DEPRESSION UPDATE
From Wondrous Words of Wisdom from World-Wise, Well-Spoken Witan, presented by the University of Wisconsin School of
Medicine and Public Health, and the Madison Institute of Medicine, Inc
Educational Objectives
| The goal of this program is to enhance the treatment of depression, especially treatment-resistant depression. After hearing
and assimilating this program, the clinician will be better able to:
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 | 1. Explain why depression is considered a lifelong illness.
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| 2. Discuss the results of 3 studies that appear to be negative.
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| 3. Distinguish chronic depression from recurrent depression, and treat both appropriately.
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| 4. Describe the role of algorithms in helping to select treatment modalities for depression.
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| 5. List the evidence-based psychotherapies that seem to be most effective in treating depression.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts
of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health
care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Gelenberg
is a consultant to AstraZeneca, Cyberonics, Eli Lilly, Forest, GlaxoSmithKline, Jazz, Novartis, Pfizer, and ZARS
Pharma, and is a speaker for GlaxoSmithKline, Pfizer, and Wyeth. Dr. Shelton is a consultant to Janssen; principal investigator
for Abbott, AstraZeneca, Eli Lilly, Janssen, Pfizer, Sanofi, and Wyeth; and a speaker for Abbott, Bristol-Myers
Squibb, Janssen, Eli Lilly, Pfizer, and Wyeth-Ayerst. The planning committee reported nothing to disclose.
Acknowledgements
Drs. Gelenberg and Shelton were recorded at Wondrous Words of Wisdom from World-Wise, Well-Spoken Witan, held
March 7-8, 2008, in Madison, WI, and sponsored by the University of Wisconsin School of Medicine and Public
Health and the Madison Institute of Medicine, Inc. The Audio-Digest Foundation thanks the speakers and the sponsors
for their cooperation in the production of this program.
| DEPRESSION: A LIFELONG ILLNESS —Alan J. Gelenberg, MD, Professor Emeritus, University of Arizona, and Distinguished
Senior Scientist, Madison Institute of Medicine, Inc, Madison, WI
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| Introduction: studies show depression recurrent condition; by 15 yr after recovery from index episode of depression,
85% of patients have had recurrence; by time patient has had ≥3 episodes, chance of further episodes 90%; even after just
one episode of major depression, chance of recurrence 50% to 80%
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| Sequenced Treatment Alternatives to Relieve Depression (STAR*D): large, multicenter, open-label, multiphase
study of 2876 depressed outpatients; level 1 consisted of 14 wk of adequate doses of citalopram, resulting in
28% to 33% remission rate on various depression-rating scales; however, many patients in remission reported residual
symptoms, and the more residual symptoms patient has, greater the likelihood of recurrence in near future
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| Subsequent levels: series of treatment levels included in STAR*D, to provide alternatives for patients for whom level-1
treatment insufficient; strategies included switching to another treatment or augmenting medication with another medication
or with psychotherapy; as those patients who were more treatment-resistant progressed to subsequent levels, remission
rates continued to decrease
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| Other findings from STAR*D: many patients have residual symptoms; patients with residual symptoms more likely to
have relapse; >50% of new-episode patients discontinue medication over first year; treated patients do better than untreated
patients when followed over several years; patients with ≥3 episodes of major depression at greater risk for recurrence
than those with <3 episodes
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| Chronic depression: defined as depressive episode that lasts >2 yr; lifetime prevalence 3% to 5%; represents 30% to
35% of all depression; ≈20% of STAR*D subjects in current, chronic major depressive episode; high rates of psychosocial
and physical impairment, suicide, and comorbidity; underrecognized and undertreated, but not treatment-resistant;
treatment responses may differ from those associated with nonchronic depression (response to antidepressant
medication appears to be slower in chronic depression); role of psychotherapy needs to be clarified
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| Treatment options: speaker advises patient who has done well on antidepressant for 1 yr to continue on same medication;
discontinuing medication associated with 50% risk for recurrence over next 2 yr
