Transcript Definition and DSM-IV Criteria Major Depressive

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Depression
Review of DSM-IV Criteria and Treatment
Jamieson Bourque, MD, MHS
Xavier Preud’homme, MD
Editor: Amy Shaheen, MD, Assistant Professor of Clinical Medicine
Duke University Medical Center
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Epidemiology
• Lifetime risk:
– Men: 7-12%
– Women 20-25%
• Increased prevalence in healthcare setting
– 2-4% in general population, 5-10% in primary care office*
• Lost productivity
– estimated $31 billion/year cost in U.S. alone.
• Risk of psychiatric co-morbidities
– 61% have a co-occurring axis I condition
– 30% have a comorbid axis II condition
– 16-30% have a history of substance abuse
*Katon, W, Schulberg, H. Epidemiology of depression in primary care. Gen Hosp Psychiatry 1992; 14:237.
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Epidemiology
• Depression in the elderly associated with:
– Significant healthcare costs
– Functional decline
• Effects on health outcomes:
– Odds Ratio (O.R.) 3-4 for risk of one-year mortality in post-MI patients
independent of other factors.*
– O.R. 3.5 for 10-year mortality after CVA
– Increased 1-year mortality on nursing home admission
– Modified criteria for major depressive disorder found an O.R. of 7.8 for inhospital mortality.
*Frasure-Smith, N, Lesperance, F, Juneau, M, et al. Gender, depression, and one-year prognosis
after myocardial infarction. Psychosom Med 1999; 61:26.
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Risk Factors
Major Risk Factors
• Female gender
• Prior history of depression
• Family history of depression in 1st degree relative
Associated Factors
• Concurrent substance abuse
• Childhood abuse
• Stressful life event
• Low self-esteem
• Lack of social supports
• Low-income
• Middle-age
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Etiology and Pathogenesis
• Primary
• Secondary
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Neuropsychiatric: CVA, dementia
Endocrine: Hypothyroidism, diabetes mellitus
Medications: Corticosteroids, interferon
Rheumatologic: SLE, chronic fatigue syndrome, fibromyalgia
Other:
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Cancer, especially pancreatic
Coronary artery disease
Hypercalcemia
Anxiety and panic disorders
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Definition and DSM-IV Criteria
Major Depressive Disorder
• 5 of the 9 criteria (next page)
– At least one being depressed mood or anhedonia
• Symptoms have been present for at least 2 weeks
• Symptoms do not meet criteria for a mixed episode
• Symptoms cause significant distress or impairment in social,
occupational, or other areas of functioning
• Symptoms are not due to a general medical condition or the direct
psychological effects of a substance (drug/medication)
– Although many of the same treatments apply even if the depression is
secondary
• Symptoms do not occur within 2 months of loss of a loved-one unless
pathologic grief is present
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Definition and DSM-IV Criteria
9 Major Criteria
1. Depressed mood (subjective or objective, such as tearful)
2. Anhedonia (markedly diminished interest or pleasure in almost all
activities, reported or observed)
3. Significant weight or appetite loss or gain (weight >5% in one month)
4. Insomnia or hypersomnia
5. Psychomotor agitation or retardation (must be observed by others)
6. Fatigue or loss of energy
7. Feelings of worthlessness or guilt (may be delusional, not just selfreproach)
8. Impaired concentration, indecisiveness
9. Recurring thoughts of death or suicide
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Definition and DSM-IV Criteria
More Major Depressive Disorder Criteria
• Must not be better characterized by a personality disorder
• No history of mixed episode, manic or hypomanic episodes
Recurrent Major Depressive Disorder
• 2 single episodes with at least 2 months between where criteria were not
met
Mixed Depressive States
• Depression with psychotic features
• Depression with anxiety
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Major Depressive Disorder Specifiers
• Seasonal Affective Disorder
– MDD episodes and full remissions occur regularly at a particular time of
year
– 2 MDD episodes related to season in the past 2 years with no episodes
unrelated
• Melancholia
– Severe depression with somatic symptoms – particularly responsive to
pharmacotherapy and ECT.
