The symptom trajectories to clinical remission in Chinese patients with unipolar major depressive disorder

There is little understanding of how unipolar major depressive disorder (UMDD) symptoms evolve in response to antidepressant treatment. The present research examined the associations between symptom trajectories and clinical remission in Chinese patients with UMDD. A total of 165 outpatients with UMDD received treatment of fluoxetine (20 mg/day) for 6 weeks and were assessed for symptom severity at weeks 1, 2, 4, and 6. We found that patients with UMDD show heterogeneity in treatment response to fluoxetine. Psychomotor retardation is a prominent symptom during the 6 weeks of assessment, and its severity at baseline is negatively associated with clinical remission.     

Treatment strategies in achieving remission in major depressive disorder

OBJECTIVE: This paper discusses strategies for achieving remission in major depressive disorder, summarizing the results of comparative studies of various antidepressants. METHOD: Antidepressant efficacy was determined as either response or remission, measured using the Hamilton Depression Rating Scale, the Clinical Global Impressions scale and other widely used instruments. RESULTS: Study results suggest an advantage to pharmacotherapy that interacts with more than one neurotransmitter system, either as single mixed-activity drugs (e.g. clomipramine, mirtazapine and venlafaxine extended-release) or combinations of medications that are individually specific for a single neurotransmitter system. CONCLUSION: Remission should be the goal of antidepressant therapy. Treatment strategies include increasing the dosage of the chosen antidepressant; switching to an antidepressant with a different mechanism of action; augmenting one antidepressant with another agent; or using combination therapy. A substantial body of data indicates that for a subset of depressed patients, activation of multiple neurotransmitter systems is beneficial in achieving remission.     

Timing of clinical improvement and symptom resolution in the treatment of major depressive disorder

The goal of the present work is to assess for the relationship between the timing of clinical improvement and the resolution of depressive symptoms in Major Depressive Disorder (MDD). 182 MDD outpatients (40.5+/-9.7 years; 53.8% female) who responded following an 8-week, 20 mg, open trial of fluoxetine were included in the analysis. The symptoms questionnaire (SQ) and Beck hopelessness scale (BHS) were also administered to 83 and 153 of these patients, respectively. Onset of clinical improvement was defined as a 30% decrease in 17-item Hamilton depression scale (HDRS-17) scores. Controlling for baseline symptom severity, we then assessed for the relationship between the timing of clinical improvement and depressive symptom at endpoint. Earlier clinical improvement in responders predicted lower HDRS-17, BHS, SQ-depression, SQ-anxiety, but not SQ-somatic symptom or SQ-anger/hostility scores at week 8. This was true regardless of whether improvement was defined as a continuous measure (30% decrease in symptom severity), as a dichotomous measure (clinical response occurring in the first two weeks of treatment). In conclusion, earlier clinical improvement with fluoxetine treatment is predictive of greater symptom resolution at endpoint. Further studies exploring the impact of various treatment modalities and placebo on the timing of clinical improvement and symptom resolution in MDD are warranted.     

Prospective study of clinical predictors of suicidal acts after a major depressive episode in patients with major depressive disorder or bipolar disorder

OBJECTIVE: The authors investigated the predictive potential of a stress-diathesis model for suicidal behavior based on correlates of past suicidal acts. In this model, suicidal acts are precipitated by stressors such as life events or a major depressive episode in the setting of a propensity for acting on suicidal urges. This diathesis is expressed as the tendency to develop more pessimism in response to a stressor and/or the presence of aggressive/impulsive traits. The predictive potential of the diathesis was tested by determining whether clinical correlates of past suicidal behavior predict suicidal acts during a 2-year follow-up of patients with a major depressive episode. METHOD: Patients with DSM-III-R major depressive disorder or bipolar disorder (N=308) were assessed at presentation for treatment of a major depressive episode. Potential predictors of suicidal acts in the 2 years after study enrollment were identified on the basis of an association with previous suicidal behavior and were tested by using Cox proportional hazards regression analysis. In addition, pessimism and aggression/impulsivity factors were generated, and their predictive ability was tested by using Cox proportional hazards regression analysis. RESULTS: The three most powerful predictors of future suicidal acts were a history of suicide attempt, subjective rating of the severity of depression, and cigarette smoking, each of which had an additive effect on future risk. The pessimism and aggression/impulsivity factors both predicted suicidal acts, and each factor showed an additive effect. CONCLUSIONS: In addition to obtaining a history of suicidal behavior, clinicians may find it useful to assess patients' current level of pessimism, aggressive/impulsive traits, and comorbidity with substance use disorders, including nicotine-related disorders, to help identify patients at risk for suicidal behavior after major depression. Interventions such as aggressive pharmacotherapeutic prophylaxis to prevent relapse or recurrence of depressive symptoms may protect such at-risk individuals from future suicidal behavior.     

