Comparison of hypothalamo-pituitary-adrenal function in treatment resistant unipolar and bipolar depression.

Altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis has been demonstrated in patients with treatment-resistant depression, although studies have often conflated patients with unipolar and bipolar depression. This is problematic given that the two groups often present with opposed neurovegetative symptom patterns. The aim of this study was to test, for the first time, whether post-awakening cortisol, a highly reliable, naturalistic measure of HPA functioning, could distinguish patients with clearly defined treatment-resistant unipolar (TRUD) and bipolar depression (TRBD). A total of 37 patients with TRUD, 17 patients with TRBD, and 47 healthy controls were recruited. Areas under the curve (AUC) with respect to the ground (g) and increase (i) of post-awakening cortisol concentrations (awakening, +15, +30, +45, +60, +90 min) were measured over two days. Patients with TRUD had higher total cortisol production in the morning hours compared to controls (AUCg, p = 0.01), while they did not differ in terms of the awakening response (AUCi, p = 0.28). By contrast, subjects with TRBD had lower total cortisol when compared to controls by trend (AUCg, p = 0.07), while they did not differ in the awakening response (AUCi, p = 0.15). A direct comparison of TRUD and TRBD revealed differences in the AUCg (p = 0.003) and AUCi (p = 0.03). This finding of comparatively elevated HPA axis activity in the morning in TRUD and attenuated HPA axis activity in TRBD attests to a fundamental biological distinction between unipolar and bipolar depression. It has implications for the understanding and treatment of bipolar depression and in differentiating the two types of depression.

Long-term symptomatic and functional outcome following an intensive inpatient multidisciplinary intervention for treatment-resistant affective disorders.

BACKGROUND: The natural history of treatment-resistant depression (TRD) is poor, with high rates of chronicity and recurrence. We describe longer-term symptomatic and functional outcome following multimodal intensive inpatient treatment for TRD. METHODS: Symptomatic and functional outcomes were assessed in 71 participants (unipolar, n=51; bipolar, n=20) with severe TRD previously treated at a specialist inpatient unit a median of 34 months (IQR 19-52) post discharge. We looked at outcomes in defined subgroups (unipolar, bipolar and psychotic) and at symptom clusters to see whether certain aspects of depression were more resistant to treatment than others. RESULTS: Symptomatic improvement during the admission was maintained at follow up: HDRS21 scores fell from admission (median 22; IQR 19-25) to discharge (median 12; IQR 7-16) and follow-up (median 10; IQR 4-18). Overall, two-thirds of patients were judged to have a good long-term outcome, while half remained in full remission at follow-up. Outcomes were more favourable in bipolar patients, patients without a history of psychosis and patients who were discharged in remission, although a minority of responders at discharge no longer met response criteria at follow up, and conversely some patients discharged as non-responders did subsequently respond. Non-remitting depression was characterised by three main factors; anxiety, cognitive difficulties and sleep disturbance. Those who remitted had better functional outcomes as did those who had experienced a more sustained response to treatment whilst inpatients. Quality of life was poor for those who did not respond to the treatment package. LIMITATIONS: Variable follow-up length. CONCLUSIONS: This difficult-to-treat population gained long-term benefits from multidisciplinary inpatient treatment. Treatment to remission was associated with more favourable outcomes. Non-responsive depression was characterised by specific symptom clusters that might be amenable to more targeted treatments.

The impact of childhood adversity on suicidality and clinical course in treatment-resistant depression.

BACKGROUND: Childhood adversity is a risk factor for the development of depression and can also affect clinical course. We investigated this specifically in treatment-resistant depression (TRD). METHODS: One hundred and thirty-seven patients with TRD previously admitted to an inpatient affective disorders unit were included. Clinical, demographic and childhood adversity (physical, sexual, emotional abuse; bullying victimization, traumatic events) data were obtained during admission. Associations between childhood adversity, depressive symptoms and clinical course were investigated. RESULTS: Most patients had experienced childhood adversity (62%), with traumatic events (35%) and bullying victimization (29%) most commonly reported. Childhood adversity was associated with poorer clinical course, including earlier age of onset, episode persistence and recurrence. Logistic regression analyses revealed childhood adversity predicted lifetime suicide attempts (OR 2.79; 95% CI 1.14, 6.84) and childhood physical abuse predicted lifetime psychosis (OR 3.42; 95% CI 1.00, 11.70). LIMITATIONS: The cross-sectional design and retrospective measurement of childhood adversity are limitations of the study. CONCLUSIONS: Childhood adversity was common amongst these TRD patients and was associated with poor clinical course, psychosis and suicide attempts. Routine assessment of early adversity may help identify at risk individuals and inform clinical intervention.

Longitudinal course of symptom severity and fluctuation in patients with treatment-resistant unipolar and bipolar depression.

