DIAGNOSIS AND TREATMENT OF DEPRESSION
| DIFFERENTIATING UNIPOLAR FROM BIPOLAR DEPRESSION —Descartes Li, MD, Associate Clinical Professor
of Psychiatry and Chief, Bipolar Disorder Program, University of California, San Francisco, School of Medicine
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| Importance of differentiating unipolar from bipolar depression: antidepressant monotherapy in individuals
with bipolar disorder can lead to rapid cycling or induction of mania; rapid cycling (>4 mood episodes in 1 yr)
particularly difficult to treat and can lead to poor outcomes; in addition to its direct consequences, mania frequently
ends in depressive episode that is even more refractory to treatment
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| Antidepressants in bipolar depression: risk for antidepressant-induced mania or rapid cycling lower when antidepressants
used in combination with mood-stabilizing agent; manic switch occurs substantially more often with
tricyclic antidepressants (TCAs) than with selective serotonin reuptake inhibitors (SSRIs); atypical antipsychotics,
particularly olanzapine and quetiapine, may have benefit in depression phase of bipolar disorder
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| Subtypes of bipolar disorder: bipolar I defined as depression with classic mania; bipolar II defined as depression
with hypomania; bipolar III (not in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-
IV]) described clinically as antidepressant-associated hypomania
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| Mania and hypomania: easily missed; often not reported by patient; majority of patients with bipolar disorder
present with depression (“who comes to see a doctor when they’re hypomanic? they’re feeling good”); in addition,
when depressed, patient may have difficulty remembering when he or she was feeling good
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| Initial evaluation: ask whether patient has history of increased energy or decreased need for sleep; inquire about family
history of bipolar disorder; involve family and significant others in evaluation; use screening instrument for bipolar
disorder (eg, Mood Disorder Questionnaire [accessible via Internet]); in general, depressive episodes more frequent
than manic or hypomanic episodes (although patients tend to be asymptomatic ≈50% of time)
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| Conversion from unipolar to bipolar disorder: several studies found high rate of conversion; rate of conversion
linear (1%-2% per year); low rate of conversion from one bipolar subtype to other; risk factors for conversion
from unipolar depression to bipolar disorder included early age of onset, severity of index episode, greater
number of episodes, presence of psychosis during depressive episode, and family history of mania; analysis of
symptom clusters showed that fears more common in individuals with bipolar disorder; sadness, insomnia, and
somatic symptoms more common in individuals with major depressive disorder
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| Diagnostic criteria for mania or hypomania: remember DIG FAST mnemonic for symptoms of mania or hypomania;
distractibility; insomnia; grandiosity; flight of ideas; activities; speech (pressured); thoughtlessness (eg,
impulsivity, increased pleasurable activities with potential for negative consequences)
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| Criteria for mixed episodes: duration 1 wk; includes agitation, insomnia, appetite dysregulation, psychotic features,
and/or suicidal thinking; look for rapidly alternating moods, sadness, irritability, and euphoria, accompanied
by criteria for both manic episode and major depressive episode; symptoms not due to direct effects of substance
or general medical condition; sometimes seen after starting antidepressant; one study suggested that agitated depression
really mixed state
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 | Depressive mixed states: defined as coexistence of manic and depressive symptoms during same period; symptoms
include criteria for both depression and mania/hypomania (ie, psychomotor agitation, distractibility, and irritability);
in addition, mixed states often present with racing thoughts, mood lability, sexual arousal, intense panic, histrionic
expressions of suffering, and pressured speech
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| Atypical depression: DSM-IV criteria include mood reactivity (ie, mood brightens in response to actual or potential
positive events) with ≥2 of the following, 1) significant weight gain or increase in appetite, 2) hypersomnia, 3)
leaden paralysis (ie, heavy leaden feelings in arms or legs), 4) longstanding pattern of interpersonal rejection sensitivity
(not limited to episodes of mood disturbance) that results in significant social or occupational impairment;
criteria for atypical depression originally conceived as basis of nonresponse to TCAs; note presence of mood reactivity
(sometimes overreactivity) to events or situations; high rate of lifetime comorbidity with anxiety disorders,
body dysmorphic disorder, eating disorders, and cluster B and cluster C personality disorders
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| Summary of clues to bipolar disorder: family history; seasonal pattern to symptoms; psychosis during major
depressive episodes; early age (<25 yr) of onset of major depressive episode; antidepressant “wear off” (ie, quick
response to antidepressant, but no long-term efficacy); lack of response to trials of ≥3 antidepressants
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| PHARMACOTHERAPY FOR DEPRESSION —John M. Zajecka, MD, Associate Professor of Psychiatry and Clinical
Director, Treatment Research Center, Rush University Medical Center, Chicago, IL
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| Introduction: depression among most disabling disorders but also among most treatable; morbidity and mortality
high
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| Stress-diathesis model of depression: posits that cell growth impaired by depression or chronic stress, which
shuts off brain-derived neurotrophic factor (BDNF), which in turn can lead to cell death in specific areas of brain,
