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©Joseph Bryer MD, Depression and Anxiety
2
Objectives: Improve recognition of the importance of
accurate diagnosis in the management of depressive and anxiety disorders
Distinguish psychiatric symptoms from psychiatric syndromes
Enhance understanding of several treatments in each major psychopharmacologic class, to support their competent use in patients with anxiety and depressive disorders
©Joseph Bryer MD, Depression and Anxiety
3
Disclosure: Not financially supported by
pharmaceutical industry Some of what will be described is OFF-
LABEL. consult manufacturer’s package insert!
©Joseph Bryer MD, Depression and Anxiety
4
First Principles: A syndrome is a collection of signs
and symptoms often occurring together, indicating a disease or illness
©Joseph Bryer MD, Depression and Anxiety
5
First Principles: In general, successful pharmacologic
treatment rests on recognizing and treating psychiatric syndromes rather than individual symptoms
©Joseph Bryer MD, Depression and Anxiety
6
First Principles: Arrive at a diagnosis before initiating
treatment, and draw conclusions about effectiveness only after adequate dosage and duration of treatment
©Joseph Bryer MD, Depression and Anxiety
7
“Clinical” Depression NOT just the symptom of low mood—
always be mindful of the difference between the medical term ‘depression’ versus its common everyday usage
©Joseph Bryer MD, Depression and Anxiety
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“Clinical” Depression a syndrome of low mood or loss of capacity for
pleasure, plus a minimum number of other possible signs and symptoms including: reduced energy or sense of health and vitality;
sense of guilt or reduced self–worth/confidence; sleep disturbance; appetite/weight disturbance; reduced optimism or hope for the future; suicidal ideas or frequent thoughts of death; increased anxiety or inner tension; complaints of poor concentration/memory; reduced or increased level of physical activity (psychomotor slowing or agitation)
©Joseph Bryer MD, Depression and Anxiety
9
Psychiatric Disorders That Often Include Depressive Syndromes:
Major Depression, single episode or recurrent
Dysthymia Bipolar depression Bipolar mixed state Bereavement (a diagnosis, but not
usually an illness/disorder)
©Joseph Bryer MD, Depression and Anxiety
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Major Depression • Depressed mood or a loss of interest or pleasure in daily activities for more than two weeks.
• Mood represents a change from the person's baseline. • Impaired function: social, occupational, educational. • Specific symptoms, at least 5 of these 9, present nearly every day: 1. Depressed mood or irritable most of the day, nearly every day,
as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful).
2. Decreased interest or pleasure in most activities, most of each day
3. Significant weight change (5%) or change in appetite 4. Change in sleep: Insomnia or hypersomnia 5. Change in activity: Psychomotor agitation or retardation 6. Fatigue or loss of energy 7. Guilt/worthlessness: Feelings of worthlessness or excessive or
inappropriate guilt 8. Concentration: diminished ability to think or concentrate, or
more indecisiveness 9. Suicidality: Thoughts of death or suicide, or has suicide plan
©Joseph Bryer MD, Depression and Anxiety
12
Dysthymia Chronic depressed state that does not meet
full criteria for major depression At least 2 of the following symptoms must be
present, impair functioning, and be present most days for at least 2 years: poor appetite or overeating insomnia or hypersomnia low energy or fatigue low self-esteem poor concentration or difficulty making
decisions feelings of hopelessness
©Joseph Bryer MD, Depression and Anxiety
14
Bipolar Disorder, Depressed
Depressive syndrome currently, with a history of either mania (Bipolar Disorder, Type I) or hypomania (Bipolar Disorder, Type II)
Look carefully for any history of mania/hypomania!
