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Major depression recurrent, causes of constant fatigue and sleepiness - For Begninners

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Time is an important defining feature in the diagnosis of major depression, its prognosis, and its tendency to recur over a lifetime. It can be argued that major depression is important because of the time it steals from people’s lives and the disability or burden of disease that it therefore imparts. The very long time constants that seem to be involved in the condition are still poorly understood, but they clearly have implications for our understanding of the neurobiology and finally for the treatment strategies that we currently adopt in trying to overcome individual episodes of depression. Major depression is conventionally defined as a collection of depressive symptoms, which, according to the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DSM-IV-TR), must have been present together for at least 2 weeks.1 The choice of a 2-week cut-off is obviously arbitrary, and if a constellation of depressive symptoms is present for only 2 weeks, such an episode is likely to be of limited clinical significance. The natural history of a depressive episode in the general population is recovery: symptoms remit, the subjective burden of depression disappears, and objective wellbeing eventually returns. Symptoms returning within the acute and continuation phases are described as relapse (of the original index episode), and those occurring after recovery (in the maintenance phase) are defined as a recurrence (and notionally as the appearance of a new episode).
The pattern in women is best established for first episodes of depression, for which life events that apparently “trigger” the episode are a relatively common observation.
There is also evidence that patients who have had an episode of depression and who have fully recovered show abnormalities in their underlying neurobiology. While implicating serotonin directly, these findings do not of course exclude a contribution from other neurotransmitter systems in mediating different components of the depressive syndrome that remain incompletely understood. Major depression is a recurrent disorder, and over a period of many years may have a major impact on the lives of individuals simply by virtue of the impact of chronic or recurrent symptoms, which are socially and personally incapacitating. As already indicated, chronicity of the depressive episode predicts reduced responsiveness.
Vagal nerve stimulation is an option for patients with chronic treatment-resistant depression, as is deep brain stimulation and even ablative neurosurgery. Elapsed time plays a key role in defining the diagnosis and course of single and recurrent episodes of major depression, treatment responses, decisions to change interventions when treatments fail, and outcomes. The long-term course of unipolar major depressive disorder (MDD) is characterized by high rates of recurrence and prolonged symptomatic chronicity.
Keeping these facts in mind, it is apparent that the primary goals of long-term, maintenance (prophylactic) treatment are to prevent a new episode of depression (a recurrence) and development of chronicity.
Pharmacotherapy is the most studied treatment modality in the long-term treatment of recurrent MDD. There is growing recognition that prophylactic treatment of depressive disorders may be inadequate in a substantial proportion of patients.
Narrator: You have a patient who has had 2 major depressive episodes within the last 5 years but has achieved remission. Current nosologies of depressive illnesses do not, however, do a very good job of categorizing chronic depression. When the validity of these distinctions is examined, it becomes apparent that this multitude of diagnoses does not reflect the clinical reality of chronic depressive illnesses. The natural history of chronic depression was well described in the work of the NIH Collaborative Study on the Psychobiology of Depression. McCullough and colleagues4 compared 681 outpatients with chronic depression for a broad range of demographic, clinical, psychosocial, family history, and treatment response variables. Those who had suffered at least 2 major depressive episodes but without full interepisode recovery. Major depression is conventionally defined as a collection of depressive symptoms present together for at least 2 weeks. The appearance, disappearance, and recurrence of depression occupy a central position in defining the disorder. Indeed, broadly speaking, the longer symptoms have been present and unremitting, the more confident one becomes of any diagnosis ofmajor depression, the greater the impact it is likely to have on personal, psychological, and social function, and the more important treatment success becomes.
These ideas imply that there is some- thing unitary about a depressive episode, and that once it has gone away, the patient moves into a different state of risk and perhaps a different state of neurobiology. Longterm study of severe episodes of depression requiring admission to hospital has shown that patients with unipolar depression tend to have characteristic rates of relapse, with rather different probabilities of recurrence after repeated episodes such that the probability of further illness is increased with each successive episode (see Figure 2). They become less obvious for recurrence in individual patients, suggesting that in some sense, patients become primed to depression and therefore more likely to develop an endogenous pattern of illness as time goes by.10 Expressed another way, with recurrent episodes of major depression, the role of environmental stressors progressively diminishes.
It has been suggested that differences between individuals with high and low genetic loading may be that to be highly loaded means to start with a greater degree of priming for the onset of a first depressive episode.