Clinical predictors of suicide in primary major depressive disorder

OBJECTIVE: Follow-up studies of patients with depressive disorders have identified only a few replicable predictors of suicide and have not explored possible interactions between them. The following analysis takes advantage of a large cohort of depressed patients given detailed, structured interviews 2 decades ago. METHOD: The data set on which this analysis is based was collected between 1976 and 1990. Research personnel administered the Schedule for Affective Disorders and Schizophrenia to 785 adults who had major depressive disorder (Research Diagnostic Criteria) but who lacked other Axis I disorders. The current analysis used the National Death Index to determine mortality status as of 2003. RESULTS: One in 4 of the 134 deaths were by suicide for an overall suicide rate of 4.2%. In comparison to the remaining 752 patients, the 33 who died by suicide were more likely to have been inpatients and to have had a history of suicide attempts at the time of baseline assessment. They had also expressed more hopelessness and had higher ratings of suicidal tendency. The last of these variables was the most robust by far and, when tested with other predictors in regression analyses, was the only one to retain significance (p < .0001). No interactions between predictors emerged. As in an earlier, similar study, the suicidal tendency rating was predictive of suicides that occurred after the first year of follow-up, which suggests that suicidal tendencies comprise a trait that persists across episodes. CONCLUSION: A global rating of suicidality appears to be the single most important predictor of eventual suicide in patients with major depressive disorder.     

A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder

Background

Some, although not all, studies report small hippocampal volume in patients with major depressive disorder (MDD) relative to healthy controls. Here, we explore the contribution of key demographic and clinical variables to this difference.

Methods

We used meta-analytic techniques to provide an updated analysis of data from 32 magnetic resonance imaging studies of hippocampal volume in patients with MDD.

Results

Our analysis confirmed the difference in hippocampal volume, but only among patients with MDD whose duration of illness was longer than 2 years or who had more than 1 disease episode. We found no such effect in studies that included patients who did not fit these criteria. The effect was limited to children and middle-aged or older adults. Analyzed collectively, studies including young adult patients showed equivalent hippocampal volumes across MDD patients and controls, a result that may be attributable to a reduced burden of illness in this population. Age at onset of disease, severity of depression at the time of scanning, sex and slice thickness did not contribute to differences in hippocampal volume between patients with MDD and controls.

Limitations

The small size of many of the clinical and demographic subgroups may have limited statistical power to detect between-group differences.

Conclusion

Although all studies were cross-sectional, our results suggest that hippocampal volume reductions generally occur after disease onset in patients with MDD. These findings have implications for the timing of clinical interventions aimed at reducing the impact of MDD on neuronal structure and function.     

Concordance between clinician and patient ratings as predictors of response, remission, and recurrence in major depressive disorder

We conducted a secondary analysis of data from the Prevention of Recurrent Episodes of Depression With Venlafaxine Extended Release (ER) for Two Years (PREVENT) trial to evaluate whether discrepancies between clinician and patient ratings of depression severity were predictive of response, remission, and recurrence during treatment for a depressive episode. Patients who self-rated depression severity in concordance with the clinician (“concordant patients”) were defined as having a standardized patient-rated Inventory of Depressive Symptoms-Self Report (IDS-SR₃₀) score minus standardized clinician-rated Hamilton Rating Scale for Depression (HAM-D₁₇) score <1 SD from mean. Non-concordant patients (“underrating patients” [−1 SD], “overrating patients” [+1 SD]) were identified. Cohorts were compared for remission and response on the HAM-D₁₇, Clinician Global Impression--Severity (CGI-S), and IDS-SR₃₀ during acute and continuation therapy and time to recurrence during maintenance therapy. During acute treatment female patients were more likely to overrate their depression severity compared to the clinician; older age predicted overrating during continuation treatment. Overrating patients had a slower onset of response on the HAM-D₁₇ during acute treatment (P = 0.004). There were no differences between cohorts for remission or response on the HAM-D₁₇ or CGI-S. Overrating patients at week 10 had lower remission and response rates on the IDS-SR₃₀ during continuation therapy (32% and 50%, respectively; P ≤ 0.001) compared with underrating patients (76%, 77%) or concordant patients (64%, 78%). Patient concordance at the end of continuation therapy did not predict recurrence during maintenance therapy, indicating that patient rating scales may be useful in tracking recurrence during maintenance therapy. Poor agreement between patient- and clinician-ratings of depression severity is primarily a state phenomenon, although it is trait-like for some patients.     

