Atypical depression, atypical temperament and a differential antidepressant response to fluoxetine and nortriptyline

We examined the personality characteristics of depressed patients with and without atypical depression. Of 195 depressed outpatients in a randomized treatment trial of fluoxetine or nortriptyline, 16 met DSM-IV criteria for atypical depression. We compared the personality traits and disorders in those with and without atypical depression. In atypical depression, fluoxetine was superior to nortriptyline. On the Temperament and Character Inventory, those with atypical depression had high attachment, low persistence, and high anticipatory anxiety. A temperament construct of these dimensions was associated with a differential antidepressant response, regardless of other atypical features. A temperament derived measure of "rejection sensitivity" defines a group of depressed patients with a differential antidepressant response, regardless of reversed vegetative symptoms.     

A differential response to nortriptyline and fluoxetine in melancholic depression: the importance of age and gender

OBJECTIVE: To consider the impact of age and gender on the antidepressant response to nortriptyline and fluoxetine in melancholic depression. METHOD: Of 191 depressed patients, 113 met study criteria for melancholia. All patients were randomized to receive either fluoxetine or nortriptyline. Response rates, defined as an improvement of 60% or more on the Montgomery Asberg Depression Rating Scale over 6 weeks of antidepressant treatment on an intention to treat basis, were examined by age, and by age and gender. RESULTS: Melancholic depressed patients 40 years or older, especially men, had a markedly superior response to nortriptyline compared with fluoxetine. Conversely, melancholic depressed patients, age 18-24 years, especially women, had a markedly superior response to fluoxetine. CONCLUSION: Age and gender appear to be critical variables in understanding differential antidepressant responses to tricyclic antidepressants and selective serotonin reuptake inhibitors in melancholic depression.     

Nortriptyline versus fluoxetine in the treatment of depression and in short-term recovery after stroke: a placebo-controlled, double-blind study

OBJECTIVE: This study compared nortriptyline and fluoxetine with placebo in the treatment of depression and in recovery from physical and cognitive impairments after stroke. METHOD: A total of 104 patients with acute stroke enrolled between 1991 and 1997 entered a double-blind randomized study comparing nortriptyline, fluoxetine, and placebo over 12 weeks of treatment. The majority of patients were recruited from a rehabilitation hospital in Des Moines, Iowa, but other enrollment sites were also used. Both depressed and nondepressed patients were enrolled to determine whether improved recovery could be mediated by mechanisms unrelated to depression. Nortriptyline in doses of 25 mg/day gradually increased to 100 mg/day or fluoxetine in doses of 10 mg/day gradually increased to 40 mg/day or identical placebo were given over 12 weeks. Response to treatment of depression for individual patients was defined as a greater-than-50% reduction in scores on the Hamilton Rating Scale for Depression and no longer fulfilling diagnostic criteria for major or minor depression. Improved recovery for a treatment group was defined as a significantly higher mean score from baseline to end of the treatment trial, compared with patients treated with placebo, on measures of impairment in activities of daily living and levels of cognitive and social functioning. RESULTS: Nortriptyline produced a significantly higher response rate than fluoxetine or placebo in treating poststroke depression, in improving anxiety symptoms, and in improving recovery of activities of daily living as measured by the Functional Independence Measure. There was no effect of nortriptyline or fluoxetine on recovery of cognitive or social functioning among depressed or nondepressed patients. Fluoxetine in increasing doses of 10-40 mg/day led to an average weight loss of 15. 1 pounds (8% of initial body weight) over 12 weeks of treatment that was not seen with nortriptyline or placebo. CONCLUSIONS: Given the doses of medication used in this study, nortriptyline was superior to fluoxetine in the treatment of poststroke depression. Demonstrating a benefit of antidepressant treatment in recovery from stroke may require the identification of specific subgroups of patients, alternative measurement scales, or the optimal time of treatment.     

Childhood neglect and abuse as predictors of antidepressant response in adult depression

Background: Childhood neglect and abuse are recognized as risk factors for depression, but are not often studied as predictors of treatment response in depression. Methods: Clinically depressed outpatients (n=195) were asked about childhood experiences before beginning a randomized antidepressant trial with either fluoxetine or nortriptyline. Three treatment outcomes were measured: Adequate trial, six‐week response and two months sustained recovery. Results: Patients reporting low paternal care (paternal neglect), as measured by the Parental Bonding Instrument (PBI), were less likely to complete an adequate six‐week trial of medication. Patients who reported high maternal protection (maternal overprotection) on the PBI had poorer treatment response in the short‐term at six weeks, and longer term, for two months of sustained recovery. However, abuse, whether sexual, physical, or psychological in nature, did not predict treatment response. Conclusions: The experience of having a neglectful father or an overprotective mother was more predictive of response to treatment for depression than abuse, suggesting that the quality of ongoing intra‐familial relationships has a greater impact on treatment outcomes for depression than experiences of discrete abuse in childhood. Depression and Anxiety, 2009. © 2009 Wiley‐Liss, Inc.     

