Implementing guidelines for depression on antidepressant prescribing in general practice: a quasi-experimental evaluation.

BACKGROUND: Internationally, guidelines for depression recommend a stepped care approach, implying that antidepressant medication should not be offered as a first step treatment to patients with sub-threshold or mild depression. In the Netherlands, antidepressant prescribing rates in general practice as a first treatment step are considered to be high. The aim of this study was to evaluate the implementation of guideline recommendations on antidepressant prescribing. METHODS: A quasi-experimental study with a non-equivalent naturalistic control group and three years follow-up was performed in the general practice setting in the Netherlands. General Practitioners (GPs) participated in a national Quality Improvement Collaborative (QIC), focusing on the implementation of a guideline based model for a stepped care approach to depression. The model consisted of self-help and psychological treatment options for patients with milder symptoms as an alternative to antidepressants in general practice. Changes in antidepressant prescription rates of GPs were documented for a three-year period and compared to those in a control group of GPs, selected from an ongoing national registration network. RESULTS: A decrease of 23.3% (49.4%-26.1%) in antidepressant prescription rates for newly diagnosed patients with depressive symptoms was found within the intervention group, whereas no difference occurred in the reference group (50.3%-52.6%). The decrease over time was significant, compared to the usual care group (OR 0.44, 95% CI: 0.21-0.92). CONCLUSIONS: An implementation program using stepped care principles for the allocation of depression interventions resulted in reduced antidepressant prescription rates in general practice. GPs can change prescribing behaviour within the context of a QIC.

Quality improvement in depression care in the Netherlands: the Depression Breakthrough Collaborative. A quality improvement report.

BACKGROUND: Improving the healthcare for patients with depression is a priority health policy across the world. Roughly, two major problems can be identified in daily practice: (1) the content of care is often not completely consistent with recommendations in guidelines and (2) the organization of care is not always integrated and delivered by multidisciplinary teams. AIM: To describe the content and preliminary results of a quality improvement project in primary care, aiming at improving the uptake of clinical depression guidelines in daily practice as well as the collaboration between different mental health professionals. METHOD: A Depression Breakthrough Collaborative was initiated from December 2006 until March 2008. The activities included the development and implementation of a stepped care depression model, a care pathway with two levels of treatment intensity: a first step treatment level for patients with non-severe depression (brief or mild depressive symptoms) and a second step level for patients with severe depression. Twelve months data were measured by the teams in terms of one outcome and several process indicators. Qualitative data were gathered by the national project team with a semi-structured questionnaire amongst the local team coordinators. RESULTS: Thirteen multidisciplinary teams participated in the project. In total 101 health professionals were involved, and 536 patients were diagnosed. Overall 356 patients (66%) were considered non-severely depressed and 180 (34%) patients showed severe symptoms. The mean percentage of non-severe patients treated according to the stepped care model was 78%, and 57% for the severely depressed patient group. The proportion of non-severely depressed patients receiving a first step treatment according to the stepped care model, improved during the project, this was not the case for the severely depressed patients. The teams were able to monitor depression symptoms to a reasonable extent during a period of 6 months. Within 3 months, 28% of monitored patients had recovered, meaning a Beck Depression Inventory (BDI) score of 10 and lower, and another 27% recovered between 3 and 6 months. CONCLUSIONS AND DISCUSSION: A stepped care approach seems acceptable and feasible in primary care, introducing different levels of care for different patient groups. Future implementation projects should pay special attention to the quality of care for severely depressed patients. Although the Depression Breakthrough Collaborative introduced new treatment concepts in primary and specialty care, the change capacity of the method remains unclear. Thorough data gathering is needed to judge the real value of these intensive improvement projects.

Screening for depression in high-risk groups: prospective cohort study in general practice.

BACKGROUND: Currently only about half of the people who have major depressive disorder are detected during regular health care. Screening in high-risk groups might be a possible solution. AIMS: To evaluate the effectiveness of selective screening for major depressive disorder in three high-risk groups in primary care: people with mental health problems, people with unexplained somatic complaints and people who frequently attend their general practitioner. METHOD: Prospective cohort study among 2005 people in high-risk groups in three health centres in The Netherlands. RESULTS: Of the 2005 people identified, 1687 were invited for screening and of these 780 participated. Screening disclosed 71 people with major depressive disorder: 36 (50.7%) already received treatment, 14 (19.7%) refused treatment and 4 individuals did not show up for an appointment. As a final result of the screening, 17 individuals (1% of 1687) started treatment for major depressive disorder. CONCLUSIONS: Screening for depression in high-risk populations does not seem to be effective, mainly because of the low rates of treatment initiation, even if treatment is freely and easily accessible.