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| Cognitive Behavioral Analysis System of Psychotherapy (CBASP): form of psychotherapy designed specifically for
treatment of chronic depression; combined with medication in several studies; in acute treatment phase, response rate
to either treatment alone, ≈50%, and to combination therapy, 85%; patients with early life trauma and depression did
better when treated with psychotherapy than with medication; in maintenance study, patients who continued on nefazodone
had better results than those who switched to placebo
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| Conclusions from all studies of chronic depression: treatment works; 50-50 chance of improvement with antidepressant
medication or psychotherapy alone; combination may be better; patients with chronic depression who do better on
treatment obtain additional improvements when treatment continued for 4 to 7 mo; maintenance therapy better than
placebo; risk for relapse lower in chronic depression than in recurrent major depression
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| Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP) study:
follow-up study to see whether treatment with CBASP truly helps; all patients started on antidepressant; patients who
achieved remission in 8 to 12 wk dropped from study to continue maintenance therapy elsewhere; those who achieved
less than full remission randomized (according to complicated algorithm) to medication plus CBASP, medication plus
supportive psychotherapy, or medication alone; conclusions—chronic forms of major depression still undertreated;
overall remission 45% with 2 adequate medication trials over 24 wk; augmentation with CBASP or supportive therapy
did not add value in short run; questions to be answered with 2-yr follow-up study (under way) include determining
whether psychotherapy serves as mediator or moderator of response, and whether delayed, longer term effects of psychotherapy
possible
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| 2-yr maintenance treatment: Prevention of Recurrent Episodes of depression with VENlafaxine XR for Two years (PREVENT);
multicenter, randomized, double-blind, placebo-controlled trial of outpatients >18 yr of age with history of ≥3
lifetime episodes of major depression, with ≥2 episodes in past 5 yr; study includes acute and continuation phases of
treatment and 2 successive 1-yr maintenance phases; results of acute phase and 6-mo continuation phase show no differences
in response or remission rates between fluoxetine (selective serotonin reuptake inhibitor [SSRI]) and venlafaxine
(serotonin and norepinephrine reuptake inhibitor [SNRI]); in maintenance phase, patients on fluoxetine stayed
on fluoxetine; of those on venlafaxine, some stayed on venlafaxine and some switched to placebo; fluoxetine and venlafaxine
did equally well, but comparison questionable because no patients on fluoxetine switched to placebo; results
of second year of maintenance treatment suggest that staying on either drug better than switching to placebo
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| Conclusions: major depressiong—typically chronic and/or recurrent; costly and carries heavy disease burden; increases
mortality from multiple causes; treatments “far from perfect” and hard to personalize; nevertheless, sequential treatments
can produce reasonable chance of achieving remission and improving function; many patients have preference about type
of treatment, and their preferences should be honored when possible; little data to indicate which medication or which
form of psychotherapy best; important that treatment be measurement-based, rational, and collaborative
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| TREATMENT-RESISTANT DEPRESSION —Richard C. Shelton, MD, James G. Blakemore Research Professor and Vice
Chair for Research, Department of Psychiatry, and Professor, Department of Pharmacology, Vanderbilt University School
of Medicine, Nashville, TN
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| Introduction: speaker suggests that “what” of treatment (ie, which treatment to use next) less important than “how” (ie,
which philosophical principles used to drive treatment choices)
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| Sample patient history: patient started on venlafaxine 75 mg/day, and increased to higher dose (150 mg/day) at 5 mo;
subsequently switched to citalopram 20 mg/day at 10 mo; bupropion, 100 mg/day, added at 13 mo, then increased to 200
mg/day at 17 mo; finally, buspirone 15 mg/day added at 19 mo; mistakes in this treatment include underdosing, delay of
dosage titration, illogical treatment steps, and treatment based on symptoms instead of syndrome; likely outcome that
40% of patients will have discontinued treatment by 3 mo and two-thirds by 6 mo; discontinuation less likely related to