Mortality and poststroke depression: a placebo-controlled trial of antidepressants

OBJECTIVE: Poststroke depression has been shown to increase mortality for more than 5 years after the stroke. The authors assessed whether antidepressant treatment would reduce poststroke mortality over 9 years of follow-up. METHOD: A total of 104 patients were randomly assigned to receive a 12-week double-blind course of nortriptyline, fluoxetine, or placebo early in the recovery period after a stroke. Mortality data were obtained for all 104 patients 9 years after initiation of the study. Demographic and clinical measurements were collected at 3, 6, 9, 12, 18, and 24 months after the stroke. Survival data were analyzed by using the Kaplan-Meier method. RESULTS: Of the 104 patients, 50 (48.1%) had died by the time of the 9-year follow-up. Of 53 patients who were given full-dose antidepressants, 36 (67.9%) were alive at follow-up, compared with only 10 (35.7%) of 28 placebo-treated patients, a significant difference. Logistic regression analysis showed that the beneficial effect of antidepressants remained significant both in patients who were depressed and in those who were nondepressed at enrollment, after the effects of other factors associated with mortality (i.e., age, coexisting diabetes mellitus, and chronic relapsing depression) were controlled. There were no intergroup differences in severity of stroke, impairment in cognitive functioning and activities of daily living impairment, and other medications received. CONCLUSIONS: Treatment with fluoxetine or nortriptyline for 12 weeks during the first 6 months poststroke significantly increased the survival of both depressed and nondepressed patients. This finding suggests that the pathophysiological processes determining the increased mortality risk associated with poststroke depression last longer than the depression itself and can be modified by antidepressants.     

Treatment choice after one antidepressant fails: a survey of northeastern psychiatrists

BACKGROUND: Because limited evidence exists to help clinicians choose the next step after a depressed patient fails to respond to an adequate trial of an antidepressant, I conducted a survey to explore psychiatrists' treatment choices. METHOD: I asked 118 northeastern psychiatrists what they would do next in response to a clinical vignette of an inpatient with DMS-III-R major depression who failed to respond to 4 weeks of nortriptyline at adequate blood levels. RESULTS: Lithium augmentation was chosen by more than a third (33.9%) of psychiatrists. Other choices, in order of decreasing frequency, were continuing nortriptyline for another 2 weeks (17.8%) and switching to either fluoxetine (16.1%), electroconvulsive therapy (11.0%), or a monoamine oxidase inhibitor (6.8%). Only one psychiatrist each chose thyroid augmentation or bupropion. CONCLUSIONS: The surveyed psychiatrists overwhelmingly preferred lithium augmentation over other strategies to manage treatment-resistant depression. Research on comparative strategies is lacking and urgently needed.     

Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients: a pilot double-blind randomized trial

Depression is one of the most common neuropsychiatric conditions, with a lifetime prevalence approaching 17%. Although a variety of pharmaceutical agents is available for the treatment of depression, psychiatrists find that many patients cannot tolerate the side effects, do not respond adequately, or finally lose their response. On the other hand, many herbs with psychotropic effects have far fewer side effects. They can provide an alternative treatment or be used to enhance the effect of conventional antidepressants. A number of recent preclinical and clinical studies indicate that stigma and petal of Crocus sativus have antidepressant effect. Our objective was to compare the efficacy of petal of C. sativus with fluoxetine in the treatment of depressed outpatients in an 8-week pilot double-blind randomized trial. Forty adult outpatients who met the DSM- IV criteria for major depression based on the structured clinical interview for DSM- IV participated in the trial. Patients have a baseline Hamilton Rating Scale for Depression score of at least 18. In this double-blind and randomized trial, patients were randomly assigned to receive capsule of petal of C. sativus 15 mg bid (morning and evening) (Group 1) and fluoxetine 10 mg bid (morning and evening) (Group 2) for a 8-week study. At the end of trial, petal of C. sativus was found to be effective similar to fluoxetine in the treatment of mild to moderate depression (F=0.03, d.f.=1, P=0.84). In addition, in the both treatments, the remission rate was 25%. There were no significant differences in the two groups in terms of observed side effects. The present study is supportive of other studies which show antidepressant effect of C. sativus.     