Treatment strategies to improve and sustain remission in major depressive disorder

Major depressive disorder (MDD) is an often chronic, recurrent illness affecting large numbers of the general population. In recent years, the goal of treatment for MDD has moved from mere symptomatic response to that of full remission (ie, minimal/no residual symptoms). The recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial stewed that even with systematic measurement-based treatment, approximately one third of patients reach full remission after one treatment trial, with only two thirds reaching remission after four treatment trials. Treatment-resistant depression (TRD) is therefore a common problem in the treatment of MDD, with 60% to 70% of all patients meeting the criteria for TRD, Given the huge burden of major depressive illness, the low rate of full recovery remains suboptimal. The following article reports on some current treatment strategies available to improve rates of, and to sustain, remission in MDD.     

Psychosocial and neurocognitive profiles in depressed patients with major depressive disorder and bipolar disorder

Previous studies have revealed psychosocial and cognitive impairments in patients during depression. The primary aim of this study was to investigate whether patients with major depression (MDD) and bipolar disorder (BD) differ in psychosocial and neurocognitive profiles. A second aim was to examine whether cognitive impairments are homogeneous among depressed patients. Patients with MDD (n = 16) and BD (n = 14) were enrolled during a major depressive episode. About half of them had comorbidities, including personality, substance use, and anxiety disorders. Information was collected about symptomatology and psychosocial functioning, whereas an exhaustive neuropsychological battery was administered to assess cognition. During a depressive episode, MDD and BD patients had global psychosocial dysfunction, characterized by occupational and relational impairments. A cognitive slowing was also observed, as well as deficits related to alertness, spontaneous flexibility, sustained and divided attention. Moreover, severity of depression and cognitive functions were significantly associated with psychosocial functioning. In the case of severe mood disorders, psychosocial and neurocognitive functioning seem similar among MDD and BD patients during a depressive episode. In addition to an altered daily functioning, the neurocognitive profile was heterogeneous with regard to the nature and extent of cognitive deficits. Executive functions, as well as verbal learning and memory, were preserved better than attentional processes.     

Pharmacogenomic predictors of citalopram treatment outcome in major depressive disorder

Objectives. A significant proportion of patients with major depressive disorder (MDD) do not improve following treatment with first-line antidepressants and, currently, there are no objective indicators of predictors of antidepressant response. The aim of this study was to investigate pre-treatment peripheral gene expression differences between future remitters and non-responders to citalopram treatment and identify potential pharmacogenomic predictors of response. Methods. We conducted a gene expression study using Affymetrix HG-U133 Plus2 microarrays in peripheral blood samples from untreated individuals with MDD (N = 77), ascertained at a community outpatient clinic, prior to an 8-week treatment with citalopram. Gene expression differences were assessed between remitters and non-responders to treatment. Technical validation of significant probesets was carried out by qRT-PCR. Results. A total of 434 probesets displayed significant correlation to change in score and 33 probesests were differentially expressed between eventual remitters and non-responders. Probesets for SMAD 7 (SMA- and MAD-related protein 7) and SIGLECP3 (sialic acid-binding immunoglobulin-like lectin, pseudogene 3) were the most significant differentially expressed genes following FDR correction, and both were down-regulated in individuals who responded to treatment. Conclusions. These findings point to SMAD7 and SIGLECP3 as candidate predictive biomarkers of antidepressant response.     

Controlled double-blind trial of phenytoin vs. fluoxetine in major depressive disorder