Polymorphisms in the brain-specific thyroid hormone transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients.

INTRODUCTION: Some hypothyroid patients continue to have significant impairments in psychological well-being, despite adequate treatment with levothyroxine (LT4). T4 transport across the blood-brain barrier is one of the crucial processes for thyroid hormone action in the brain. OATP1C1, a thyroid hormone transporter expressed at the blood-brain barrier, is considered to play a key role in delivering serum T4 to the brain. OBJECTIVE: To examine whether polymorphisms in OATP1C1 are determinants of well-being, neurocognitive functioning and preference for replacement therapy with a combination of LT4 and liothyronine (LT3). DESIGN AND PARTICIPANTS: We studied 141 patients with primary autoimmune hypothyroidism, adequately treated with LT4 monotherapy and participating in a randomized clinical trial comparing LT4 therapy with LT4-LT3 combination therapy. OUTCOME MEASUREMENTS: Different questionnaires on well-being and neurocognitive tests were performed at baseline. Serum thyroid parameters, OATP1C1-intron3C > T, OATP1C1-Pro143Thr and OATP1C1-C3035T polymorphisms were determined. RESULTS: Allele frequencies of the OATP1C1 polymorphisms in patients with primary hypothyroidism were similar to those of healthy controls. Both the OATP1C1-intron3C > T and the OATP1C1-C3035T polymorphism, but not the OATP1C1-Pro143Thr polymorphism, were associated with symptoms of fatigue and depression. OATP1C1 polymorphisms were not associated with measures of neurocognitive functioning or preference for combined LT4-LT3 therapy. CONCLUSIONS: OATP1C1 polymorphisms are associated with fatigue and depression, but do not explain differences in neurocognitive functioning or appreciation of LT4-LT3 combination therapy. Future studies are needed to confirm these findings.

Diagnostic accuracy of the mood module of the Patient Health Questionnaire: a systematic review.

OBJECTIVE: The nine-item mood module of the Patient Health Questionnaire (PHQ-9) was developed to screen and to diagnose patients in primary care with depressive disorders. We systematically reviewed the psychometric literature on the PHQ-9 and performed a meta-analysis to ascertain its summary sensitivity and specificity. METHODS: EMBASE, PubMed and PsycINFO were used to search literature up to July 2006. Studies were included if (1) they investigated the diagnostic accuracy of the PHQ-9 and (2) the PHQ-9 had been compared with a reference test. The quality of the studies was appraised using the Quality Assessment of Diagnostic Accuracy Studies. We calculated sensitivity, specificity and confidence intervals for each included study. We used the random effects model to calculate the summary sensitivity and specificity. RESULTS: We found a sensitivity of 0.77 (0.71-0.84) and a specificity of 0.94 (0.90-0.97) for the PHQ-9. The positive predictive value in an unselected primary care population was 59%, which increased to 85-90% when the prior probability increased to 30-40%. CONCLUSION: In primary care, the PHQ-9 is a valid diagnostic tool if used in selected subgroups of patients with a high prevalence of depressive disorder.

Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review.