A twelve-week, double-blind, randomized comparison of nortriptyline and paroxetine in older depressed inpatients and outpatients.

Selective serotonin reuptake inhibitors may be less efficacious than tricyclic antidepressants in the treatment of severe depression in older patients. The authors compared the 12-week clinical outcome of older depressed patients treated with nortriptyline or paroxetine in a double-blind randomized comparison in 116 psychiatric inpatients and outpatients (mean age: 72+/-8 years) who presented with a major depressive episode or melancholic depression. Discontinuation and response rates were compared in patients who began or who completed treatment. The discontinuation rate due to side effects was significantly higher with nortriptyline than with paroxetine (33% vs. 16%). There were no significant differences between the rates of response in the Intent-to-Treat analysis (nortriptyline: 57% vs. paroxetine: 55% ), or the Completer analysis (nortriptyline: 78% vs. paroxetine: 84%). Although paroxetine appears to be better tolerated than nortriptyline, the efficacy of these two drugs does not appear to differ in the acute treatment of older depressed patients, including hospitalized patients and those with melancholic features.     

Drug treatment of depression in frail elderly nursing home residents.

The authors conducted a randomized, double-blind, 10-week clinical trial of two doses of nortriptyline in eight nursing homes. Sixty-nine patients, average age 79.5 years, were randomized to receive regular doses (60 mg-80 mg/day) vs. low doses (10 mg-13 mg/day) of nortriptyline. Among the more cognitively intact patients, there was a significant quadratic relationship defining a "therapeutic window" for nortriptyline plasma levels and clinical improvement. There were also significant differences in plasma level-response relationships between depressed patients who were cognitively impaired and those who were more cognitively intact. Depression remains a syndrome that responds to specific treatment, even in frail nursing home patients, and those depressions that occur in patients with significant dementia may represent a treatment-relevant condition with a different plasma level-response relationship than in depression alone.     

Persistence of cognitive impairment in geriatric patients following antidepressant treatment: a randomized,double-blind clinical trial with nortriptyline and paroxetine

Cognitive dysfunction is common in older persons suffering from a major depression. However, the degree to which this dysfunction is reversible with successful treatment of the depression remains uncertain. The present study examined the effects that treatment (randomized double-blind design) with either an SSRI (paroxetine) or a tricyclic antidepressant (nortriptyline) had on cognition in older depressed patients. The patients' performance was compared to that of a group of normal controls of similar age and education. Patients and controls were administered measures of working memory, information-processing speed, episodic memory and attention five times over the course of a 12 week trial. At baseline, the patients performed more poorly than the elderly controls on all cognitive measures. While the patients' performance did improve over the course of their treatment, the magnitude of this improvement did not exceed that produced in the elderly controls by practice alone. The same pattern of results was evident in both intent-to-treat and responder analyses. Thus, there was no evidence that the depressed patients' cognitive performance normalized after response to antidepressant therapy. Neither the patients' age at onset nor their baseline level of cognitive functioning influenced the amount by which their performance improved over the 12 week trial. There was no difference between paroxetine and nortriptyline in the amount of cognitive change associated with treatment. The present results suggest that cognitive dysfunction persists in older depressed patients even after their mood disorder has responded to antidepressant medications.     

The relationship of personality disorders to treatment outcome in depressed outpatients

BACKGROUND: Many clinicians believe that depressed patients with comorbid personality disorder(s) may respond differently to standard treatments than patients with depression alone. Personality disorders appear to be common among patients with depression, suggesting potentially significant treatment implications for a large group of patients. METHOD: Subjects with DSM-III-R major depression were recruited for a study looking at prediction of antidepressant response. All patients were assessed using the Structured Clinical Interviews for DSM-III-R Axis I and Axis II, as well as rated on the Hamilton Rating Scale for Depression and the Montgomery-Asberg Depression Rating Scale (MADRS). Patients were then randomly assigned to treatment with fluoxetine or nortriptyline and reassessed at 6 weeks. The major outcome measure was percentage reduction in MADRS scores. RESULTS: Of the 183 patients who completed the personality disorder assessment, 45% had at least 1 comorbid personality disorder. Subjects with comorbid personality disorders were slightly younger, more depressed at baseline, had poorer social adjustment, more general psychopathology, and more chronic depression. Despite these differences, the presence of a comorbid personality disorder did not adversely affect overall outcome at 6 weeks, but there was an interaction between having a comorbid personality disorder and drug type. The major effect was that patients with a cluster B personality disorder did relatively poorly on nortriptyline compared with fluoxetine treatment. CONCLUSION: The finding that the presence of a comorbid personality disorder does not affect overall treatment response is similar to that reported by some recent studies. The finding that patients with cluster B personality disorders respond poorly to nortriptyline is also consistent with a small literature on borderline personality disorder.     