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Associated Conditions
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Grief/Bereavement
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Response to loss of a loved-one. Typically resolves by 13 months.
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Pathologic grief → MDD mixed with PTSD
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Excessive worthlessness/guilt, symptom persistence, suicidality, intrusive images, avoidance behavior
Dysthymia
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Chronic, low-intensity depression-like state with anhedonia, low self-esteem, and low energy
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Symptoms must be present for at least 2 years
Bipolar Disorder
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Diagnosed if the depressed patient has ever had a manic or hypomanic state
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Different treatment is provided for depression in this state, especially to prevent rapid mood
cycling
Atypical Depression (Depression NOS, “Mild depression”)
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2-4 MDD criteria for at least 2 weeks, often characterized by weight gain and hypersomnia.
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20% have significant social disability at 1 year
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Classification
Depressed Mood or Anhedonia
DSM-IV Criteria
5-9
Prior Manic
Episode?
Yes
Bipolar
Disorder
2-4
No
Major
Depressive
Disorder
<2 years
Depression
NOS
≥ 2 years
Dysthymic
Disorder
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Symptom
Duration
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Diagnostic Techniques
• Screening – performed with 2 questions:
– “Over the past 2 weeks, have you felt down, depressed, or hopeless?”
– “Over the past 2 weeks, have you felt little interest/pleasure in doing things?”
• Additional Workup (if either of the above are positive)
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Ask specific/closed-end questions about the 9 diagnostic DSM-IV criteria
Ask about substance abuse and comorbid psychiatric conditions
Perform a medical ROS and medication history to rule-out secondary causes
Perform laboratory evaluation:
• TSH, electrolytes, serum B12, folate, ECG
– Assessment of suicide risk
• Thoughts, intent, plan, means, prior attempts, family history
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General Treatment Measures
• Patient Education
– Reassurance, associated physical symptoms, portrayal as a medical disease
with a biochemical etiology.
– Importance of medication compliance.
• Exercise
– May be effective in older adults
• RCT of 156 pts ≥age 50 showed no difference over 16 weeks between 3x/week
exercise, sertraline, or combination therapy.
– ?Social interaction effect of exercise, highly motivated group
• Phototherapy
– May have an effect similar to pharmacotherapy in non-seasonal depression,
but studies are limited and more research is needed.
Blumenthal, JA, Babyak, MA, Moore, KA, et al. Effects of exercise training on older
patients with major depression. Arch Intern Med 1999; 159:2349.
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Psychotherapy
• Multiple techniques: Cognitive behavioral, interpersonal, marital/family
therapy, problem-solving treatment.
– 12-20 weekly sessions
• Efficacy in AHCPR 1993 Guidelines:
– Cognitive, behavioral, interpersonal therapies: 46, 55,
and 52 percent efficacy respectively.1
– Similar results in subsequent studies looking at these and problem-solving
therapy.
• Comparable efficacy to pharmacotherapy in RCT of 240 patients.2
• Sustained benefits – similar to that of patients maintained on
pharmacotherapy.
1 Depression
Guideline Panel. Depression in Primary Care: Treatment of Major Depression: Clinical Practice Guideline. US Dept of Health and Human Services,
Public Health Service, Agency for Health Care Policy and Research. AHCPR publication 93-0551, Rockville, MD 1993.
2DeRubeis, RJ, Hollon, SD, Amsterdam, JD, et al. Cognitive therapy vs medications in the treatment of moderate to severe depression. Arch Gen Psychiatry 2005;
62:409.