side effects as to lack of improvement (people with depression easily discouraged); premature discontinuation of treatment
increases risk for relapse and recurrence
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| Utility of algorithms: result from evidence base; provide information to support treatment decisions; determine
whether sequence of treatments matters; encourage ongoing assessment of symptoms and measurement-based care; establish
critical decision points for determining if patient well, if dose-limiting side effects present, and if patient at top of
range of recommended dosing
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| Measurement-based care: determining whether patient has gotten well requires organized or systematic evaluation;
speaker prefers Quick Inventory of Depressive Symptoms (QIDS), fourth version, which is 16-item version of Inventory of
Depressive Symptoms (IDS); both available at www.IDS-QIDS.org
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| Texas Medication Algorithm Project (TMAP): objective of initial study to compare algorithm-driven decision-
making with treatment as usual (TAU); algorithm similar to that of STAR*D; results after 3 mo showed TAU ≈50% as effective
as algorithm-driven treatment; speaker suggests that algorithm encouraged clinicians to proceed along treatment
course
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| STAR*D (additional information): algorithm similar to that of TMAP; limitations include no TAU condition (raising
questions about assay sensitivity) and stratified randomization design (negating cross-comparison between treatments);
summary of findings—depression difficult to treat to remission; fairly high proportion of patients (≈70%)
eventually remit; treatment urgent because dropout rates high among patients who perceive no improvement; in level 1,
combination therapies did equally well; in level 2, citalopram plus bupropion better than buspirone; in level 3, triiodothyronine
better than lithium; in level 4, venlafaxine plus mirtazapine better than tranylcypromine
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| Monoamine oxidase inhibitors (MAOIs): speaker finds them effective (even after multiple stages of treatment); however,
difficult for patients to tolerate
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| If patient starts treatment, what is likelihood that he or she will get well if treatment continued, compared to likelihood of
getting well if treatment discontinued? at level 1, switching from citalopram to other monotherapy “not all that effective,
generally speaking”; at level 2, “clear winner” citalopram plus bupropion; at level 3, mirtazapine and nortriptyline
performed poorly due to dropouts; T3 augmentation did surprisingly well; at level 4, “things didn’t go very well at all,
but the venlafaxine and mirtazapine were a bit better”; however, at each level, treatment-responsive patients filtered out
until level 4 included most resistant of treatment-resistant patients
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| Summary of study data: depression difficult to treat, especially to complete remission; difficult to keep patients well
over time; in STAR*D, “fairly high proportion” of patients eventually remitted; treatment urgent because dropout high
among patients who do not recover
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| TMAP guidelines on depression: preliminary report in press; after initial assessment and discussion of evidence-
based psychotherapies, start with monotherapy (no evidence that any one treatment superior to any other in treatment-naive
patients); treatment adjustments — if patient responds, continue treatment course; if response partial, augment with
bupropion, mirtazapine, venlafaxine, buspirone, or T3 ; if change minimal, switch to alternative monotherapy from different
class of antidepressant; if patient has not responded to first 2 levels, augment with tricyclic antidepressant (with or
without lithium or MAOI); if still no response, various combinations recommended (consider SSRI or SNRI with atypical
antipsychotic medication or electroconvulsive therapy [ECT]); among atypical antipsychotics, speaker favors olanzapine
and aripiprazole, but advises caution, due to weight gain and possibility of developing metabolic syndrome with olanzapine;
also, all atypical antipsychotics associated with small but definite risk for tardive dyskinesia; beyond level 4, “data
start getting very, very thin”; consider ECT or vagal nerve stimulation (VNS), combined with antidepressant medication;
any steps taken beyond this likely untried and unproven
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| Evidence-based psychotherapies: cognitive behavioral therapy (CBT); cognitive therapy in treatment and prevention