Relevance of DMS-III depressive subtype and chronicity of antidepressant efficacy in atypical depression. Differential response to phenelzine, imipramine, and placebo

One hundred ninety-four nonmelancholic depressed outpatients with features of atypical depression took part in a 6-week randomized trial of imipramine hydrochloride, phenelzine sulfate, and placebo. Their courses of illness were also rated for chronicity. Significantly more patients responded to phenelzine (71%) than to imipramine (48%), which benefited significantly more patients than placebo (26%). Both chronicity and DMS-III diagnosis predicted response on several outcome measures. For example, patients with dysthymic disorder responded better to treatment than did those with major depression, suggesting that dysthymic disorder can be treated with medication. Placebo response correlated inversely with chronicity, regardless of DMS-III diagnosis. Atypical depression and longitudinal course of illness may add to the usefulness of DMS-III depressive diagnosis as a predictor of antidepressant response.     

Effectiveness of fluoxetine and doxepin in treatment of melancholia in depressed patients

It has been suggested that serotonin reuptake inhibitors (SSRIs) may be less effective than tricyclic antidepressants (TCAs) in treatment of melancholic depression. We treated 36 depressed ambulatory patients with doxepin or fluoxetine in a double-blind, randomized 6-week trial with placebo run-in. Seven patients treated with doxepin and 13 patients treated with fluoxetine met diagnostic criteria for melancholic depression. Average daily dose was 169.4 ± 41.6 mg for doxepin and 36.8 ± 18 mg for fluoxetine. We observed a 50% response rate in both treatment groups, using as outcome criterion reduction of Hamilton Depression Scale Score to less than 10. Regardless of how strict the definition of response, we found fluoxetine to be as effective as doxepin in our group of melancholic outpatients. Depression and Anxiety 7:69–72, 1998. © 1998 Wiley-Liss, Inc.     

Paroxetine versus nortriptyline in the continuation and maintenance treatment of depression in the elderly

Elderly depressed patients are vulnerable to recurrence of depression and benefit from long-term antidepressant therapy. Physicians increasingly use selective serotonin re-uptake inhibitors (SSRIs) as maintenance therapy, although in the absence of data showing that SSRIs are as efficacious as tricyclic antidepressants (TCAs) in the prevention of depression relapse and recurrence. Our objective was to evaluate, in an open trial, the efficacy of paroxetine versus nortriptyline for preventing recurrence of depression in the elderly. Elderly patients with major depression were randomly assigned in a double-blinded fashion to receive either paroxetine or nortriptyline for the acute treatment of depression. Patients who did not respond or tolerate their assigned medications were crossed over openly to the comparator agent. Patients whose depression remitted continued antidepressant medication (paroxetine n = 38; nortriptyline n = 21) during an open 18-month follow-up study. We examined the rates of and times to relapse and to termination of treatment for any reason. Paroxetine (PX) and nortriptyline (NT) patients had similar rates of relapse (16% vs. 10%, respectively) and time to relapse (60.3 weeks vs. 58.8 weeks, respectively) over 18 months. A lower burden of residual depressive symptoms and side effects during continuation and maintenance treatment was evident in nortriptyline-treated patients. Paroxetine and nortriptyline demonstrated similar efficacy in relapse and recurrence prevention in elderly depressed patients over an 18-month period.     