eg, hippocampus; treatment of depression, whether antidepressants, electroconvulsive therapy (ECT), or some
forms of psychotherapy, restores function of gene that makes BDNF and may prevent or reverse damage
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| Important to achieve full remission: similar to medical illness, depression should be treated to full remission
and ultimately to full recovery; remission now standard of care in treating depression; remission of symptoms gateway
to sustained recovery
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| Definitions: response—clinically significant reduction in baseline symptoms and severity (in clinical research, requires
50% reduction in baseline Hamilton Rating Scale for Depression [HAM-D] scores or HAM-D score ≤15);
remission—absence of symptoms (in clinical research, requires HAM-D score ≤7 or minimal or no symptoms);
recovery—sustained period of remission following an episode of major depression; relapse—return of major depressive
episode during continuation treatment (ie, before recovery); recurrence—new episode of depression following
recovery from previous episode; remission decreases risk for relapse or recurrence, while residual depressive
symptoms associated with greater risk for relapse
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| Response vs remission: ≤70% of patients who respond to therapy fail to remit; 30% to 40% of patients achieve remission
in short-term clinical trials; residual emotional and physical symptoms jeopardize achieving remission and
increase risk for relapse or recurrence
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| Potentially modifiable factors associated with treatment-resistant depression: inaccurate diagnosis; failure
to achieve remission; inadequate trial of therapy (dose or duration); nonadherence; intolerance of treatment; inaccurate
assessment or response to treatment; psychosocial factors
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| “Think outside the DSM-IV box”: depressive symptoms vary over time and may be psychiatric, somatic, or both;
potential symptoms include anhedonia, depressed mood, anxiety, preoccupation with negative thoughts, disturbed
sleep, appetite changes, difficulty concentrating, impaired memory, low self-esteem, exaggerated guilt, suicidal
thoughts, hopelessness, fatigue, headache, chest pain, dizziness, musculoskeletal pain, back pain, gastrointestinal
complaints, and/or sexual dysfunction; overlap of symptoms of depression with those of medical comorbidity may
hinder accurate diagnosis of either
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| Differential diagnosis: neurologic disorders; endocrine disorders; other medical illness; side effects of medications;
other psychiatric illness (eg, bipolar disorder, substance use disorders, eating disorders, anxiety disorders, schizoaffective
disorders, attention-deficit/hyperactivity disorder [ADHD], and Axis II disorders)
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| Treatment-resistant depression (TRD): no universal definition; definitions emerging from scientific, diagnostic,
and treatment experiences over time; must be individualized for each patient; not to be confused with “treatment-refractory
depression,” in which patient has no response at all to treatment; TRD patients have some
response, but do not achieve full remission
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| Documenting treatment of TRD: important; keep written record of past and current treatments (including doses,
duration of doses, tolerability, and efficacy); utilize patient life charting; provide informed consent for all interventions,
including assessment of risk-benefit ratio, status of approval (or lack of approval) from Food and Drug Administration
(FDA), and side effects; allow patient to ask questions; involve significant others when possible; update
information at each visit; keep up-to-date with new treatment modalities; document target symptoms; record patient’s
level of psychosocial functioning at baseline and at all visits
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| Management of TRD: confirm diagnosis; seek second opinion from trusted colleague; document thoroughly; consider
psychosocial interventions; switch treatments; consider combination treatment, augmentation, and investigational treatments
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| Management of depression: treatment modalities currently available include antidepressant medications, ECT,
vagus nerve stimulation (VNS), time-limited psychotherapies, phototherapy, and augmentation
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| Antidepressant potentiation: many modalities not FDA-approved for augmentation; some have more empirical
data than others; some show greater efficacy than others; available agents include VNS, lithium, thyroid hormone,
atypical antipsychotics, stimulants, buspirone, modafinil, carbamazepine, divalproex sodium, lamotrigine,
dopamine agonists, estrogen replacement, buprenorphine, S-adenosylmethionine (SAM-e), inositol,
phototherapy, and time-limited psychotherapy (ie, cognitive behavioral therapy [CBT], cognitive behavioral
analysis system of psychotherapy [CBASP], or individual treatment plan [ITP])
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| Antidepressant switch, treatment combination, or augmentation? first check literature, looking for strategies for
which safety and efficacy established; maximize dose of antidepressant currently being used; assess number and
outcome of previous therapy trials; determine how rapid response must be; consider cost; research potential drug
interactions; determine adherence; establish degree of symptomatology; speaker’s rule of thumb—if improvement
<25%, switch to another antidepressant (and provide method of bridging antidepressants); if improvement
25% to 50%, switching and augmentation have equal chance of working; if improvement >50%, augment
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| Combination vs augmentation: tailor treatment to symptoms; consider medications with synergistic or enhanced activity;
if remission occurs, assess risk-benefit ratio (“if it ain’t broke, don’t fix it”); document thoroughly