However, in addition, it is now understood that depression has an impact on simple memory performance, which is also potentially cumulative with episode recurrence and may contribute to a professional disability and difficulties in employment.
There is a certain symmetry in this when looked at from the patient perspective, since recurrent and chronic depression steal significant fractions of the lifetime of individual patients.
The primary goals of continuation andmaintenance treatment are to prevent a fast relapse into depression or new episode of depression (recurrence).
50% to 85% of the patients who suffer a depressive episode will have another episode of major depression.1 The likelihood of a recurrence increases with the number of previous depressive episodes and the severity of the current episode. A recurrence is an episode that appears after a completely asymptomatic period (remission) has been achieved for a 6-month period.4,5 The consideration of the patient’s course of illness and treatment history is essential for the implementation ofmaintenance phase therapy. Most publications are reporting responder and remitter rates together with end-point differences in depression rating scales such as different versions of the HAM-D or the MADRS scale using the “last observation carried forward” (LOCF) method, which follows all included patients.
Even mild-to-moderate side effects during maintenance treatment may lead to noncompliance with the consequence of symptom worsening and increased risk of recurrence. Current evidence suggests that maintenance treatment should be continued as long as the risk of recurrence persists. Food and Drug Administration for maintenance therapy for major depressive disorder during electroconvulsive therapy. Thase: Well, the major one is just how many prior episodes they have had and with what kind of frequency of recurrence. Zajecka: People who have clinical comorbid medical illnesses, such as cardiovascular disease and cancer, are already at a greater risk for depression and should be considered too for maintenance. Blier: It is well known that pregnancy does not protect against depression, and it is very important that antidepressant medications are maintained throughout pregnancy if there is a significant risk of relapse. Thase: The risk of depression for the mother is so substantial, that an uncertain risk of teratogenicity for the child pales in comparison to the almost certainty of the mother becoming depressed.
Dunner: Kupfer also posed a 2-year extension of the 3-year Pittsburgh study, showing again that those survivors on imipramine after 3 plus years, when randomized to placebo after that period of time, their recurrences were rather quick in the next 2-year period. Pollack: The psychosocial interventions should be continued after the discontinuation of the medication to give the patients some tools if they did start to have some recurrence of symptoms. Pollack: Outside of major teaching centers, it is relatively difficult to get empirically-based cognitive-behavioral psychotherapies. Dunner: The AHCPR Guidelines for treatment of depression, which were published more than a decade ago, suggested that the acute episode be treated for almost a year and that recurrent episodes be treated somewhat longer.

Keller: There is another factor in maintenance treatment and that is that the vast majority of people for whom we put on maintenance treatment, discontinue the maintenance treatment.
Pollack: Data suggests that if somebody stops their medication and then relapses or has recurrent symptoms and restarts the medication, that they will ultimately respond, but it will take longer. Dunner: First, I give patients the data about recurrence, which is pretty high for people with multiple episodes.
For MDD, symptoms must be present continuously for 2 weeks and may be characterized by a single episode or be recurrent. The term "double depression" was introduced by Keller and colleagues3 in 1982 to describe patients with MDD and a preexisting chronic minor depression (now called dysthymic disorder).
The longer symptoms have been present and unremitting, the more confident one becomes of any diagnosis of major depression, and the greater the impact the depression is likely to have on personal, psychological, and social function.
Accordingly, the domain of time is central in the diagnosis of major depression, its prognosis, and its tendency to recur often over a lifetime.
Cognition as an end point in the treatment of depression is a new concept, but one that seems set to assume increasing importance.
Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Conceptualization and rationale for consensus definitions of terms in major depressive disorder—remission, recovery, relapse, and recurrence.
The interrelationship of neuroticism, sex, and stressful life events in the prediction of episodes of major depression.
A longitudinal study of personality and major depression in a population-based sample of male twins. Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the “kindling” hypothesis. Affective modulation of anterior cingulate cortex in young people at increased familial risk of depression.
Low-dose tryptophan depletion in recovered depressed patients induces changes in cognitive processing without depressive symptoms.
Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatients.
Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology Guidelines. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials.
Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review.
A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly recurrent major depressive disorder. Even though no definite recommendation can be given as to when prophylactic therapy should be initiated, it is clearly indicated in situations associated with a high risk of recurrence (Table I).