Randomized double-blind placebo-controlled donepezil augmentation in antidepressant-treated elderly patients with depression and cognitive impairment: a pilot study

OBJECTIVE: To assess combined antidepressant and cognitive enhancer treatment in elderly patients presenting with depression plus cognitive impairment. METHODS: Twenty-three elderly (>50 years old) depressed, cognitively impaired (DEP-CI) patients participated in a pilot study. We evaluated whether, after 8 weeks of open antidepressant treatment, donepezil HCl (Aricept) would afford added cognitive benefit compared to placebo in a randomized 12-week trial. A subsample continued in an 8-month extension phase of open treatment with donepezil. Neuropsychological testing (NPT) was performed and antidepressant response monitored at baseline and the 8, 20, and 52-week time points. RESULTS: At 8-weeks, the antidepressant response rate was 61% (14/23). Improvement in SRT immediate recall (SRT-IR; e.g. episodic verbal memory) was observed in responders compared to non-responders. During the 12-week, placebo-controlled, donepezil add-on trial, patients on donepezil showed further improvement in SRT-IR versus patients on placebo. In the open extension phase, patients who continued open donepezil treatment (n = 6) maintained improvement in memory and tended to show an advantage over patients who never received donepezil and were evaluated at the 52-week time point (n = 6). There were no observed significant donepezil effects on non-memory cognitive domains. CONCLUSION: These preliminary findings suggest that addition of a cholinesterase inhibitor (AChEI) following antidepressant medication treatment in elderly Dep-CI patients may improve cognition, and support the need for a confirmatory, larger randomized placebo-controlled trial.     

Clinical and treatment response characteristics of late-life depression associated with vascular disease: a pooled analysis of two multicenter trials with sertraline

1. The safety and efficacy of sertraline in the treatment of moderate-to-severe major depression in elderly outpatients, aged 60 years and older, with comorbid vascular disease was evaluated. 2. An analysis of the pooled results for the sertraline treatment group drawn from two prospective, randomized, double-blind studies (sertraline vs. fluoxetine, and sertraline vs. nortriptyline) was done. Patients were retrospectively categorized into one of 3 clinical groups: 1) patients with a current diagnosis of hypertension but no other past or present cardiovascular illness (HTN), 2) patients reporting a current or past history of cardiovascular illness, but excluding hypertension (VASC), and 3) patients with no hypertension, and no other comorbid vascular illness (NoVASC). Patients received 12-3. weeks of double-blind treatment with sertraline in flexible daily doses in the range of 50 - 150 mg (in the nortriptyline comparator trial) or 50 - 100 mg (in the fluoxetine comparator trial). 4. Sertraline treatment yielded comparable levels of response in all 3 groups (response criterion: CGI-much or very much improved) at treatment endpoint on both a completer analysis (HTN, 86%; VASC, 89%; NoVASC, 77%) and significantly higher response rates on a 12-week endpoint analysis (HTN, 74%; VASC, 69%; NoVASC, 58%; p < 0.05). Sertraline treatment was well-tolerated, with no between-group differences in rates of adverse events, or in discontinuation due to adverse events. Patients taking 5 or more concomitant medications showed no difference, when compared with patients taking none-or-one concomitant medication, either in rates of adverse events, or in discontinuation due to adverse events. 5. Sertraline was found to be a safe, well-tolerated, and effective as an antidepressant in elderly patients suffering from hypertension and other forms of vascular comorbidity.     

Borderline personality disorder in major depression: symptomatology,temperament, character,differential drug response,and 6-month outcome

Among 183 depressed patients participating in a randomized long-term treatment trial of fluoxetine and nortriptyline, 30 patients had borderline personality disorder (BPD), 53 had other personality disorders (OPD), and 100 had no personality disorders (NPD). The borderline depressed patients had earlier age of onset of their depressions, more chronic depressions, more alcohol and cannabis comorbidity, and were more likely to have histories of suicide attempts and of self-mutilation. On self-report, patients with BPD and OPD reported more phobic symptoms, greater interpersonal sensitivity, and more paranoid ideation. Uniquely, BPD patients were more angry than OPD patients. BPD patients had high novelty seeking, high harm avoidance, low self-directedness, and low cooperativeness. Depressed patients with BPD did poorly in the short term if treated with nortriptyline rather than fluoxetine. After 6 months, those with BPD had a favorable outcome in regard to depressive symptoms, social adjustment, and even improvement in the character measure of self-directedness. Those with the poorest outcome were those with OPD.     

Somatic symptoms in treatment-resistant depression

The purpose of this work was to study the prevalence of somatic symptoms in patients with treatment-resistant depression (TRD) and their impact on the response to antidepressant treatment. Somatic symptoms were assessed during the screen visit with the Symptom Questionnaire (SQ) somatic symptom (SQ-SS) and somatic well-being sub-scales (SQ-SWB) in 40 patients with TRD enrolled in a 6-week open trial of nortriptyline. A logistic regression was used to test whether SQ-SS or SQ-SWB scores predicted clinical response to nortriptyline. Ninety-five percent of patients reported at least one somatic symptom. Higher SQ-SS scores during the screen visit predicted poorer response to nortriptyline. There was a trend for lower SQ-SWB scores to predict poor response to nortriptyline. None of the patients with SQ-SS scores above the mean for the sample responded to nortriptyline. The overwhelming majority of patients with TRD presented with somatic symptoms. In addition, a greater number of somatic symptoms during the screen visit placed patients at risk for further treatment resistance.     

