DEPRESSION DILEMMAS
| TREATMENT OF BREAKTHROUGH DEPRESSION —Frederick K. Goodwin, MD, Professor of Psychiatry, and
Director, Psychopharmacology Research Center, The George Washington University School of Medicine, Washington,
DC
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| Acute switch from depressed to manic phase in bipolar patients: acute switch defined as happening within 2 mo
of starting antidepressant, conservative criterion that helps determine whether switch due to antidepressant; in studies,
rate of acute switch with older antidepressants 30% to 60%, and with newer drugs, 20%; many studies done
with old or new drugs did not combine antidepressant with mood stabilizer or with adequate mood stabilizer; some
trials suggest protective benefit from mood stabilizers
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| Long-term destabilization: frequency unknown; must be established by on-and-off trials instead of randomized trials;
defined as having ≥2 episodes of mania or hypomania within study period; data about long-term destabilization
scarce, but suggest no difference between newer and older drugs and show no protective benefit from mood stabilizers
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| Studies: in maintenance-treatment study, patients randomized to lithium or lithium plus imipramine; 2.5 times more
manic episodes in group on combined treatment, suggesting lithium not protective; data on other mood stabilizers
scanty; in naturalistic study of 51 rapid cyclers on lithium and antidepressant, when antidepressant discontinued, 26
“just stopped cycling”; conclusion from combined studies is that causative association between use of tricyclic antidepressants
and rapid cycling conservatively estimated at 20%
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| Speaker’s interim analysis: found that risk-benefit ratio for short-term use of antidepressants for bipolar depression
equivocal; could not confirm whether their use beneficial or detrimental; risk-benefit ratio for long-term use of antidepressants,
even in presence of mood stabilizers, unfavorable; “doesn’t mean you never do it; it means it’s unfavorable”
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| Conclusions from all studies
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 | 1) Antidepressants may have efficacy when used emergently, but no evidence of efficacy when used for maintenance
therapy
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| 2) There are risks for mania and worsening of illness with antidepressants in some patients
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| 3) Antidepressants generally should be reserved for severe cases of acute bipolar depression and not used routinely
in mild to moderate cases
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| 4) Discontinue antidepressants within 1 to 2 mo after recovery from depression; maintain them only in patients
who repeatedly relapse soon after discontinuation of antidepressant (probably 20% of bipolar patients)
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| 5) Antidepressant monotherapy contraindicated in all bipolar disorders; no evidence it is safe as monotherapy in
bipolar II and is contraindicated in bipolar I
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| 6) Use mood stabilizer before starting antidepressant to assess antidepressant effect of mood stabilizer, except in
cases where strong response needed immediately
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| Antidepressant effect of mood stabilizers: established; expert consensus panel favored lithium over divalproex because
at that time, there were controlled studies for lithium and only open studies for divalproex; recent studies
found that paroxetine or imipramine given with lithium “didn’t add anything [in terms of antidepressant effect]
to what lithium was already doing”
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| Lithium: when >0.8 mEq/L, lithium alone as effective as lithium plus paroxetine or lithium plus imipramine in
treating bipolar depression
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| Lamotrigine: showed “nice separation” from placebo at doses of 50 and 200 mg/day
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| Other mood stabilizers: at 50 and 200 mg/day, olanzapine and olanzapine plus fluoxetine had moderately good-sized
effects; olanzapine alone had smaller effect, and item analysis indicated that most of its effect related to nonspecific
items, eg, insomnia, agitation, and anxiety, whereas olanzapine plus fluoxetine had robust effect at same level as lamotrigine
and seemed to treat items more specific to depression; results of quetiapine study (not yet published)
show 300- and 600-mg doses equivalent in “getting significant effects at the first week”
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| American Psychiatric Association guidelines: for first-line treatment of bipolar depression, use lithium or lamotrigine;
do not use antidepressants in bipolar depression, except for severe depression, and always with mood stabilizer on
board
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| DEPRESSION IN LATE LIFE —Sidney Zisook, MD, Professor of Psychiatry, University of California, San Diego,
School of Medicine, and Director of Residency Training, Veterans Affairs San Diego Healthcare System, La Jolla,
California