According to the British National Institute for Clinical Excellence (NICE) it is defined “as the extent to which a specific treatment or intervention, under ideally controlled conditions (eg, in a laboratory), has a beneficial effect on the course or outcome of disease compared with no treatment or other routine care.27 The mean differences of scores on any applied depression rating scale (typically the Hamilton Rating Scale for Depression [HAM-D] or the Montgomery Asberg Depression Rating Scale [MADRS]) between active antidepressant drugs and placebo shown in pivotal RCTs are used for decision making by the regulatory authorities to determine whether new antidepressants may receive approval or not.
Using medications with a more favorable side effect profile than the TCAs may facilitate patient compliance with pharmacotherapy, as long as these agents are effective in the maintenance treatment of depression. However, little data from formal studies are available to guide physicians in the maintenance treatment of patients suffering from recurrences during standard prophylactic treatment.12 Combination therapy administering two or even three antidepressants, maybe combined with lithium (or in case of refractoriness or intolerance lamotrigine or valproate), are treatment options for the clinician although there are little controlled data to support such polypharmacy.
Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Practice guideline for the treatment of patients with major depressive disorder (revision).
World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 2: Maintenance treatment of major depressive disorder and treatment of chronic depressive disorders and subthreshold depressions. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders in Primary Care. Evidence-based guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for Psychopharmacology guidelines.
World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for biological treatment of unipolar depressive disorders, Part 1: Acute and continuation treatment of major depressive disorder. Prophylactic effect of citalopram in unipolar, recurrent depression: placebo-controlled study of maintenance therapy.
Escitalopram maintenance treatment for prevention of recurrent depression: a randomized, placebo-controlled trial. Prevention of recurrent episodes of depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT Study.
Duloxetine in the prevention of depressive recurrences: a randomized, double-blind, placebo-controlled trial. Continuation phase treatment with bupropion SR effectively decreases the risk for relapse of depression. Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial. Comparative efficacy of lithium and amitriptyline in the maintenance treatment of recurrent unipolar depression: a randomised study.
Comparison of full-dose versus half-dose pharmacotherapy in the maintenance treatment of recurrent depression. Dose-response efficacy of paroxetine in preventing depressive recurrences: a randomized, double-blind study. Mirtazapine versus amitriptyline in the long-term treatment of depression: a double-blind placebo-controlled study.
Long-term safety and clinical acceptability of venlafaxine and imipramine in outpatients with major depression.
While safe and effective treatments exist for major depressive disorder, until recently there was only limited evidence on how to successfully treat patients who do not achieve remission after a single course of antidepressant treatment or who respond but then experience recurrent episodes. However, if someone has had a full remission on treatment and then continue to have 1 or 2 symptoms, even to a mild degree, the patient is at a high risk for recurrence. The antidepressant discontinuations study that Lee Cohen and colleagues did found that there was a risk of depression during the pregnancy. Between 1100 and 1200 subjects had recurrent major depression, with the definition being that, in addition to the current episode, they had to have had a minimum of 2 episodes in the prior 5 years. After 3 years, there was an overwhelmingly compelling advantage of people who stayed on imipramine compared to placebo who had recurrent depression.

People with depression were put on fluoxetine 20 mg and people who remitted were then switched to continue fluoxetine 20 mg, go to fluoxetine 90 mg once a week, or go to placebo for another 6 months. And, since primary care doctors see somewhere between 50% and 60% of people with depression, they are the primary treaters. Relationship of variability in residual symptoms with recurrence of major depressive disorder during maintenance treatment. Major depressive disorder: a prospective study of residual subthreshold depressive symptoms as predictor of rapid relapse. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. Recurrence prevention: efficacy of two years of maintenance treatment with venlafaxine XR in patients with recurrent unipolar major depression. Comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression.
Cognitive-Behavioral Analysis System of Psychotherapy as a maintenance treatment for chronic depression. Efficacy of interpersonal psychotherapy as a maintenance treatment of recurrent depression: contributing factors.
Cost-effectiveness of computerised cognitive-behavioural therapy for anxiety and depression in primary care: randomised controlled trial.
Computerized cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation. Online randomized controlled trial of brief and full cognitive behaviour therapy for depression. Effects of a cognitive-behavioural internet program on depression, vulnerability to depression and stigma in adolescent males: a school-based controlled trial. Continuation and maintenance electroconvulsive therapy for the treatment of depressive illness: a response to the National Institute for Clinical Excellence report. Treating major depression in primary care practice: an update of the Agency for Health Care Policy and Research Practice Guidelines.