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are frequently used as a first antidepressant for major depressive disorder but have response rates of 50% to 60% in daily practice. For patients with insufficient response to SSRIs, switching is often applied. This article aims to systematically review the evidence for switching pharmacotherapy after a first SSRI. DATA SOURCES: A systematic literature search (updated until Feb. 10, 2005) in MEDLINE, EMBASE, CINAHL, and PsychINFO (all indexed years) identified randomized, controlled trials (RCTs) and open studies investigating switching strategies. In the absence of specific keywords for switching, we performed "sensitive" searches using free text words with wildcards ($): "switch$" or ("alternat$" adj5 "treat$") or ("alternat$" adj5 "therap$") in combination with the Cochrane Collaboration search filter for RCTs, the Cochrane Collaboration Depression Anxiety and Neurosis Group search filter for major depressive disorder, and MeSH terms for antidepressants (in combination with additional text words for all antidepressive agents). Additionally, we included 4 recent Sequenced Treatment Alternatives to Relieve Depression publications. We limited searches to adults and humans but did not apply language restrictions. STUDY SELECTION: Relevant articles were retrieved and critically appraised. The methodology of the studies, the results on efficacy and dropouts due to side effects, and remarks were summarized in an evidence table. Three studies comparing a switch to venlafaxine or SSRIs were pooled. DATA SYNTHESIS: Eight RCTs and 23 open studies were identified, studying populations with different levels of treatment resistance. Definitions of response and remission rates varied between studies. Observed response rates after switching to any of the classes of antidepressants varied between 12% and 86%. Remission rates varied between 7% and 82%. The number of previous treatments with antidepressants was negatively correlated with treatment outcome. Rates of dropout due to side effects varied considerably across agents (5%-39%). Switching to venlafaxine showed a modest and clinically equivocal benefit over SSRIs (number needed to treat = 13 [95% CI = 9.1 to 25.0]). CONCLUSIONS: After a first SSRI, any switch within or between classes of antidepressants appears legitimate (second SSRI, novel dual-acting antidepressants, selective norepinephrine or nor-adrenergic/dopaminergic agents, or tricyclic anti-depressant or mianserin). No unequivocal evidence is available to prove an advantage of a between-class switch. More guidance by randomized empirical studies is needed. Clinical implications and methodological considerations for future studies are discussed.

Prediction of treatment response by HPA-axis and glucocorticoid receptor polymorphisms in major depression.

OBJECTIVE: We investigated whether treatment response is predicted by hypothalamus-pituitary-adrenal (HPA) axis parameters, or by genetic polymorphisms in the glucocorticoid receptor (GR), that regulates its feedback. METHODS: Ninety-eight outpatients completed 8 weeks of paroxetine treatment. Treatment response was defined as a 50% decrease in Hamilton Rating Scale for depression (HRSD) ratings. At baseline, 24h urinary cortisol excretion, and cortisol and ACTH concentrations in a DEX/CRH test were measured. The presence of polymorphisms in the GR DNA sequence (BclI, ER22/23EK, N363S) was determined. Prediction of treatment response was analysed by calculating response rates per tertile of an HPA-axis parameter and per GR genotype. RESULTS: The response rate in the high ACTH tertile was significantly lower as compared to the intermediate tertile, but not compared to the low tertile (response rates from high to low tertile: 33%, 67% and 42%). Carriers of the BclI polymorphism had higher ACTH values than non-carriers (baseline ACTH: 3 versus 5ng/l, p=0.02) and showed a trend towards lower decrease of HRSD rates than non-carriers (HRSD decrease: 8 versus 11, respectively, p=0.07). In a subgroup of BclI carriers, patients in the high ACTH tertile had a lower decrease in HRSD and lower response rates than patients in the low ACTH tertiles (HRSD decrease from high to low tertile: 5, 9 and 11, p<0.01). CONCLUSION: The results suggest that hyperactivity of the HPA-axis predict worse treatment outcome. The BclI polymorphism explains, in part, DEX/CRH test results and tends to be associated with worse treatment outcome.

Dose escalation for insufficient response to standard-dose selective serotonin reuptake inhibitors in major depressive disorder: systematic review.

BACKGROUND: Although selective serotonin reuptake inhibitors (SSRIs) are frequently used for major depressive disorder, only 50-60% of patients respond to a standard dose. For non-responders, dose escalation is often applied. AIM: To systematically review the evidence for dose escalation of SSRIs. METHOD: A systematic literature search in MEDLINE, EMBASE, CINAHL and PsycInfo was performed. Randomised controlled trials and meta-analyses investigating dose escalation of SSRIs were identified. Relevant articles were retrieved and critically appraised. Results were summarised in an evidence table. Pooling was not justified because of heterogeneity of the identified studies. RESULTS: Eight true dose-escalation studies and three meta-analyses were identified. The available data provided no unequivocal base for dose escalation. Dose escalation before 4 weeks of treatment at a standard dose appeared to be ineffective. CONCLUSIONS: Dose escalation of SSRIs is equivocally supported by evidence of randomised controlled trials; methodological difficulties in the studies may account for this lack of evidence.