of depression (CPT); interpersonal psychotherapy (IPT); dialectical behavioral therapy (DBT); CBASP; behavioral activation
therapy (BAT)
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| STAR*D (continued): problems with cognitive therapies — inadequate duration of therapy (12 wk; research indicates
longer duration leads to more patients getting better); inadequate training of therapists (quality of cognitive therapy appears
to be important)
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| Conclusions from psychotherapy studies: when done well, CBT works as well as medications by 16 wk of treatment
(“well done” means using CBT manual; further the clinician strays from manualized therapy, the less well his or her
patients do); prognostic indicators for good response to CBT include posttraumatic stress disorder (PTSD) and chronic
major depressive disorder (MDD); in patients with comorbid depression and anxiety disorder, medications superior to
cognitive therapy; CBT appears to reduce risk for relapse in first year (and recurrence thereafter); predictors of relapse
included incomplete remission, early-onset recurrence, chronicity, PTSD, and atypical MDD; overall outcomes in
MDD good (76%-82%) with time (“persistence pays off”); CBT derivatives (eg, DBT, adaptations for PTSD, obsessive-compulsive
disorder, and panic)
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| Behavioral activation therapy: new “stripped down” version of CBT with some supportive data; easier to train therapists
to standard
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| Conclusions about treatment-resistant depression: common and disabling; much treatment resistance can be attributed
to nonsystematic treatment; multiple treatment options effective; future options (eg, deep brain stimulation) may
provide even greater efficacy
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Suggested Reading
DeRubeis RJ et al: Cognitive therapy vs medications in the treatment of moderate to severe depression. Arch Gen Psychiatry
62:409, 2005; Fava M et al: Difference in treatment outcome in outpatients with anxious versus nonanxious depression:
a STAR*D report. Am J Psychiatry 165:342, 2008; Gelenberg AJ et al: Randomized, placebo-controlled trial
of nefazodone maintenance treatment in preventing recurrence in chronic depression. Biol Psychiatry 54:806, 2003; Harley
R et al: Adaptation of dialectical behavior therapy skills training group for treatment-resistant depression. J Nerv Ment
Dis 196:136, 2008; Huynh NN, McIntyre RS: What are the implications of the STAR*D Trial for primary care? A review
and synthesis. Prim Care Companion J Clin Psychiatry 10:91, 2008; Judd LL et al: Does incomplete recovery from
first lifetime major depressive episode herald a chronic course of illness? Am J Psychiatry 157:1501, 2000; Keller MB et
al: A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the
treatment of chronic depression. N Engl J Med 342:1462, 2000; McGrath PJ et al: Tranylcypromine versus venlafaxine
plus mirtazapine following three failed antidepressant medication trials for depression: a STAR*D report. Am J Psychiatry
163:1531, 2006; Melartin TK et al: Continuity is the main challenge in treating major depressive disorder in psychiatric
care. J Clin Psychiatry 2005, 66:220; Nemeroff CB et al: Differential responses to psychotherapy versus pharmacotherapy
in patients with chronic forms of major depression and childhood trauma. Proc Natl Acad Sci U S A 100:14293, 2003;
Nierenberg AA et al: A comparison of lithium and T(3) augmentation following two failed medication treatments for
depression: a STAR*D report. Am J Psychiatry 163:1519, 2006; Philip NS et al: Augmentation of antidepressants with
atypical antipsychotics: a review of the current literature. J Psychiatr Pract 14:34, 2008; Pintor L et al: Relapse of major
depression after complete and partial remission during a 2-year follow-up. J Affect Disord 73:237, 2003; Reynolds CF
3rd et al: Maintenance treatment of major depression in old age. N Engl J Med 354:1130, 2006; Rush AJ et al: Acute
and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry
163:1905, 2006; Rush AJ et al: STAR*D Study Team. Bupropion-SR, sertraline, or venlafaxine-XR after failure of
SSRIs for depression. N Engl J Med 354:1231, 2006; Thase ME et al: Cognitive therapy versus medication in augmentation
and switch strategies as second-step treatments: a STAR*D report. Am J Psychiatry 164:739, 2007; Thase ME:
Management of patients with treatment-resistant depression. J Clin Psychiatry 69:e8, 2008; Trivedi MH et al: Clinical
results for patients with major depressive disorder in the Texas Medication Algorithm Project. Arch Gen Psychiatry 61:669,
2004; Trivedi MH et al: STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based
care in STAR*D: implications for clinical practice. Am J Psychiatry 163:28, 2006.
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