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Medications
Classes
• TCAs
• SSRIs
• NDRI
• SNRIs
• NaSSA
• SARI
• MAO-Inhibitors
• Herbal – St. John’s Wort
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TCAs: Tricyclic Antidepressants
• All tricyclics are negative allosteric modulators and therefore block both
reuptake pumps for NE (norepinephrine) and 5-HT(serotonin)
• The tertiary amines have more potency for inhibition of 5-HT than for
NE (clonipramine, imipramine, amitriptyline)
• The secondary amines have more potency for inhibition of NE than 5-HT
(desipramine, nortriptyline)
• Numerous side effects because all tricyclics block following receptors:
- alpha1 adrenergic (dizziness, orthostatic hypotension & resulting falls)
- H1 histaminergic (drowsiness & weight gain)
- M1 muscarinic (constipation, worsening glaucoma, blurry vision,
urinary retention, tachycardia)
• All block Na channels and this has been the main reason for their
cardiac toxicity such as QTc prolongation and risk for torsade de pointe
(same as for class IA anti-arrhythmic)
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SSRIs: Selective Serotonin Reuptake Inhibitors
1/3
• Selective and more potent inhibitors of serotonin reuptake than tricyclics
• citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac)
fluvoxamine (Luvox) paroxetine (Paxil) setraline (Zoloft)
• No blockade of alpha1 adrenergic, histaminergic receptors nor Na
channels
• Slight antimuscarinic activity especially for paroxetine
• There are numerous projections & types of serotoninergic postsynaptic
receptors mediating as many functions as:
- Mood (frontal cortex)
- Akathisia/agitation, obsessions & compulsions (basal ganglia)
- Anxiety & impulsivity (limbic structures)
- Appetite, libido & temperature (hypothalamus)
- Sleep (activating reticular formation)
- Sexual dysfunction (spinal cord)
- Nausea (brainstem and gut)
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SSRIs: Selective Serotonin Reuptake Inhibitors
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2/3
Monoamine hypothesis stipulates that because of the deficiency in
monoamine, some of these receptors are up-regulated in affective and
anxiety disorders. Thus, once a SSRI is taken the increase in serotonin in
the synaptic cleft is immediate and patient might experience side-effects
before the benefits of the Rx kicks in, after the down-regulation of
postsynaptic receptors occurs (which presumably takes about 2 weeks)
Side effects are: agitation & anxiety which may lead to impulsive suicide
while mood remains hopeless, nausea, delayed orgasm
Too much serotonin leads to the serotonin syndrome with: myoclonus,
diarrhea, confusion, hypomania, agitation, hyperreflexia, shivering,
incoordination, fever and diaphoresis
N Engl J Med 2005; 352:1112-1120, Mar 17, 2005
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SSRIs: Selective Serotonin Reuptake Inhibitors
3/3
• In addition SSRIs are potent inhibitors of CYP 450 thus playing an
important role in drug-drug interactions
- CYP450 1A2: fluvoxamine (potent)
- CYP450 2C9: fluvoxamine (potent), sertraline (weak)
- CYP450 2C19: fluoxetine, fluvoxamine
- CYP450 2D6: (es)citalopram (weak), fluoxetine (potent),
fluvoxamine, paroxetine (potent), sertraline
- CYP450 3A4: (nor)fluoxetine, fluvoxamine, sertraline (weak)
• For the purpose of treating depression, all SSRIs offer comparable
efficacy if prescribed for at least 4 weeks at their usual dose :
- 10 mg for escitalopram
- 20 mg for fluoxetine, paroxetine, citalopram
- 50-100 mg sertraline
- 100 mg fluvoxamine
• However in anxiety disorders they are not all comparable (check FDA
approval)
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NDRI: Noradrenaline and Dopamine Reuptake Inhibitor
• Bupropion is a weak dopamine and NE reuptake inhibitor (Wellbutrin)
• Bupropion is metabolized into its hydroxylated active metabolite which
is a potent NE reuptake blocker
• Effective for patients who cannot tolerate side effects of SSRIs (or
TCAs) such as sexual dysfunction or to nonresponders to SSRIs
• May lower seizure threshold so contraindicated in patients with such
known history as well as patients with eating disorders (probably because
of the contribution of electrolytes imbalances to seizures)
• Of course same molecule was also approved, though commercialized
under a different name, for nicotine dependence (Zyban). For that matter