Thyrotropin, but not a polymorphism in type II deiodinase, predicts response to paroxetine in major depression.

OBJECTIVE: The determinants of response to antidepressant treatment in major depression are unknown at present. The aim of the present study was to establish whether response is predicted by Hypothalamus-Pituitary-Thyroid (HPT) axis parameters or by a recently discovered polymorphism in the enzyme type II deiodinase (DII), which catalyzes the production of T3 in the brain. DESIGN: We analyzed prediction of response to paroxetine treatment by calculating response rates per tertile of HPT-axis parameters and per DII genotype. METHODS: Ninety-eight outpatients with major depression (DSM-IV) were included. Serum concentrations of TSH, FT4 and delta TSH in a DEX/CRH-TRH test were measured. In addition, the presence of a polymorphism in the DII sequence (Thr92Ala) was determined. RESULTS: The overall treatment response was 48 of 98 patients (49%). After exclusion of patients with subclinical hypothyroidism and/or TPO antibodies (n = 16), higher serum TSH significantly predicted response (response rate per tertile from low to high TSH: 36%, 42%, and 67%). Heterozygous patients for the DII polymorphism (44%) had slightly lower serum TSH (P = 0.03) as compared to patients with the wild-type DII (47%). The polymorphism was unrelated to treatment response. CONCLUSION: Higher serum TSH was associated with response to paroxetine in patients with major depression.

Glucocorticoids and relapse of major depression (dexamethasone/corticotropin-releasing hormone test in relation to relapse of major depression).

BACKGROUND: Knowledge of pathogenic mechanisms and predictors of relapse in major depressive disorder is still limited. Hypothalamic-pituitary-adrenocortical (HPA) axis dysregulation is thought to be related to the development and course of depression. METHODS: We investigated whether dexamethasone/corticotropin-releasing hormone (DEX/CRH) test parameters were related to the occurrence of relapse in 45 outpatients with clinically remitted major depression. The DEX/CRH test was administered before and after 8 weeks of antidepressant treatment. RESULTS: Posttreatment maximal adrenocorticotropic hormone (ACTH) and maximal cortisol levels, as well as delta ACTH and delta cortisol levels, were significantly higher (all p < .05) among patients who relapsed (n = 22) compared with patients in whom no relapse occurred (n = 23). Higher posttreatment maximal cortisol response on the DEX/CRH test was associated with shorter "relapse-free survival" (p = .05). CONCLUSIONS: In outpatients with clinically remitted major depression, higher posttreatment maximal cortisol levels on the DEX/CRH test were associated with relapse of major depression.

Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism.

OBJECTIVE: Hypothyroidism is associated with neurocognitive impairment. Sparse data suggest that treatment of hypothyroidism, resulting in a return to euthyroidism, may be associated with only partial recovery of overall neurocognitive functioning. The aim of this study was to assess neurocognitive functioning and well-being in euthyroid patients with primary hypothyroidism on adequate thyroxine (T4) treatment. We also investigated whether serum TSH and thyroid antibodies are determinants of neurocognitive functioning and well-being. DESIGN: We assessed neurocognitive functioning and well-being in 141 patients with primary hypothyroidism. METHODS: Neurocognitive test results and scores on questionnaires measuring well-being of 141 patients were compared with the reference values for these tests as published and used in Dutch clinical neuropsychological practice. Assessment of neurocognitive functioning included tests for cognitive or psychomotor speed, attention, working memory as well as learning and memory. Well-being was measured with the Symptom Check List-90 total score and the Rand 36-item Health Survey subscales for 'mental health' and 'vitality'. RESULTS: Patients showed poor performance on various domains of neurocognitive functioning compared with mean standard reference values, especially on a complex attention task and on verbal memory tests. Levels of well-being were significantly lower for patients compared with those of the general population. Neither serum TSH nor thyroid antibodies were determinants of neurocognitive functioning and well-being. CONCLUSION: The results of this study suggest that neurocognitive functioning as well as psychological well-being may not be completely restored in patients with hypothyroidism, despite T4 treatment.

Preventing relapse/recurrence in recurrent depression with cognitive therapy: a randomized controlled trial.

