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21.04.2014

Treatment for major depressive disorder recurrent, panic disorder symptoms test - Within Minutes

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To obtain credit, study the material and complete the CME Posttest and Registration Form as instructed at the end of the activity.
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the University of California, Irvine School of Medicine, and the CME Institute of Physicians Postgraduate Press, Inc.
This Online Insight was published in January 2007 and is eligible for AMA PRA Category 1 Credit through January 31, 2009.
Narrator: You have a patient who has had 2 major depressive episodes within the last 5 years but has achieved remission. Narrator: You have a patient who has successfully responded to acute and continuation antidepressant treatment and has achieved remission. Narrator: You have a patient who has been treatment resistant to antidepressants, even in combination with mood stabilizers.
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. A meta-analysis of discontinuation randomized controlled trials (RCTs) in patients with MDD reported that 60% of patients on placebo relapsed in the year after randomization and 29% relapsed in months 12 to 36.24 For clinical decision making it is also useful to express the relative benefit of an active treatment over placebo using the “number needed to treat” (NNT). The efficacy of antidepressant medication in the acute treatment of MDD in adults is well proven by a large number of RCTs.13,14 This has been investigated in many RCTs comparing active antidepressants with placebo treatment and with active comparators. Side effects and tolerability of medications are key considerations in maximizing adherence to treatment, and they should be as minimal as possible. There is growing recognition that prophylactic treatment of depressive disorders may be inadequate in a substantial proportion of patients.
Since the classic descriptions, depression has been conceived as an episodic and recurrent illness.
This article provides an update on the diagnosis, causation, and treatment of chronic depressive problems, with a focus on the recently introduced diagnostic category of persistent depressive disorder (PDD). In DSM-III and DSM-IV, the protracted forms of depression have been conceptualized as dysthymia and by the chronic specifier of major depressive episodes. In DSM-III and DSM-IV, dysthymia was trumped by MDD and was only diagnosed if the threshold for a major depressive episode was not met in the initial 2 years of symptoms. While the merger of dysthymia and chronic depression into PDD is well justified by their strong sequential comorbidity and similar implications for prognosis and treatment, several aspects of the new diagnosis are not well supported by evidence and may not be useful. The assumption that most individuals with chronic depression also fulfill the dysthymia criteria may not hold consistently enough—it creates a group of individuals who suffer from chronic depression but do not receive the PDD diagnosis. Patients who receive inadequate treatment and fail to reach remission are at risk for poor long-term outcomes, including ongoing morbidity and mortality from other psychiatric and medical conditions, impaired psychosocial function, and increased tendency to relapse.
The University of California, Irvine School of Medicine, is accredited by the ACCME to provide continuing medical education for physicians. Food and Drug Administration for maintenance therapy for major depressive disorder during electroconvulsive therapy. Keller: Traditionally, continuation therapy is thought of as treatment that will suppress the symptoms in an episode that is still current and has not yet been fully resolved. Dunner: The design of continuation therapy studies has been to take patients who respond to an antidepressant during the acute treatment phase and then continue some patients on antidepressants and switch others to placebo. 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.
Thase: There is evidence that phototherapy and other chronobiologic interventions may have added value for those patients. Zajecka: The point is that even if there is seasonal worsening, try to get them to that place of remission through the whole year, whatever treatments were used. Dunner: I would rather treat the more severely seasonal mood disorder patients with a maintenance pharmacotherapy than relying on them to come in next year for their bright light therapy. Thase: So unless patients are asymptomatic, they are at risk, even if they meet criteria for remission. Dunner: Well, that raises an interesting question about the teratogenetic risk of long-term treatments. 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. Thase went on to comment that although they were permitted to use doses up to 300 milligrams a day of venlafaxine, which is higher than the approved dose for the once daily formulation, a secondary analysis of patients who received approved doses, that is 75 milligrams to 225 milligrams per day, confirmed the preventive effect. 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.
Thase: Even when patients tell you that they are adherent to treatment, there may be some amount of misadventure in their dosing. Keller: Current evidence suggests that you should keep people on the same dose for maintenance as was necessary to bring about a recovery or a remission. Blier: I agree, but I think that as we go on in time, there may be a need for increasing the dose and certainly not decreasing the dose if we want a favorable outcome.
Pollack: There is data about initiating the cognitive-behavioral therapy during the discontinuation of benzodiazepines before panic disorder with the idea that not only does that help get them through the withdrawal, but it may also have some salutary effect in terms of preventing relapse down the road. 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. Keller: It is absolutely crucial that a commitment is made by the primary care group or practitioner to align themselves with therapists who are capable of delivering these treatments. Zajecka: A small study recently published out of the Netherlands showed that for patients who received acute ECT and were then randomized to get placebo or imipramine, those who got imipramine did well in the long run, certainly relative to placebo.
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. Blier: Basically, 50% of the patients never go beyond the 3-month maintenance phase of their treatment. Keller: Think about approaching the patient when you know there is a high likelihood they will stop the 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. 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. Depressive episodes with clear onset and offset and sharp contrast with one’s usual mood and behaviors are perhaps the most conspicuous feature of severe mood disorders.