©Joseph Bryer MD, Depression and Anxiety
15
Bipolar Disorder, Depressed Bipolar depressive symptoms are often
(not always) atypical: hypersomnia, hyperphagia/weight gain, marked fatigue
antidepressant treatment in bipolar disorder, especially in the absence of a mood stabilizer, can increase depressive symptoms, manic symptoms and mood instability/cycling
©Joseph Bryer MD, Depression and Anxiety
16
Bipolar Disorder, Depressed careful addition of antidepressant may
be considered if, first, two or more mood stabilizers fail to treat depression
among antidepressants, bupropion appears to have least risk of increasing mood instability, for example provoking mania or increasing mood cycling
©Joseph Bryer MD, Depression and Anxiety
17
Bipolar Disorder, Mixed State
Depressive syndrome PLUS manic symptoms concurrently
Mixed states frequently resemble anxious (agitated) depression. Consider the possibility of bipolarity especially when seemingly major depressed patients become more irritable, more anxious, more impulsive, or develop insomnia when treated with antidepressant
©Joseph Bryer MD, Depression and Anxiety
19
Bereavement
A normal grief reaction may meet symptom criteria for major depression, but is usually self-limited and not substantially impairing or life-threatening
Especially severe or prolonged grief reactions may warrant pharmacologic treatment, including antidepressant and/or anxiolytics
©Joseph Bryer MD, Depression and Anxiety
20
Anxiety Disorders
Generalized Anxiety Disorder Panic Disorder, with or without
agoraphobia Obsessive Compulsive Disorder Social Anxiety Disorder Post-traumatic Stress Disorder Specific Phobia Acute Anxiety Disorder—acute situational
anxiety that impairs function
©Joseph Bryer MD, Depression and Anxiety
21
Generalized Anxiety Disorder
Excessive and uncontrollable anxiety or worry about multiple issues that persists for at least six months, and interferes with functioning
Often associated with somatic symptoms: fatigue, muscle tension, nausea, otherwise unexplained aches and pains, etc.
©Joseph Bryer MD, Depression and Anxiety
22
Panic Disorder
Episodes of intense anxiety, often unprovoked, associated with somatic manifestations including palpitations, tremor, fear of dying or passing out, difficulty breathing, chest pain, numbness/tingling, fear of loss of control
May or may not be associated with agoraphobia (fear and avoidance of public/crowds)
©Joseph Bryer MD, Depression and Anxiety
23
Obsessive Compulsive Disorder
Repetitive, intrusive, unwanted thoughts/images (obsessions) or behaviors (compulsions) that the individual is unable to stop, and that interfere with functioning
©Joseph Bryer MD, Depression and Anxiety
24
A Note on Delirium (Acute Encephalopathy) Always includes some clouding of
consciousness (altered level of alertness and/or impaired attention and concentration) usually acute onset usually associated with increased anxiety usually associated with disturbed
sleep/wake cycle
©Joseph Bryer MD, Depression and Anxiety
25
A Note on Delirium (Acute Encephalopathy) Usually associated with other cognitive
impairments that might make diagnosis obvious, but can produce ANY other psychological symptom or syndrome
©Joseph Bryer MD, Depression and Anxiety
26
A Note on Delirium (Acute Encephalopathy) Treating anxiety or depressive syndrome
that is due to delirium/encephalopathy is unlikely to help (and may be harmful), and distract from identifying and correcting the true cause (often infectious, metabolic or medication-induced) of the delirium
©Joseph Bryer MD, Depression and Anxiety
27
Antidepressant Pharmacology Essentially all believed to work by
increasing neurotransmission in serotonin, norepinephrine, and/or dopamine systems
Most inhibit re-uptake of released transmitter back into the releasing cell: SSRI SNRI tricyclic antidepressants bupropion
©Joseph Bryer MD, Depression and Anxiety
28
Antidepressant Pharmacology Besides re-uptake blockade, others increase
transmitter availability by : blocking transmitter breakdown (MAO
Inhibitors), or blocking auto-receptor inhibition of further
transmitter release (mirtazapine)
©Joseph Bryer MD, Depression and Anxiety
30