Little is currently known about the long-term course of symptom severity and fluctuation in patients with treatment-resistant depression (TRD). We assessed this using the longitudinal interval follow-up evaluation in 115 patients with TRD (84 unipolar, 31 bipolar) with 1-7 years (median 36 months) of follow-up. Of the follow-up months, 39.2% were spent asymptomatic and 21.1% at sub-threshold symptom level, while 15.8% were spent at mild, 13.9% at moderate, and 10.0% at severe depressive episode level. Significantly more unipolar than bipolar patients were continuously symptomatic during follow-up (43% vs. 29%). Patients had a mean of 1.0 (S.D.=1.2) symptom severity level fluctuations per year. High fluctuating patients had significantly poorer global functioning and quality of life. Although most patients with TRD achieve an asymptomatic state, they continue to fluctuate and experience depressive symptoms in the majority of months, mostly at subclinical or mild severity. However, there are important differences between unipolar and bipolar TRD, with unipolar patients more likely to experience an unremitting depressive state. Additionally, a more fluctuating longitudinal illness course is associated with poorer function and quality of life, and with a bipolar diagnosis. We suggest that the longitudinal illness course is an important outcome to be considered in future TRD research.

Prediction of longer-term outcome of treatment-resistant depression in tertiary care.

BACKGROUND: Systematic studies on the outcome of treatment-resistant depression are scarce. AIMS: To describe the longer-term outcome and predictors of outcome in treatment-resistant depression. METHOD: Out of 150 patients approached, 118 participants with confirmed treatment-resistant depression (unipolar, n = 77; bipolar, n = 27; secondary, n = 14) treated in a specialist in-patient centre were followed-up for between 8 and 84 months (mean = 39, s.d. = 22). RESULTS: The majority of participants attained full remission (60.2%), most of whom (48.3% of total sample) showed sustained recovery (full remission for at least 6 months). A substantial minority had persistent subsyndromal depression (19.5%) or persistent depressive episode (20.3%). Diagnosis of bipolar treatment-resistant depression and poorer social support were associated with early relapse, whereas strong social support, higher educational status and milder level of treatment resistance measured with the Maudsley Staging Method were associated with achieving quicker remission. Exploratory analysis of treatment found positive associations between treatment with a monoamine oxidase inhibitor (MAOI) in unipolar treatment-resistant depression and attaining remission at discharge and at final follow-up, and duloxetine use predicted attainment of remission at final follow-up. CONCLUSIONS: Although many patients with treatment-resistant depression experience persistent symptomatology even after intensive, specialist treatment, most can achieve remission. The choice of treatment and presence of good social support may affect remission rates, whereas those with low social support and a bipolar diathesis should be considered at higher risk of early relapse. We suggest that future work to improve the long-term outcome in this disabling form of depression might focus on social interventions to improve support, and the role of neglected pharmacological interventions such as MAOIs.

Long-term impact of residual symptoms in treatment-resistant depression.

OBJECTIVE: Although commonly encountered, little work has defined the longitudinal course of treatment-resistant depression (TRD) and the influence of residual posttreatment symptoms on longer-term outcome. The aim of our study was to assess the impact of posttreatment clinical states on longer-term outcome. METHOD: Patients (n = 118) with TRD received specialist inpatient treatment and were followed-up for a median of 3 years. Longitudinal outcome dichotomized into good and poor outcome was used as the primary outcome and functional measures were used as secondary outcomes. RESULTS: Among 118 treated patients, 40 (34%) entered clinical remission, 36 (31%) entered partial remission, and 42 (37%) remained in episode at discharge. At follow-up, 35% had longitudinally defined poor outcome. Posttreatment clinical status was the main predictor of both poor and good outcome. Nearly 50% of patients achieved postdischarge recovery, and subsequently had longer-term outcome, comparable with patients discharged in remission. Patients who remained in episode posttreatment were more symptomatically and functionally impaired. CONCLUSION: Posttreatment clinical states are a useful guide to clinicians for projecting the longer-term outcome of patients with TRD. The persistence of residual or syndromal symptoms predicts a poorer longer-term outcome, whereas treatment to remission is associated with better outcomes.

Prospective evaluation of specialist inpatient treatment for refractory affective disorders.

BACKGROUND: Little data exist to inform the treatment of severe and resistant affective disorders. We report here the effectiveness of specialist multimodal inpatient treatment for refractory affective disorders. METHODS: Prospective evaluation of 225 consecutive patients admitted to the National Affective Disorders Unit between 2001 and 2008. RESULTS: Patients were highly treatment-resistant: most had already received ECT, lithium augmentation and over 10 prior treatment trials. Even so, sequential assessment with the Hamilton Depression Rating Scale found that 69% showed a clinical response (≥ 50% reduction in Hamilton score) to intensive therapy during admission; 50% continued to sustain a full response and 71% at least a partial response on discharge. Patients' self-ratings (57% very much or much improved, 24% slightly improved) and relative and referrer reports (75% and 68% respectively rated patients as improved) gave similar levels of improvement. LIMITATIONS: This was an observational study, without any untreated control group. The generalisability of the findings is limited by the highly specialised nature of the unit. CONCLUSIONS: Most patients with depression highly resistant to prior treatment respond to specialist and intensive multimodal inpatient therapy.