The effects of adherence to antidepressant treatment guidelines on relapse and recurrence of depression. Substance use disorder comorbidity in major depressive disorder: a confirmatory analysis of the STAR*D cohort. Treatment approaches to major depressive disorder relapse, part 2: reinitiation of antidepressant treatment. Although this term appears commonly in the clinical literature and comes closest to reflecting the clinical reality of chronic depression, it is not a DSM diagnosis and must be captured in DSM-IV by assigning 2 diagnoses (MDD and dysthymia). Thus, in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the duration of illness was an independent predictor of failure to respond to treatment in a large population (over 3000) of index cases of major depression, all treated systematically with citalopram.2 The STAR*D finding echoes those from other studies showing that the duration of illness may well have an impact that is both statistically and clinically significant.
These factors seem to be translated into depressive episodes by themoderating effect of adversity, either in the formof acute life events or chronic difficulties in the face of which patients may develop episodes of clinical depression.7 The excess of depressive episodes usually reported in women was associated in a study by Kendler et al with depressive episodes in the context of low stress, but this finding requires confirmation. With increasing numbers of previous episodes (up to approximately 10 episodes), the association between life events and new depressive episodes fell approximately linearly. This implies that a challenge for the future is to reliably shorten all the time periods that are currently too often long and uncontrolled in depression. Education does not only reduce treatment attrition, but also leads to a better outcome.8 Strategies to prepare patients and their families for maintenance treatment include education on the typical course of the illness, treatment options, medication effects and side effects, use of (daily) selfreport instruments to track mood and early warning signs of relapse or recurrence, long-term perspectives, and projected end of treatment. In the case of trials investigating the efficacy of antidepressants, patients with a history of treatment failures and long depressive index episodes are generally also excluded from participation. It appears that the likelihood of a recurrence increases with the number of previous depressive episodes.
This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on major depressive disorder. So, of those who stayed on the active drug imipramine, only about 20% had a recurrence after 3 years; whereas, those on placebo, I believe the recurrence rate was close to 80%.
Having reverse vegetative symptoms may increase your likelihood of responding to one treatment or another, but once you have responded, you are likely to get the same benefit from continued treatment that you would if you had other forms of recurrent depression.
Now, the major criticism of the CORE study is that these were not patients who had already failed on a prevention medication strategy; so, the CORE study presents medication maintenance perhaps in a more favorable light than you would when you would be considering maintenance ECT. Depression is a life-long disorder and patients and clinicians ought to be using rating scales to monitor how the patients are doing. Extending treatment for an additional 6 months (continuation therapy) can reduce the likelihood of relapse by about 70%, and extending treatment for another 12 months or longer (maintenance therapy) can reduce the risk of recurrence. Response is defined as a 50% reduction in symptoms from baseline, followed by a continuing reduction in symptoms to a point defined as remission (usually a fixed point on a rating scale like the Hamilton Rating Scale for Depression). Most patients receive antidepressants during the acute and continuation phase, and the best treatment recommendation to prevent relapse and recurrence of depression is to continue the antidepressant medication at the same dose during these treatment phases as well. In the first year, there was a highly significant advantage to remaining on venlafaxine compared to placebo with regard to recurrence. So, these 2 factors are very important and often neglected when we prolong or maintain patients on the antidepressant because marijuana or alcohol abuse can be a very important factor for relapse of depression. Also, there can be no major depressive episode during the first 2 years of the disturbance (1 year for children and adolescents). It is durations of illness of up to 2 years that seem to have the most major impact in lowering subsequent rates of response to acute treatment.
Response is followed by a continuing reduction of symptoms to a point defined as remission (usually a level of symptoms defined by a fixed point on a rating scale like the Hamilton Rating Scale for Depression [HAM-D]).
Randomized placebo-controlled efficacy studies (RCTs, usually conducted 1 or 2 years after remission) indicate that all major classes of antidepressants are effective in preventing recurrence of depression with about a twofold higher relapse rate with placebo treatment.
Only with long-term antidepressant treatment can the risk of development of serious depressive illness with a high relapse and suicide rate be stopped or at least reduced. But, even if they are off the medication and they have not had symptoms, I think it is still a good idea for them to monitor their moods on a weekly basis just to make sure that the depression has not come back again. There was an overwhelming probability in that second year, if you went to placebo, you would have a recurrence.

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