Serotonin-specific re-uptake inhibitors (SSRI) fluoxetine (Prozac®), sertraline (Zoloft®), paroxetine (Paxil®), fluvoxamine (Luvox®), citalopram (Celexa®), escitalopram (Lexapro®), vilazodone (Viibryd®), clomipramine* (Anafranil®)
©Joseph Bryer MD, Depression and Anxiety
31
Serotonin-specific re-uptake inhibitors (SSRI) They have varying potencies for
serotonin reuptake inhibition, plus more modest reuptake effects on other transmitter systems, that may explain variable effectiveness in different patients
©Joseph Bryer MD, Depression and Anxiety
32
Serotonin-specific re-uptake inhibitors (SSRI) At least one member of the SSRI class
(not every drug for all indications) is approved for use in: major depression generalized anxiety disorder obsessive compulsive disorder panic disorder social phobia posttraumatic stress disorder
©Joseph Bryer MD, Depression and Anxiety
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SSRI Side Effects
Early: nausea, diarrhea, headache, somnolence/insomnia; increased anxiety/low mood, suicidal thoughts
Late (often not resolving with more time): tremor; sexual side effects (reduced libido, delayed/absent orgasm, occasionally reduced arousal) in 30-50% in my experience
©Joseph Bryer MD, Depression and Anxiety
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SSRI Side Effects Rare but significant:
hyponatremia, increased bleeding time
©Joseph Bryer MD, Depression and Anxiety
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SSRI Discontinuation Symptoms frequent momentary dizziness tearfulness irritability
Emergence coincides with half-life of parent drug and active metabolites
May persist for days or weeks
©Joseph Bryer MD, Depression and Anxiety
36
Clinical Tips with SSRI Use
Pay attention to half-life: shortest half-life (paroxetine) generally most troublesome with discontinuation symptoms; rarely see discontinuation symptoms with fluoxetine Every other day dosing reasonable with
fluoxetine, generally not with others
©Joseph Bryer MD, Depression and Anxiety
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Clinical Tips with SSRI Use With prominent anxiety—especially
panic—use lower dosing and slower titration, since anxiety often worsened early in treatment.
Except for fluoxetine, usually start at half the effective daily dose and increase in 5-7 days to minimum approved effective dose. (In panic disorder, even lower starting doses and slower titrations)
©Joseph Bryer MD, Depression and Anxiety
38
Serotonin/Norepinephrine Re-uptake Inhibitors (SNRI) venlafaxine (Effexor® immediate
release, Effexor XR®) duloxetine (Cymbalta®) desvenlafaxine (Pristiq®) levomilnacipran (Fetzima®)
©Joseph Bryer MD, Depression and Anxiety
39
Serotonin/Norepinephrine Re-uptake Inhibitors (SNRI) dual re-uptake blocking agents may be
more effective at treating depressed patients to remission than SSRI’s
also appear beneficial in managing some types of chronic pain (especially neuropathic pain)
©Joseph Bryer MD, Depression and Anxiety
40
Serotonin/Norepinephrine Re-uptake Inhibitors (SNRI) at least one member of the SNRI class
(not every drug for all indications) is approved for use in: major depression generalized anxiety disorder panic disorder Not usually effective for obsessive
compulsive disorder, posttraumatic stress disorder, or social phobia
©Joseph Bryer MD, Depression and Anxiety
41
SNRI Side Effects
Early: nausea, diarrhea, constipation, headache, somnolence/insomnia; increased anxiety/low mood, suicidal thoughts
Late (often not resolving with more time): increased blood pressure (dose-dependent) in some patients; tremor; sexual side effects (reduced libido, delayed/absent orgasm, occasionally reduced arousal) in 20-40% in my experience
©Joseph Bryer MD, Depression and Anxiety
42
SNRI Side Effects Rare but significant:
hyponatremia increased bleeding time
©Joseph Bryer MD, Depression and Anxiety
43
SNRI Discontinuation Symptoms frequent momentary dizziness shock-like sensations (“brain zaps”) tearfulness irritability fatigue
©Joseph Bryer MD, Depression and Anxiety
44
Clinical Tips with SNRI Use
except for Pristiq®, most SNRI’s require some dose titration—e.g., Cymbalta® 30 mg x 7 days, then 60 mg per day; Effexor XR® 37.5 mg x 7 days, then 75 mg per day—to minimize side effects