The Maudsley Staging Method for treatment-resistant depression: prediction of longer-term outcome and persistence of symptoms.

OBJECTIVE: A recently proposed multidimensional method of staging treatment resistance in depression, the Maudsley Staging Method (MSM), has been shown to predict short-term outcome of treatment. This study tested whether the MSM predicts longer-term clinical outcome. We hypothesized that patients with higher scores on the MSM would experience a worse longer-term outcome in terms of time spent in a depressive episode and level of functional impairment. METHOD: From May through July of 2008, we followed up patients with treatment-resistant depression discharged from an inpatient unit of an affective disorders service; all had MSM scores previously calculated from preadmission clinical data. We used the Longitudinal Interval Follow-up Evaluation (LIFE) chart to determine the monthly symptomatic course of depression blind to initial MSM scores. We employed a regression model to adjust for various confounding factors, including variable duration of follow-up, to determine the independent association of MSM scores with persistence of depressive disorder. RESULTS: We assessed 62 of 80 eligible patients (78%) in a median follow-up duration (interquartile range) of 29.5 (19.0-52.5) months. The MSM independently predicted (1) being in an episode for 50% or longer of the follow-up duration (OR = 2.11, 95% CI = 1.25 to 3.57), (2) being in an episode at the time of follow-up assessment (OR = 1.89, 95% CI = 1.17 to 3.05), (3) being persistently in an episode throughout the follow-up period (OR = 2.01, 95% CI = 1.14 to 3.54), and (4) total months spent in a depressive episode (OR = 1.22, 95% CI = 1.06 to 1.40). The MSM also predicted functional impairment. Antidepressant count and the Thase and Rush model did not independently predict persistence of depression or functional impairment. CONCLUSION: The MSM appears to have reasonable predictive validity regarding the longer-term course of illness, particularly persistence of depressive episodes. The MSM may be a useful, and possibly an improved, alternative to existing models of staging of treatment-resistant depression.

A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method.

OBJECTIVE: Treatment resistance is a common clinical phenomenon in depression. However, current unitary models of staging fail to represent its complexity. We aimed to devise a model to stage treatment-resistant depression, taking into account the core factors contributing to treatment failure. METHOD: We reviewed the literature to identify factors consistently associated with treatment resistance. We also analyzed data from a subgroup of patients discharged from a specialist inpatient unit for whom adequate data were obtainable. RESULTS: We present a points-based staging model incorporating 3 factors: treatment, severity of illness, and duration of presenting episode. In this model, the rating of symptom severity ranges from subsyndromal depression (score 1) to severe syndromal depression with psychosis (score 5). Antidepressant treatment is rated on a 5-point subscale based on number of medications used, while duration of the presenting episode is rated on a 3-point subscale. The overall level of resistance estimated using this model varies from minimal resistance (score of 3) to severe resistance (score of 15). The rating system allows the overall severity of treatment resistance to be summarized either as a single numeric score or under a single descriptive category. It may also be possible to specify categories (mild, moderate, and severe) based on severity of resistance. Analysis of inpatient data indicates that the factors incorporated in the model and the model itself have some predictive validity. CONCLUSION: This staging model has reasonable face and predictive validity and may have better utility in staging treatment resistance than currently available methods.

The ratio of cortisol/DHEA in treatment resistant depression.

OBJECTIVE: Hypercortisolaemia has been well described in depression and may be a factor associated with treatment resistance. The role of the more abundant adrenal steroid dehydroepiandrosterone (DHEA) has been recently investigated, with some evidence that it may have an antiglucocorticoid effect. This study measured cortisol, DHEA and their ratio in treatment resistant depression (TRD) and healthy controls and also related these measures to treatment outcome. METHOD: Plasma cortisol, DHEA and cortisol/DHEA ratio were determined at 0900h in 28 patients with TRD and 40 healthy controls. The measures were repeated following inpatient treatment in a subgroup of 21 patients and related to the outcome of such treatment. The stability of cortisol/DHEA ratios was assessed with 2 hourly samples from 0900 to 1700h in a subgroup of 15 controls. RESULTS: Basal levels of cortisol and the cortisol/DHEA ratio were higher in patients compared to controls. Whilst cortisol levels were lower after treatment, there was no relationship between cortisol levels and treatment outcome. In contrast, treatment responders had significantly lower DHEA on admission and a higher cortisol/DHEA ratio both on admission and on discharge. Cortisol/DHEA ratios were stable between 9 a.m. and 5 p.m. CONCLUSIONS: In addition to cortisol, the cortisol/DHEA ratio is raised in TRD; thus, there is no evidence that DHEA levels could negate the increased glucocorticoid activity in TRD. Patients with a more abnormal cortisol/DHEA ratio, possibly indicating greater biological dysfunction, responded preferentially to inpatient therapy, though the raised cortisol/DHEA ratio persisted after response. The cortisol/DHEA ratio is stable throughout the day and may be a more practical biological marker of TRD.