This article reports on the outcome of a randomized controlled trial of cognitive group therapy (CT) to prevent relapse/recurrence in a group of high-risk patients diagnosed with recurrent depression. Recurrently depressed patients (N = 187) currently in remission following various types of treatment were randomized to treatment as usual, including continuation of pharmacotherapy, or to treatment as usual augmented with brief CT. Relapse/recurrence to major depression was assessed over 2 years. Augmenting treatment as usual with CT resulted in a significant protective effect, which intensified with the number of previous depressive episodes experienced. For patients with 5 or more previous episodes (41% of the sample), CT reduced relapse/recurrence from 72% to 46%. Our findings extend the accumulating evidence that cognitive interventions following remission can be useful in preventing relapse/recurrence in patients with recurrent depression.

Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine/3,5,3'-triiodothyronine therapy.

INTRODUCTION: Some patients on levothyroxine replacement display significant impairment in psychological well-being, compared with sex- and age-matched controls. Levothyroxine-treated patients can be assumed to derive T3 exclusively from deiodination of T4, which, in the central nervous system, is regulated by type II deiodinase (DII). OBJECTIVE: We investigated whether two recently identified polymorphisms in the DII gene (DII-ORFa-Gly3Asp and DII-Thr92Ala) are determinants of well-being and neurocognitive functioning and associated with a preference for replacement with a combination of T3 and T4. METHODS: Genotypes for both polymorphisms were determined in 141 patients with primary autoimmune hypothyroidism, adequately treated with levothyroxine monotherapy and participating in a randomized clinical trial comparing T4 therapy with T4/T3 combination therapy. Questionnaires on well-being and neurocognitive tests were performed at baseline. RESULTS: Allele frequencies in patients with primary hypothyroidism were similar to those of healthy blood bank donors (32.0 vs. 33.9% for DII-ORFa-Gly3Asp and 40.4 vs. 38.8% for DII-Thr92Ala). DII polymorphisms were not associated with measures of well-being, neurocognitive functioning, or preference for combined T4/T3 therapy. CONCLUSION: The DII-ORFa-Gly3Asp and DII-Thr92Ala polymorphisms do not explain differences in well-being, neurocognitive functioning, or appreciation of T4/T3 combination therapy in patients treated for hypothyroidism.

Thyroid and adrenal axis in major depression: a controlled study in outpatients.

OBJECTIVE: Major depressive disorder has been associated with changes in the hypothalamus-pituitary-thyroid (HPT) axis and with hypercortisolism. However, the changes reported have been at variance, probably related to in- or outpatient status, the use of antidepressant medication and the heterogeneity of depression. We therefore conducted a controlled study in unipolar depressed outpatients who had been free of antidepressants for at least 3 months. DESIGN: We assessed endocrine parameters in 113 depressed outpatients and in 113 sex- and age-matched controls. METHODS: Patients were included if they had a major depression according to a Structural Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (DSM), fourth edition (SCID-IV) and if they had a 17-item Hamilton rating scale for depression (HRSD) score of > or =16. Endocrine parameters contained serum concentrations of TSH, (free) thyroxine, tri-iodothyronine, cortisol, thyroid peroxidase (TPO) antibody titre and 24-h urinary excretion of cortisol. RESULTS: The serum concentration of TSH was slightly higher in depressed patients as compared with controls (P < 0.001), independent of the presence of subclinical hypothyroidism and/or TPO antibodies (n = 28). All other HPT axis parameters were similar in both groups. The 24-h urinary cortisol excretion was similar in patients and controls. In atypical depression, serum cortisol was lower than in non-atypical depression (P = 0.01). Patients with neither melancholic depression nor severe depression (HRSD > or =23) had altered endocrine parameters. Finally, serum TSH values could not be related to cortisol values. CONCLUSION: When compared with matched control subjects, outpatients with major depression had slightly higher serum TSH, while urinary cortisol levels were similar. Furthermore, we observed lower serum cortisol in atypical depression than in non-atypical depression.

Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial.