BACKGROUND: Phenytoin was the first non-sedative anticonvulsant introduced and is still the anticonvulsant most widely used worldwide in neurology. Given the efficacy of the anticonvulsant lamotrigine in the depressed phase of bipolar disorder, a critical theoretical question is whether other anticonvulsants used in treating bipolar disorder might be similarly effective. We therefore undertook a controlled trial of phenytoin versus fluoxetine in major depressive disorder. METHOD: Data were collected from July 2001 to July 2003. Thirty-three subjects entered the study. All patients met DSM-IV criteria for major depressive disorder and scored a minimum of 18 on the 24-item Hamilton Rating Scale for Depression (HAM-D) at baseline. After a 3-day washout of any previous medications, patients were randomly assigned to fluoxetine or phenytoin in identical capsules. Each capsule contained phenytoin 100 mg or fluoxetine 7 mg plus cornstarch. Patients started with 1 tablet daily and increased every other day until they were taking 1 tablet 3 times daily with meals. Blood phenytoin levels were taken after 1 week, 3 weeks, and 6 weeks, and dosage was adjusted to achieve blood levels of 10 to 20 microg/mL, to a maximum dose of 4 capsules per day or a minimum dose of 2 capsules per day. Fluoxetine patients were assigned dummy blood phenytoin levels by the control psychiatrist such that the treating physician would raise the number of capsules to at least 3 per day (20 mg of fluoxetine). RESULTS: Thirty-three patients entered the study, and 28 (N = 14 in each treatment group) completed at least 3 weeks and were included in the data analysis. Patients who dropped out after week 3 (3 patients) were included in the study as last value carried forward. There was no difference between treatment groups in overall rate of response or speed of response. CONCLUSION: The absence of a placebo arm in our study allows for the possibility that neither treatment was more effective than placebo. However, the exclusion of past fluoxetine nonresponders and the minimum HAM-D score at baseline of 18 make this possibility unlikely.     

Brain metabolic changes associated with symptom factor improvement in major depressive disorder.

BACKGROUND: Symptoms of major depressive disorder (MDD) have been linked to regional brain function through imaging studies of symptom provocation in normal control subjects and baseline studies of subjects with MDD. We examined associations between change in depressive symptom factors and change in regional brain metabolism from before to after treatment of MDD. METHODS: Thirty-nine outpatients with MDD underwent 18F-fluorodeoxyglucose positron emission tomography scanning before and after treatment with either paroxetine or interpersonal psychotherapy. Associations were determined between changes in regional brain metabolism and changes in four Hamilton Depression Rating Scale factors (anxiety/somatization [ANX], psychomotor retardation [PR], cognitive disturbance [COGN], and sleep disturbance) and two corresponding Profile of Mood States subscales (tension [TENS] and fatigue [FATIG]). RESULTS: Improvement in ANX, PR, TENS, and FATIG factors was associated with decreasing ventral frontal lobe metabolism. Improvement in ANX and TENS was also associated with decreasing ventral anterior cingulate gyrus (AC) and anterior insula activity, whereas improvement in PR was associated with increasing dorsal AC activity. COGN improvement was associated with increasing dorsolateral prefrontal cortex metabolism. CONCLUSIONS: Brain regions that show significant relationships with symptom provocation in normal control subjects have similar relationships with MDD symptoms as they improve with treatment.     

Psychosocial disability during the long-term course of unipolar major depressive disorder

BACKGROUND: The goal of this study was to investigate psychosocial disability in relation to depressive symptom severity during the long-term course of unipolar major depressive disorder (MDD). METHODS: Monthly ratings of impairment in major life functions and social relationships were obtained during an average of 10 years' systematic follow-up of 371 patients with unipolar MDD in the National Institute of Mental Health Collaborative Depression Study. Random regression models were used to examine variations in psychosocial functioning associated with 3 levels of depressive symptom severity and the asymptomatic status. RESULTS: A progressive gradient of psychosocial impairment was associated with a parallel gradient in the level of depressive symptom severity, which ranges from asymptomatic to subthreshold depressive symptoms to symptoms at the minor depression/dysthymia level to symptoms at the MDD level. Significant increases in disability occurred with each stepwise increment in depressive symptom severity. CONCLUSIONS: During the long-term course, disability is pervasive and chronic but disappears when patients become asymptomatic. Depressive symptoms at levels of subthreshold depressive symptoms, minor depression/ dysthymia, and MDD represent a continuum of depressive symptom severity in unipolar MDD, each level of which is associated with a significant stepwise increment in psychosocial disability.     

Evaluation of symptoms of major depressive disorder. Self-report vs. clinician ratings

The authors examine the relationship between self-reported and interviewer ratings of individual symptoms of major depressive disorder. The overall rate of agreement between the self-reported and clinician ratings was about 80% for 14 of the 18 symptoms, and the median Kappa for determining the presence or absence of the symptoms was .62. Disagreement was greatest for psychomotor disturbance, decreased concentration, and indecisiveness. The authors discuss how the unreliability of interviewer assessments limits the amount of agreement between self-reported and clinician ratings.     