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| Prevalence of depression in late life: reported as <2% in community-dwelling elderly, but speaker doubts accuracy
of this statistic; in primary care clinics, 10% of patients ≥65 yr of age have diagnosable depression; among nursing-
home residents, 20% have major depression
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| Depression in elderly: underdiagnosed and undertreated because it presents differently in elderly than in younger
people; in elderly, psychologic symptoms often absent or denied; elderly more likely to say “I’m stressed” than
“I’m sad or depressed”; somatic complaints more common in elderly, with hypochondriasis as very common presenting
complaint (“worrying about health rather than worrying about being depressed”); when older person has
acute or subacute onset of not being able to care for self or of being more dependent, “rule out depression before
anything else”; cognitive dysfunction common presentation of depression in elderly; irritability “may be the hallmark
symptom of depression”; patient seldom says “I’m irritable,” but family or friends report it; anxiety may be
presenting symptom in elderly; anhedonia more common manifestation of depression in elderly than in younger
people
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| Adverse life events: all people experience loss as they age, but not norm for elderly to have major depressive symptoms;
presence of major depression often missed in elderly because “it’s so understandable that an older person
might feel demoralized or unhappy or blue”
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| Vascular depression: vascular disease increasingly recognized as cause of depression in elderly; depression rarely
occurs for first time in someone ≥65 yr of age, and when it does occur, often manifestation of general medical or
neurologic condition; clinical characteristics include reduced depressive ideation, increased psychomotor retardation,
and cognitive dysfunction; there may be findings on magnetic resonance imaging (MRI); in treatment, people
with vascular depression take longer to respond to medications; study shows that people with vascular depression
respond particularly well to problem-solving therapy; study underway to compare problem-solving therapy to traditional
antidepressants and to combination therapies
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| In elderly, depression usually lifelong process: if patient has had lifelong depression, he or she will continue to be
depressed unless clinician intervenes, so preventive therapy after treatment of acute episode important; several studies
show that at 1-yr follow-up, of patients treated for depression, one third got well and remained well, almost one
third never got well and had chronic depression despite treatment, 22% got well but developed new episode of depression
within 1 yr, and 14% died during year (in elderly, depression predicts increased mortality and earlier time to
dying); undertreatment major risk factor for people with chronic depression or recurrent episode within year; more
severe symptoms, more cognitive impairment, and more physical illness at baseline predictive of poor prognosis or
recurrence; study showed that risk for recurrence higher in older-aged group (≥70 yr of age) in first year than in
younger-aged group, but both did equally well in treatment
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| Can recurrence be prevented with treatment? study compared placebo, interpersonal psychotherapy, nortriptyline,
and combination of interpersonal psychotherapy and nortriptyline and showed advantage of combination
therapy greatest in patients ≥70 yr of age; overall, combination therapy best for preventing episodes of depression,
medication alone better than placebo, and interpersonal psychotherapy alone not significantly better than placebo
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| Consequences of late-life depression: utilization of health care increases, quality of life diminishes, existing comorbid
conditions worsen, survival decreases, and suicide rates increase; people ≥65 yr of age represent 12% of population
but 25% of suicides; suicide attempts not as common in elderly as in younger people, but attempts succeed
more often; suicide rate increases 2.5 times in people ≥70 yr of age, and elderly white men at highest risk; over life
cycle, women at about equal risk for depression from puberty through late life, but rate for men changes over life
cycle; rates of depression and suicide always higher for men, especially elderly white men
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| Can suicide be prevented with treatment? study showed that in primary care setting, having depression care manager
involved in depressed patients’ cases increased speed and degree of recovery from depression and dramatically
reduced rate of suicidal ideation; depression care manager provided diagnosis to primary care provider,
advised him or her if patient suicidal, recommended therapy, provided algorithm for therapy, educated patients and
families about depression, encouraged adherence to treatment regimen, and offered psychotherapy to those patients
who wanted it
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| Making diagnosis of depression: complicated by many factors in elderly, including ageism, comorbid medical and
neurologic illnesses, cognitive decline with age, and multiple losses that elderly have experienced