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| Combination and augmentation in patients with comorbid illness: if patient has comorbid ADHD, augment with
stimulant or atomoxetine; if comorbid obsessive-compulsive disorder, premenstrual dysphoric disorder, or eating
disorder, augment with SSRI; if comorbid anxiety disorder, augment with buspirone, benzodiazepine, or atypical
antipsychotic; if personal or family history of bipolar disorder, augment with lithium, lamotrigine, carbamazepine,
or atypical antipsychotics; let management of side effects guide treatment
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| Management of residual symptoms: if residual symptom is anxiety, augment antidepressant with buspirone, benzodiazepine,
atypical antipsychotic, or anticonvulsant; if residual side effect is psychosis, augment with atypical or
conventional antipsychotic
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| Psychotic depression: psychosis common symptom of depression, but can be subtle; consider differential diagnosis,
especially bipolar disorder, substance use or abuse, and medical condition; treat with antidepressant plus
atypical or conventional antipsychotic for minimum of 12 wk, or with ECT alone or in combination with medications
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| Bipolar depression: American Psychiatric Association (APA) treatment guidelines recommend lithium or lamotrigine
as first-line treatment; antidepressant monotherapy not recommended; treatment of breakthrough depression during
prophylactic treatment—if depression mild or moderate, optimize prophylaxis with mood stabilizer; if depression
severe, add SSRI or second mood stabilizer to current mood stabilizer; for depression with rapid cycling,
“strictly avoid antidepressants”; use current mood stabilizer plus second mood stabilizer; initial treatment should include
lithium or valproate (although lamotrigine acceptable alternative); for refractory depression, consider ECT or
VNS
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| Psychotherapy: data indicate time-limited psychotherapy may augment pharmacotherapy, but sample sizes in trials
small; data also indicate continuation psychotherapy may protect against relapse
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Educational Objectives
| The goal of this program is to educate the listener about the diagnosis and treatment of depression. After hearing and
assimilating this program, the clinician will be better able to:
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| 1. Differentiate unipolar from bipolar depression.
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| 2. Determine the likelihood of conversion from unipolar depression to bipolar disorder.
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| 3. Explain the stress-diathesis model of depression.
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| 4. Distinguish response from remission and recovery, and relapse from recurrence.
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| 5. Consider a range of treatments for unipolar and bipolar depression.
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Suggested Reading
Akiskal HS et al: Switching from ‘unipolar’ to bipolar II. An 11-year prospective study of clinical and temperamental
predictors in 559 patients. Arch Gen Psychiatry 52:114, 1995; Akiskal HS, Benazzi: Family history validation
of the bipolar nature of depressive mixed states. J Affect Disord 73:113, 2003; Angst J et al: Diagnostic
conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J Affect
Disord 84:149, 2005; Benazzi F et al: Toward a validation of a new definition of agitated depression as a bipolar
mixed state (mixed depression). Eur Psychiatry 19:85, 2004; Bremner JD et al: Hippocampal volume
reduction in major depression. Am J Psychiatry 157:115, 2000; Goldberg JF et al: Risk for bipolar illness in patients
initially hospitalized for unipolar depression. Am J Psychiatry 158:1265, 2001; Hirschfeld RM et al: Perceptions
and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-
Depressive Association 2000 Survey of Individuals with Bipolar Disorder. J Clin Psychiatry 64:161, 2003; Judd
LL et al: A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II
disorder. Arch Gen Psychiatry 60:261, 2003; Perugi G et al: The high prevalence of “soft” bipolar (II) features in
atypical depression. Compr Psychiatry 39:63, 1998; Santarelli L et al: Requirement of hippocampal neurogenesis
for the behavioral effects of antidepressants. Science 301:805, 2003; Shelton RC et al: A randomized, double-
blind, active-control study of sertraline versus venlafaxine XR in major depressive disorder. J Clin Psychiatry
67:1674, 2006; Simon GE: Long-term prognosis of depression in primary care. Bull World Health Organ 78:439,
2000; Suppes T et al: Texas Consensus Conference Panel on Medication Treatment of Bipolar Disorder. The Texas
Implementation of Medication Algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry
66:870, 2005; Vermetten E et al: Long-term treatment with paroxetine increases verbal declarative memory
and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry 54:693, 2003; Zajecka JM, Albano D:
SNRIs in the management of acute major depressive disorder. J Clin Psychiatry 65(Suppl 17):11, 2004; Zajecka
JM: Clinical issues in long-term treatment with antidepressants. J Clin Psychiatry 61(Suppl 2):20, 2000; Zajecka
JM: Treating depression to remission. J Clin Psychiatry 64(Suppl 15):7, 2003.
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. Zajecka disclosed he has received grant/research support from AstraZeneca, Bristol-Myers Squibb, Cyberonics,
Eli Lilly, Johnson & Johnson, Novartis, Somaxon, and Wyeth; has served as a consultant for Abbott, Eli Lilly, Pfizer,
and Wyeth; and he is on the Speaker’s Bureaus of Abbott, AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly,
GlaxoSmithKline, Pfizer, and Wyeth.
Dr. Li was recorded at New Frontiers in Depression Research and Treatment, held March 24-26, 2006, in San Francisco,
CA, and sponsored by the University of California, San Francisco, School of Medicine. Dr. Zajecka was recorded
at Inspiring Insights from Incandescent Illuminati, held March 10-11, 2006, 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.
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