Potential peripheral biological predictors of suicidal behavior in major depressive disorder

Previous studies have shown that dysfunctions in the serotonin system and hypothalamic-pituitary-adrenal axis (HPA) are associated strongly with suicidal behavior and suicide, especially among individuals with major depressive disorder. Suicidal behavior has been explained using both the stress-diathesis model and the state-trait interaction model. Specifically, diatheses, or trait-dependent risk factors, are associated with dysfunctions in the serotonin system; however, stress responses, or state-dependent factors, are associated with HPA hyperactivity. Decreases in cholesterol and brain-derived neurotrophic factor (BDNF) levels have been associated with impaired brain plasticity among individuals with suicidal behavior. Decreased serotonin functioning has been measured using cerebral spinal fluid (CSF) 5-HIAA, fenfluramine challenge studies, and platelet 5-HT2A receptors. HPA axis dysfunction has been evaluated with the dexamethasone suppression test. Cholesterol and BDNF levels have been measured in blood serum or plasma.Nevertheless, challenges to finding promising and accessible neurobiological predictors of suicide and suicidal behavior remain. As suicide behavior is a complex phenomenon, a combined or multidimensional approach, including each of the aforementioned methods, may be required to predict suicide risk among individuals with major depressive disorder.     

Predictors of fluoxetine remission for hospitalized patients with major depressive disorder

Aim: The goal of treating major depressive disorder is to achieve remission. This prospective study aimed to identify predictors of remission in a cohort of depressive inpatients who received fluoxetine. Methods: A total of 131 newly hospitalized patients with major depressive disorder received a fixed dose of 20 mg/day (the recommended dose from the literature) of fluoxetine for 6 weeks. Symptom severity was assessed using the 17‐item Hamilton Depression Rating Scale at weeks 0, 1, 2, 3, 4 and 6. Remission was defined as a score of ≤7 on the 17‐item Hamilton Depression Rating Scale after 6 weeks of treatment. We compared the remitters and non‐remitters in terms of baseline variables. The Short‐Form‐36 pain interference item was used to assess pain. It was classified as high (score ≥ 3) or low (score < 3). Results: A total of 31 (27.7%) of 112 completers remitted after 6 weeks of treatment. The remitters and non‐remitters did not differ in baseline variables, except pain interference, baseline depression severity, and depression improvement at week 1. Conclusion: These findings obtained from newly hospitalized major depression patients support the previous notion that pain interference, depression severity, and early improvement can be the predictors for remission. Patients with high pain interference, a greater depression severity or a less early improvement are likely to require aggressive treatment early. These data require confirmation and extension to outpatients and other antidepressants.     

Coping in panic and major depressive disorder. Relative effects of symptom severity and diagnostic comorbidity.

This study used the Ways of Coping Checklist to examine coping style in patients with panic and major depressive disorders. The relative contribution of distress (symptom severity) and diagnostic comorbidity was determined in three sets of diagnostic subgroups: patients suffering from both panic and major depressive disorders (compared with either disorder alone); panic patients with and without agoraphobia (regardless of concurrent depression); and patients with versus without a concurrent axis II personality disorder. Use of less problem-focused and more emotion-focused coping was strongly correlated with level of distress and was associated with all three examples of diagnostic comorbidity when level of distress was used as a covariate. Regression analyses showed that, except for the presence of a personality disorder, distress was a much stronger predictor of coping than diagnostic subtype.     

Psychosocial functioning in youths at high risk to develop major depressive disorder

OBJECTIVE: To compare the psychosocial functioning of children and adolescents at high risk of major depressive disorder with youths with acute major depressive disorder and healthy controls. METHOD: High-risk (n = 57), major depressive disorder (n = 71), and healthy control (n = 48) youths and their families were recruited from 1987 to 1996 and assessed for psychopathology using standardized instruments. Except for 16 children who had disruptive disorders, the high-risk children were free of psychopathology. A parent completed the Psychosocial Schedule to evaluate the mother-child, father-child, marital relationships, and child-friend relationships and the child's school performance. RESULTS: Overall, high-risk and healthy controls had similar psychosocial functioning. Marital relationships were worse in the high-risk children with psychopathology. Youths with major depressive disorder had significantly more psychosocial problems and school difficulties than those at high risk and healthy controls in most domains measured. Controlling for age, pubertal stage, race, sex, family composition, current and lifetime parental depression, and current and lifetime parental nonmood psychopathology yielded similar results. CONCLUSIONS: The family and peer interactions of high-risk youths were similar to the interactions of healthy controls. Although family dysfunctional patterns seem to mainly depend on the child's depressive symptoms, longitudinal studies are needed to establish causality.