlation between postdexamethasone values obtained on two admissions was highly significant, however. Distinctions between bipolar and unipolar depression and between primary and secondary depression by rates of nonsuppression were inconsistently significant across admissions but were clearer when results from both admissions were pooled and patients with an abnormal DST on either admission were considered nonsuppressors. While abnormal escape from dexamethasone suppression occurs in a significant proportion of depressed patients, this phenomenon may only partially overlap the depressive syndrome in time. Negative DST results in patients with primary depression must be interpreted in this light.

A controlled study of cellular immune function in affective disorders before and during somatic therapy.

Lymphocyte blastogenesis induced by lectins (PHA, Con A, and PWM) was assessed in 27 drug-free patients with unipolar (n = 21) or bipolar (n = 5) depression and 13 normal controls. Fifteen patients were restudied after clinical remission. Symptomatic patients did not differ from controls nor did endogenous and nonendogenous depressions differ in their lymphocyte blastogenesis response to any of the three lectins. However, a significant reduction in lymphocyte blastogenesis with both PHA and Con A stimulation was found following somatic treatment. Cellular immune function appears to be normal in depressed patients, although the somatic therapies are associated with a reduction in this function.

The Inventory for Depressive Symptomatology (IDS): preliminary findings.

The Inventory for Depressive Symptomatology (IDS) is a new measure of depressive signs and symptoms. Both self-report and clinician-rated versions are under development. The IDS-SR (self-report) was completed by 289 patients, 285 of whom were outpatients. Unipolar major depression (n = 174), bipolar disorder (n = 44), euthymic (S/P unipolar or bipolar) depression (n = 33), and other psychiatric disorders (n = 38) were included. The IDS-SR had good internal reliability (coefficient alpha = 0.85), and significantly correlated with both the Hamilton Rating Scale for Depression (HRSD) (r = 0.67) and the Beck Depression Inventory (BDI) (r = 0.78). The clinician-rated IDS (IDS-C) was administered to 82 outpatients (75 with unipolar or bipolar disorder, 5 with other psychiatric disorders, and 2 euthymic (S/P unipolar) depressions). Coefficient alpha (0.88) suggested strong internal consistency. The IDS-C correlated highly with both the HRSD (r = 0.92) and the BDI (r = 0.61). Discriminant and factor analyses provided evidence for construct validity for both the IDS-C and IDS-SR. Both scales significantly differentiated endogenous from nonendogenous depression defined by Research Diagnostic Criteria (RDC). Factor structures for the IDS-SR revealed four factors: mood/cognition, anxiety, selected endogenous symptoms, and hyperphagia-hypersomnia. The IDS appears applicable to both inpatients and outpatients with endogenous, atypical, and nonendogenous major depression, and may have utility with dysthymics.

The effect of dosage on the dexamethasone suppression test in normal controls.

A sample of 23 drug-free, normal adult subjects, aged 23 to 50 years, received 1 mg dexamethasone p.o. at midnight. Serum cortisols were obtained at 0800h, 1600h, and 2330h pre- and postdexamethasone. Only 1 of these 23 subjects (4.3%) evidenced nonsuppression, as defined by any postdexamethasone serum cortisol value of greater than 4.0 micrograms/dl. A dose of 0.75 mg dexamethasone was administered to 23 drug-free, normal adult subjects, 20 of whom participated in the above 1 mg trial. Six of these 23 (26.1%) showed nonsuppression at a threshold of 4.0 micrograms/dl. Another 11 normal adults who were taking various prescription medications (e.g., sympathomimetics, nasal decongestants, birth control pills, thyroid hormones) or who were suffering from untreated upper respiratory infections, venereal infections, or allergies were tested with 1 mg of dexamethasone. In this sample, 7 of 13 (53.8%) showed nonsuppression. These findings suggest that: (1) 1 mg of dexamethasone is the lowest effective dose that can be used in diagnostic testing for melancholic depression; (2) a false-positive response to the dexamethasone suppression test (DST) may occur with infections, allergies, or possibly with certain prescription medications. Further studies of the effects of illness and/or medications on DST responses are needed.

TRH-induced prolactin release is blunted in females with endogenous unipolar major depression.

Twenty-five women with unipolar primary major depressive disorder (20 endogenous, 5 nonendogenous) and 20 female control subjects were studied with the thyrotropin-releasing hormone stimulation test (TRH-ST). Prolactin (PRL) levels were measured before and after TRH administration for patients and control subjects. For patients, thyrotropin (thyroid-stimulating hormone; TSH) levels were measured from the same serum specimens as PRL levels, and the 1 mg dexamethasone suppression test (DST) was performed. Patients with endogenous depression (ED) had significantly lower maximal serum PRL levels (max PRL) following TRH, and a significantly reduced increase over basal serum PRL (delta max PRL) compared to normal controls (NC). Nonendogenous depressed (NED) patients did not differ significantly from the ED or NC groups on either of these measures. For the ED group, delta max PRL was inversely correlated with severity of depressive symptomatology. Basal PRL levels did not differentiate the depressed subgroups (ED, NED) from each other or from the NC group. Depressed patients with blunted delta max PRL values tended to have blunted delta max TSH values and vice versa. Almost all patients with blunting of either delta max PRL or delta max TSH were also DST nonsuppressors; conversely, only about half (7 of 12) of patients who were DST nonsuppressors had either blunted delta max PRL or delta max TSH. Patients with clinical diagnoses of melancholia or psychotic features were significantly more likely to have blunted delta max PRL values than patients without these diagnoses. A disturbance of central noradrenergic function could explain these findings.