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| Depression in medical illness: underdiagnosed and undertreated; many illnesses of elderly associated with high
rates of depression; when depression occurs with medical illness, both worse, with more pain, disability, chronicity,
and mortality; some medications (eg, steroids, interferon) also lead to depressive symptoms, if not full-blown
depressive syndrome; drug abuse and alcoholism often missed because clinicians often think elderly do not
abuse drugs and alcohol; biggest culprit polypharmacy, which is norm among elderly (speaker recommends getting
patient off all drugs possible as soon as possible)
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| Clues to diagnosis: many symptoms of depression, eg, problems with sleep and/or concentration, also found in
medical illnesses and can confuse diagnosis; consider depression if patient looks sad or fearful, is socially withdrawn,
is less talkative, shows deterioration in self-care, is irritable, is increasingly dependent, or if thought content
is brooding, self-pitying, pessimistic, or expresses sense of failure or of deserving illness
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| Do antidepressants work in physically ill? yes, according to meta-analysis of 13 published placebo-controlled trials
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| Depression vs dementia: possible for patient to have both; people do have cognitive decline as they get older, which
increases difficulty of making diagnosis of depression (eg, patient may not be able to remember symptoms or may
not be good historian); much overlap between symptoms of depression and of Alzheimer’s disease; helpful hints—
patient with primary dementing disorder and depression usually complains more of cognitive deficits than of depression;
depressed older patients do not complain of mood disturbances but of, eg, being increasingly forgetful; on other
hand, people with early cognitive decline deny forgetfulness as long as possible, saying “I’m only stressed”; depressed
person’s emphasis on failures, demented person’s on achievements; affective symptoms in depression tend
to be more pervasive, while in demented patient, affect tends to be more labile and shallow, with less pervasive depressive
symptomatology; in depression, onset tends to be acute or subacute; onset in dementia more gradual, with
difficulty dating onset; attempt underway to redefine depression in context of Alzheimer’s disease, with some proposed
criteria
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| Adverse life events: if depression occurs after bereavement, Diagnostic and Statistical Manual of Mental Disorders,
4th Edition (DSM-IV) says to diagnose it as grief, but speaker thinks that incorrect; “if somebody meets criteria for
depression, it’s depression”; depression that occurs after bereavement as painful, disruptive, and disabling as any
other depression
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| Comprehensive treatment plan in elderly: includes full medical work-up, education of patient and family, psychosocial
intervention, and biologic treatment
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| Unorthodox methods in elderly: touching—elderly often have sensory deprivation, may not have loved ones
around, and prudent touching can improve patient’s well-being; alcohol—sometimes occasional drink (“half a
glass of wine or so”) can improve socialization; hormones—may help perimenopausal women; in some circumstances,
hormones added to antidepressants can improve response; exercise—important for everybody, but especially
helpful in depressed elderly; psychotherapy—shown to be effective in elderly
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| Considerations for treatment in elderly: start antidepressant at low dose and increase slowly; do not stop antidepressant
too soon; if patient not responding but not having side effects, increase dose of antidepressant; consider
adding depression case manager to practice
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| Conclusions: depression in elderly underrecognized and undertreated; recognition and treatment complicated by comorbid
medical illness, cognitive decline, and losses; use all available modalities of treatment, not just medication;
treat for long enough period; recognize that it takes longer to get response in elderly, and do not get impatient; once
response seen, continue treatment long enough to ensure patient goes into full remission and stays well
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Educational Objectives
| The goal of this program is to educate the listener about the treatment of breakthrough depression and of depression
in late life. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss the risks of using antidepressants in patients with bipolar depression.
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| 2. Determine the best treatment for the bipolar patient with breakthrough depression.
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| 3. Explain how the manifestations of depression in the elderly differ from those in younger patients.
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| 4. List factors that complicate the diagnosis of depression in the elderly.
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| 5. Develop a comprehensive treatment plan for elderly patients with depression.