Early fluoxetine treatment of post-stroke depression

Objective: Poststroke depression is a frequent psychiatric complication after stroke that may have strong negative impact on rehabilitation therapy and functional recovery. This study was conducted to show the efficacy and safety of early treatment with the selective serotonin reuptake inhibitor fluoxetine in post-stroke depressed patients. Methods: This double-blind, randomized placebo-controlled study was of patients within two weeks after stroke. Moderate to severe depressed patients (determined by Hamilton Depression Scale (HDS) > 15, the Beck Depression Inventory (BDI) and the Clinical Global Impression (CGI) Scale) were randomized to receive either 20 mg/d fluoxetine or placebo for 3 months. Beside the psychiatric assessment, patients were evaluated by use of the Scandinavian Stroke Scale (SSS), the Mini-Mental-State-Examination (MMSE) and the Barthel-Index (BI). An open-label long-term follow up was done 18 months after the initial assessment. Results: 54 depressed patients of an inpatient population of 242 consecutive stroke patients aged 25 to 85 years entered the trial within the first two weeks post-stroke. 50 patients completed the trial per-protocol. The initial severity of depression was comparable in the two groups (mean baseline HDS score 32.8 in the fluoxetine vs. 30.3 in the placebo group), as were neurological symptom severity and demographic parameters. Significant improvement was seen in both groups within 4 weeks of treatment, whereas no advantages of fluoxetine could be observed at this time. This indicates a high degree of spontaneous recovery during early rehabilitation therapy. BDI scores of patients treated with fluoxetine further decreased until the follow-up at 12 weeks, whereas the scores increased again in the placebo group. This depressive relapse of the placebo patients after the end of most rehabilitation efforts was evident at a long-term follow-up 18 months after inclusion, when patients who had been treated with fluoxetine were significantly less depressed. No side effects of fluoxetine treatment were detected. Conclusions: The advantages of fluoxetine were obvious at the follow-up 18 months after inclusion, but could not be demonstrated within the first three months of controlled treatment. The multitude of therapeutic efforts that take place in the early phase of rehabilitation might have facilitated spontaneous recovery from depression and might have hindered benefits of antidepressant treatment to become obvious. Fluoxetine treatment was well tolerated and safe. Received: 5 February 2002, Received in revised form: 8 October 2002, Accepted: 28 October 2002 Correspondence to Stefan Fruehwald, MD     

Melancholia: definitions,risk factors,personality, neuroendocrine markers and differential antidepressant response

OBJECTIVE: To evaluate the CORE measure of melancholia, against the DSM-IV construct of melancholia. To evaluate the validity of both the CORE and DSM-IV constructs of melancholia against psychosocial risk factors, anxiety and personality disorder comorbidity, neuroendocrine markers and differential anti depressant response to fluoxetine and nortriptyline. METHOD: One hundred and ninety-five outpatients with major depression were evaluated for melancholia with both the DSM-IV criteria and the CORE evaluation. Both constructs were evaluated for validity against psychosocial risk factors, comorbidity, biological markers and differential antidepressant response. RESULTS: The CORE measure has satisfactory interrater reliability when used dimensionally, but has unacceptably low agreement for making a categorical diagnosis of melancholia. There is remarkably poor agreement (kappa = 0.11) between the CORE and DSM-IV criteria for melancholia. Neither the DSM-IV nor CORE criteria for melancholia identified subgroups of patients with better childhood environments or less anxiety or personality disorder comorbidity.The CORE criteria for melancholia, but not DSM-IV, identified patients with neuroendocrine disturbance. CORE scores also were associated with differential responses to fluoxetine and nortriptyline, but not in anticipated directions. Thus, high CORE scores were associated with a higher recovery rate with fluoxetine than nortriptyline. CONCLUSION: While the episode specifier of melancholia should be retained in diagnostic systems, the DSM-IV criteria were not validated against any of the variables examined in this study.The CORE construct of melancholia, was validated against neuroendocrine measures, and was associated with a differential antidepressant response. However, the limits imposed by interrater reliability,suggest the CORE measure should be used dimensionally and not to make a categorical diagnosis of melancholia.