Controversy remains about the value of combined treatment with levothyroxine (LT4) and liothyronine (LT3), compared with LT4 alone in primary hypothyroidism. We compared combined treatment with LT4 and LT3 in a ratio of 5:1 or 10:1 with LT4 monotherapy. We conducted a double-blind, randomized, controlled trial in 141 patients (18-70 yr old) with primary autoimmune hypothyroidism, recruited via general practitioners. Inclusion criteria included: LT4 treatment for 6 months or more, a stable dose for 6 wk or more, and serum TSH levels between 0.11 and 4.0 microU/ml (mU/liter). Randomization groups were: 1) continuation of LT4 (n = 48); 2) LT4/LT3, ratio 10:1 (n = 46); and 3) LT4/LT3, ratio 5:1 (n = 47). Subjective preference of study medication after 15 wk, compared with usual LT4, was the primary outcome measure. Secondary outcomes included scores on questionnaires on mood, fatigue, psychological symptoms, and a substantial set of neurocognitive tests. Study medication was preferred to usual treatment by 29.2, 41.3, and 52.2% in the LT4, 10:1 ratio, and 5:1 ratio groups, respectively (chi2 test for trend, P = 0.024). This linear trend was not substantiated by results on any of the secondary outcome measures: scores on questionnaires and neurocognitive tests consistently ameliorated, but the amelioration was not different among the treatment groups. Median end point serum TSH was 0.64 microU/ml (mU/liter), 0.35 microU/ml (mU/liter), and 0.07 microU/ml (mU/liter), respectively [ANOVA on ln(TSH) for linear trend, P < 0.01]. Mean body weight change was +0.1, -0.5, and -1.7 kg, respectively (ANOVA for trend, P = 0.01). Decrease in weight, but not decrease in serum TSH was correlated with increased satisfaction with study medication. Of the patients who preferred combined LT4/LT3 therapy, 44% had serum TSH less than 0.11 microU/ml (mU/liter). Patients preferred combined LT4/LT3 therapy to usual LT4 therapy, but changes in mood, fatigue, well-being, and neurocognitive functions could not satisfactorily explain why the primary outcome was in favor of LT4/LT3 combination therapy. Decrease in body weight was associated with satisfaction with study medication.

Triiodothyronine addition to paroxetine in the treatment of major depressive disorder.

There is evidence that thyroid hormone T3 increases serotonergic neurotransmission. Therefore, T3 addition to antidepressants may improve treatment response in major depression. In nonrefractory depression, T3 addition to tricyclic antidepressants indeed accelerates treatment response. Current therapeutic practice favors selective serotonin reuptake inhibitors. This is the first study to investigate the efficacy of T3 addition to paroxetine in major depression. One hundred thirteen patients with major depressive disorder were randomly assigned to 8 wk of double-blind outpatient treatment with low-dose T3 (25 microg), high-dose T3 (25 microg twice daily), or placebo in addition to paroxetine 30 mg daily. A total of 106 patients started treatment and were included in the outcome analysis. Response rate after 8 wk (reduction of Hamilton Rating Scale for Depression score > or = 50%) was 46% in all three treatment arms (P = 0.99). T3 addition did not accelerate clinical response to paroxetine, nor was an effect of T3 found when only women were analyzed. Patients on T3 addition reported more adverse events than patients on placebo comedication. In conclusion, these results do not support a role for T3 addition to selective serotonin reuptake inhibitors in the treatment of nonrefractory major depressive disorder. On the contrary, more adverse reactions occurred in T3-treated patients.

Elevated salivary dehydroepiandrosterone-sulfate but normal cortisol levels in medicated depressed patients: preliminary findings.

Major depression is often associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In contrast to cortisol, dehydroepiandrosterone-sulfate (DHEA-S) has been less extensively studied in depressed patients. This study examined salivary morning and evening levels of cortisol and DHEA-S in 13 medicated, unipolar, non-psychotic depressed patients and 13 healthy volunteers. Diurnal declines in cortisol and DHEA-S levels were found in both depressed and control groups. In patients compared with controls, DHEA-S was significantly elevated, in conjunction with normal cortisol levels. Based on DHEA-S at 22:00 h only, 77% of the subjects were correctly classified in a discriminant analysis as depressed or control. When simultaneously entered in a multiple regression analysis, DHEA-S (morning and evening) and cortisol (evening only) predicted symptom severity in depressed patients. These preliminary results suggest that DHEA-S may be a more sensitive indicator of depression and symptom severity than cortisol in medicated but still clinically depressed patients.