consider starting the Rx 15 days prior to full cessation of smoking
possibly in addition to the use of nicotine patch or other nicotine
substitution
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SNRIs: Serotonin and Noradrenaline Reuptake Inhibitors
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Selective 5-HT and NE reuptake inhibitors
Prime examples are: venlafaxine (Effexor) and duloxetine (Cymbalta)
At usual therapeutic doses, little alpha1, muscarinic M1 or histaminergic H1
antagonisms. Yet because of their effect on the adrenergic system, the blood
pressure is increased
SNRIs are like TCAs but without their usual side-effects. However at very high
dose venlafaxine found to block the Na channel thus cardiotoxicity might still
occur
Causes dual action on serotonin and adrenergic systems thus amplifying, in
theory, theses two systems synergistically. Yet this has never been established by
RTC trails
Thought to be good agents for SSRIs responders but not remitters
Venlafaxine antagonizes the NE reuptake above the dose of 150 mg daily, and
therefore becomes a different antidepressant with an increase in its daily dose. In
fact above 225 mg daily it becomes a weak inhibitor of the dopamine reuptake in
addition to its effect on NE and 5-HT
Duloxetine seems to work on both 5-HT and NE at the same starting dose
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NaSSA: Noradrenergic & Specific Serotoninergic ATD
• Very different drugs devoid on any monoamine reuptake inhibition, yet
increasing both NE and 5-HT
• Prime examples are: mirtazapine (Remeron) and mianserin (Lerivon)
though weaker
• The mode of action is via a presynaptic alpha2 adrenergic antagonism
that increases NE transmission on NE neurons but also 5-HT
transmission on serotoninergic neurons
• In addition, specifically block postsynaptically 5HT2A/C and 5-HT3
receptors thus reducing side effects such as anxiety, sexual dysfunction
and nausea but also increases appetite (and often weight) and increases
slow-wave sleep
• Unfortunately also anti-histaminergic H1 and therefore induces
drowsiness and also likely weight gain (and possibly metabolic
syndrome)
• Above a dose of 15 mg in hs, mirtazapine becomes a more activating
medication via its increased adrenergic effect
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SARI: Serotonin Antagonist/Serotonin Reuptake Inhibitor
• Prime examples are trazodone (weak antidepressant) and nefazodone
• Block selectively serotonin reuptake but in a less potent manner than
tricyclics or even SSRIs
• Also offer powerful post-synaptic 5HT2A/C antagonism which not only
reduces the risks of classic SSRIs side-effects (anxiety, sexual sideeffects) but also increases sedation and slow-wave sleep as well as as
appetite (and thus weight)
• In addition, blockade of 5HT2A/C receptors stimulate 5HT1A which may
further help reduce depressive symptoms
• Nefazodone though not a SSRI is a potent inhibitor of 3A4 (risk of
rhabdomyolysis when combined with normal to high doses of statins, for
example)
• Some antimuscarinic side-effects and orthostatic hypotension with
trazodone (be careful with elderly patients)
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MAO-Inhibitors
• Information given in case you manage a patient started on a MAOI by a
specialist
• MAO-A metabolizes 5-HT and NE selectively
• MAO-B involved in metabolism of dopamine as well as amines acting as protoxins metabolized into toxins that may cause neuronal damages
• Classic MAOIs are irreversible and non-selective meaning both the MAO-A
and MAO-B enzyme activity cannot be restored unless new enzymes are
synthesized: phenelzine, trancypromine, isocarboxazid
• Such drugs are linked to blood pressure complications via the so-called
“cheese effect” involving tyramine and leading to a surge in release of
monoamines
• RIMAs are antidepressant acting as reversible and selective inhibitors of
MAO-A, such as moclobemide, presenting a safer profile in terms of
paroxystic blood pressure elevation
• Deprenyl is a selective MAO-B inhibitor
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Herbal Remedies
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The extracts from Hypericum perforatum L (St John's wort) have been
shown to possess clinical efficacy in the therapy of mild to moderate
depression although some negative reports exist as well (see Duke study
by Davidson et al JAMA 2002; 287: 1807−1814)