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Discussed on This Program
Bupropion hydrochloride [Wellbutrin, Zyban]
Carbamazepine (several trade names)
Citalopram hydrobromide [Celexa]
Divalproex sodium [Depakote]
Fluoxetine hydrochloride [Prozac, Sarafem]
Imipramine hydrochloride [Tofranil]
Lamotrigine [Lamictal]
Lithium (several formulations and trade names)
Olanzapine [Zyprexa]
Olanzapine and fluoxetine hydrochloride [Symbyax]
Paroxetine hydrochloride [Paxil]
Quetiapine fumarate [Seroquel]
Sertraline hydrochloride [Zoloft]
Venlafaxine hydrochloride [Effexor]
Suggested Reading
Blazer DG: Depression and social support in late life: a clear but not obvious relationship. Aging Ment Health 9:497,
2005; Cairney J, Krause N: The social distribution of psychological distress and depression in older adults. J Aging
Health 17:807, 2005; Ganguli M et al: Alcohol consumption and cognitive function in late life: a longitudinal community
study. Neurology 65:1210, 2005; Ghaemi SN, Goodwin FK et al: Antidepressants in bipolar disorder: the
case for caution. Bipolar Disord 5:421, 2003; Ghaemi SN, Ko JY, Goodwin FK: The bipolar spectrum and the antidepressant
view of the world. J Psychiatr Pract 7:287, 2001; Goodwin FK: Rationale for using lithium in combination
with other mood stabilizers in the management of bipolar disorder. J Clin Psychiatry 64(Suppl 5):18, 2003;
Gyulai L et al: Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology
28:1374, 2003; Hybels CF et al: Residual symptoms in older patients treated for major depression. Int J Geriatr
Psychiatry 20:1196, 2005; Katon WJ et al: Cost-effectiveness of improving primary care treatment of late-life depression.
Arch Gen Psychiatry 62:1313, 2005; Keck PE Jr: Evaluation and management of breakthrough depressive
episodes. J Clin Psychiatry 65(Suppl 10):11, 2004; Malhi GS, Mitchell PB, Salim S: Bipolar depression: management
options. CNS Drugs 17:9, 2003; Nierenberg AA, Alpert JE: Depressive breakthrough. Psychiatr Clin North
Am 23:731, 2000; Post RM et al: Rate of switch in bipolar patients prospectively treated with second-generation antidepressants
as augmentation to mood stabilizers. Bipolar Disord 3:259, 2001; Sable JA, Dunn LB, Zisook S: Late-
life depression. How to identify its symptoms and provide effective treatment. Geriatrics 57:18, 2002; Soldani F,
Goodwin FK et al: Relapse after antidepressant discontinuation. Am J Psychiatry 161:1312, 2004; Subramaniam
H, Mitchell AJ: The prognosis of depression in late life versus mid-life: implications for the treatment of older
adults. Int Psychogeriatr 17:533, 2005; Thase ME, Sachs GS: Bipolar depression: pharmacotherapy and related
therapeutic strategies. Biol Psychiatry 48:558, 2000; Thase ME: Bipolar depression: issues in diagnosis and treatment.
Harv Rev Psychiatry 13:257, 2005; Tiemeier H et al: A multivariate score objectively assessed health of depressed
elderly. J Clin Epidemiol 58:1134, 2005; Vieta E et al: A randomized trial comparing paroxetine and
venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers. J Clin Psychiatry 63:508, 2002;
Zisook S et al: Bupropion sustained release for bereavement: results of an open trial. J Clin Psychiatry 62:227, 2001.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Goodwin disclosed that he has research support from Abbott Laboratories, GlaxoSmithKline, Solvay, Janssen,
Pfizer, Lilly, Forest, Sanofi, and BMS; he is on the Speakers’ Bureau of Solvay, GlaxoSmithKline, Pfizer, Lilly, and
Bristol Myers Squibb; and is a consultant to GlaxoSmithKline, Lilly, Pfizer, Bristol Myers Squibb, Solvay, and Novartis.
Dr. Zisook disclosed that he is on the Speakers’ Bureau of and is a consultant to GlaxoSmithKline and Forrest.
Dr. Goodwin was recorded at Biopsychiatric Brilliance Bestowed by Brobdingnagian Bellwethers, held March 4-5,
2005, in Madison, Wisconsin, and sponsored by the University of Wisconsin Medical School and the Madison Institute
of Medicine. Dr. Zisook was recorded at the West Coast Geriatric Psychiatry Conference, held February 10-13,
2005, in San Diego and sponsored by the University of California, San Diego, School of Medicine. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
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