Dysthymia was characterized by milder symptoms not fully meeting criteria for MDD, but lasting 2 years or longer and meriting clinical attention because of the cumulative burden of long-standing symptoms. Major depressive episodes could be specified as chronic if the full criteria were continuously met for 2 years or longer. This new division of depressive disorders gives more weight to duration than to severity of symptoms.
While it is undisputable that prolonged duration and nonepisodic character are relevant, there is no good justification for the 2-year cutoff. 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. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information. Invariably, antidepressant continuation treatment for the next 6 to 12 months works much better than placebo, showing the need for continuation treatment with all of our treatments, including psychotherapy. I favor phototherapy in people with milder disorders and pharmacotherapy in people with more severe disorders.
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. Those people who were treated with psychotherapy alone were continued for an additional 6 months on psychotherapy, so that would be 9 months.
But, in the classic Pittsburgh maintenance study, how much time the psychotherapist actually spent doing interpersonal psychotherapy during the long-term phase of the study had everything to do with whether IPT actually worked for prevention.
And, since primary care doctors see somewhere between 50% and 60% of people with depression, they are the primary treaters. And, clearly because of the cost and the ongoing life disruption of having periodic ECT treatments, you should go into maintenance ECT only when ECT has clearly worked and pharmacologic prevention strategies, including antidepressant in combination with mood stabilizer, have failed. My understanding is that the average duration of an antidepressant in the United States is about 100 days and that has been stable for the past 10 years.
But, until we find the treatments or other means to really control it, we have to start perceiving this as a potentially long-term, life-long illness in many patients. In general, we do not include patients who have such problems into acute treatment trials because this can decrease the remission rate.
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.
Chronic coadministration of olanzapine and fluoxetine activates locus coeruleus neurons in rats: implications for bipolar disorder.
Relapse in patients on long-term fluoxetine treatment: response to increased fluoxetine dose. 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. Discontinuation of benzodiazepine treatment: efficacy of cognitive-behavioral therapy for patients with panic disorder. Feasibility and acceptability of telephone psychotherapy program for depressed adults treated in primary care. 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. 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. Usual responder rates vary between 32% and 70%,28 HAM-D17 differences between active and placebo treatment after 6 to 8 weeks of treatment often reach only 3 to 4 absolute points, but represent mean reductions in comparison to the scores before treatment of about 50% to 60%. The standard exclusion criteria of most trials, which have become much more stringent over the past decade, do exclude a significant number of patients suffering from suicidality, comorbid axis I disorders, and medical illnesses. 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.
A randomized, placebo-controlled trial of sertraline for prophylactic treatment of highly recurrent major depressive disorder. 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. Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. The clinical significance of antidepressant treatment effects cannot be derived from placebo-verum response differences. 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. The symptomatic criteria for dysthymia differed in part from those for major depressive episode, with an emphasis on low self-esteem and hopelessness (Table 1). DSM-5 defines PDD on the basis of the set of symptoms for dysthymia, with the assumption that most individuals who meet the full symptoms for MDD also meet criteria for dysthymia. 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, individuals in their second episode who have features such as poor symptom control, concomitant alcohol abuse, or anxiety disorders, those would be indications for maintenance treatment. They were treated with venlafaxine and fluoxetine for 10 weeks in the acute phase and then continued in a 6-month continuation phase. 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. And, in the absence of a large study using first-line treatments which suggests it is okay to lower it, I would stay with the higher dose.
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. The fact is that we are, as a society, not really close to the treatment guidelines that have been proposed. Depression is a life-long disorder and patients and clinicians ought to be using rating scales to monitor how the patients are doing. 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. The final choice of prophylactic agent does depend on how individual patients respond to and tolerate treatment with antidepressants and lithium. 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. 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. Patients’ preference and their own or their family member’s experience with maintenance treatment are also helpful in the choice of the medication.
In the first year, there was a highly significant advantage to remaining on venlafaxine compared to placebo with regard to recurrence. So, it was either a very good preventive treatment or a worthless preventive treatment based on the quality and focus of the therapy.
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. 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. Ghaemi30 has estimated that fewer than 10% of depressed patients qualify for, and agree to, participate in available RCTs of antidepressants. Maintenance for 5 years or indefinitely is recommended for those patients at greater risk, particularly where two or three attempts to withdraw medication have been followed by another episode within 1 year. Those people who stayed well on treatment were then double-blindly randomized to stay on venlafaxine or to go to placebo. 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. 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. There was an overwhelming probability in that second year, if you went to placebo, you would have a recurrence. Although concerns about the generalizability of results fromplacebo RCTs can be raised, RCTs testing the efficacy of a new antidepressant in comparison with placebo remain the gold standard for proof of efficacy requested by the regulatory authorities. Nevertheless, according to NICE and regulatory authorities such as the EMA, RCTs remain the most important method for establishing treatment efficacy and estimating the clinical effectiveness of antidepressants.



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