Several in vitro studies have indicated that H. perforatum and its
phloroglucinol constituent hyperforin act via a blockade of serotonin (5HT), noradrenaline (NA) and possibly dopamine (DA) reuptake in a
manner similar to most of the current antidepressant
Notably, St John’s wort is a potent inducer of the CYP450 1A2, 2D6 and
3A4 and this can lead to significant drug-drug interaction usually via
loss of efficacy (i.e. OCPs and resulting pregnancies)
It can also be implicated in serotonin syndrome especially when
combined with a SSRI
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Medication Choice
• Would start treatment with a SSRI or SNRI
• NaSSA or NDRI would be reasonable alternatives for a moderate
depression
• For the treatment of depression, most ATDs are comparable
• Yet, after more than 40 years of RTCs, amitriptyline remains slightly
more efficacious with a NNT of 40 but a NNH of 8*
• The choice of a medication should be based on your level of familiarity
and also account for the anticipated side-effects profile and patient
preferences
• Given the availability of ATDs, would leave choice of a TCA or MAOI
to a specialist and would not consider herbal treatment as first line agent
* British Journal of Psychiatry 2001;178:129-44
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Therapy Initiation and Monitoring
• SSRI:
-When initiating treatment with a SSRI, make sure the therapeutic dose is
targeted (usually can be started directly at that dose, sometimes a quick
2-step titration may be preferred)
- Close follow-up (weekly) is recommended at first especially if suicidal
ideation is an issue (another reason to consider referral to a specialist)
- Educating patient and family about time course of response is important
as well as covering psychoeducation and information about side-effects
• SNRI:
- Remember they offer a different profile of side-effects (i.e. possible
increase in blood pressure)
- Venlafaxine works differently as dose is increased, at low dose though
acts like a SSRI so same considerations for management of suicide risks
apply
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Treatment Duration
• Critical because when sub-optimal treatment is provided or none, 50 to
85% of patients having a first episode will have at least one more
subsequent one, with 10 to 20% developing a chronic course
• The first episode should be treated for 6 months even when patient
improves within the first weeks
• Notably, the duration of treatment with an antidepressant for a depressive
episode but in the setting of a a bipolar disorder is different and should
also be referred to a specialist
• When a patient has had at least 3 episodes of depression - unipolar, i.e.
no (hypo)mania – long-term maintenance antidepressive therapy
becomes the norm
• Superior prophylaxis for patients who have suffered several recurrences
is achieved with full-dose of active antidepressant medication compared
to lesser doses
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Refractory Depression
• Really a matter for referral to a specialist:
- Diagnosis might need to be reconsidered
- Adjunct treatments may be needed
- MAOIs and TCAs should be considered
- Mood stabilizers might help
- And of course, referral for ECT
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Prognosis
• Full remission in moderately depressed patients:
• 46.4, 46.3 and 24.4% for pharmacotherapy, psychotherapy and placebo
with 37.1, 22.2 and 54.4% of dropouts respectively*
• Relapse/Recurrence:
– 41% on placebo vs. only 18% on an active treatment**
* American Journal of Psychiatry 2002;159(8):1354-60
** Lancet 2003;361(9358:653-61
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Conclusions
• Efficacy between SSRIs and TCAs did not differ in a meta-analysis of
trials restricted to primary care but significantly more patients on TCA
withdrew specifically because of side-effects*
• Choose an ATD based on your familiarity, side-effects profile, risks for
adverse drug-drug interactions and patient’s preferences
• SSRIs or SNRIs are probably best choices for non-psychiatrists
• Support patient closely especially with initiation of treatment
• Target the lowest therapeutic dose
• Maintain treatment for at least 6 months if not longer in recurrent
depression
• Refer complicated, suicidal, refractory or bipolar cases to a specialist
•British Medical Journal 2003;326(7397):1014
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