generally, SNRI’s likely to be more “activating” or energizing than SSRI’s (this may be a positive or negative characteristic)
©Joseph Bryer MD, Depression and Anxiety
45
Clinical Tips with SNRI Use discontinuation symptoms generally
more likely to be troublesome than SSRI’s if slow dose taper doesn’t work, consider
several week course of fluoxetine, then attempt SNRI stoppage/taper again
©Joseph Bryer MD, Depression and Anxiety
46
Miscellaneous Antidepressants
bupropion (Wellbutrin® IR, SR, XL) likely works through dopamine and
norepinephrine re-uptake inhibition generally stimulating/energizing very, very small risk of sexual side effects
and weight gain not usually a first choice for prominent
anxiety symptoms or co-morbid anxiety disorders
©Joseph Bryer MD, Depression and Anxiety
47
Miscellaneous Antidepressants mirtazapine (Remeron®)
alpha-2 adrenergic auto-receptor antagonist—blocks inhibition of further transmitter release
paradoxically, often too sedating in “young”, but very well tolerated in elderly
prominent anti-anxiety and weight-promoting effects
few or no discontinuation symptoms
©Joseph Bryer MD, Depression and Anxiety
48
Miscellaneous Antidepressants trazodone (Desyrel®)
mostly used for sleep (25-150 mg HS), since
usually too sedating at antidepressant doses (300-600 mg HS)
©Joseph Bryer MD, Depression and Anxiety
49
Less Frequently Used Antidepressant Classes tricyclic antidepressants (e.g.,
nortriptyline, amitriptyline, desipramine, imipramine) low doses may have benefit in chronic pain,
especially neuropathic at antidepressant doses, should have baseline
EKG to rule out intraventricular conduction delay, and should monitor with blood levels of drug (only antidepressants with well-defined therapeutic window), 10-12 hours after most recent dose
©Joseph Bryer MD, Depression and Anxiety
50
Less Frequently Used Antidepressant Classes MAO Inhibitors (Parnate®, Marplan®,
Nardil®, EMSAM® patch) very effective and often well tolerated,
but fear of hypertensive crisis and serotonin syndrome limits use
high risk of drug-drug interactions except for minimum dose of EMSAM, all
also require low tyramine diet
©Joseph Bryer MD, Depression and Anxiety
51
General Considerations in Treatment of Depression SSRI’s or SNRI’s are generally first-line
agents in some cases, bupropion or mirtazapine
may be first line choices: bupropion: hypersomnolent, marked
fatigue, apathy, seasonality may make bupropion first choice
mirtazapine: insomnia, marked anxiety, appetite/weight loss may make mirtazapine first choice
©Joseph Bryer MD, Depression and Anxiety
52
General Considerations in Treatment of Depression Any given antidepressant is about 60% likely
to lead to marked improvement in depressive symptoms, and about 30-45% likely to lead to complete remission of depressive syndrome
Generally, treat patients to remission for about one year, then consider taper off However, lifetime recurrence rates are 50% for
one prior episode, increasing to 90% if patient has had three prior episodes of depression
©Joseph Bryer MD, Depression and Anxiety
53
General Considerations in Treatment of Depression Failure of one agent at an adequate
dosage and duration (5-6 weeks, except 6-8 weeks in elderly) should lead to trial with another agent in same or different class
©Joseph Bryer MD, Depression and Anxiety
54
General Considerations in Treatment of Depression In treatment resistant depression,
pharmacologic options include: Combine antidepressants: e.g., SSRI or SNRI +
bupropion, SSRI or SNRI + mirtazapine, SSRI + tricyclic. Often, there are drug interactions to reduce metabolism of added agent, so lower doses may be required
Augmentation of antidepressant: l-methylfolate, buspirone, low-dose lithium, atypicals (including aripiprazole [Abilify®], quetiapine, risperidone), stimulants (e.g., methylphenidate [Ritalin®])
©Joseph Bryer MD, Depression and Anxiety
55
Agents Specific for Anxiety Syndromes or Symptoms Benzodiazepines Buspirone Miscellaneous, Off-Label: gabapentin,
pregabalin sometimes helpful for GAD Anxiety/Agitation: neuroleptics (e.g.,
haloperidol), atypical antipsychotics
©Joseph Bryer MD, Depression and Anxiety
56
Benzodiazepines for Anxiety Syndromes or Symptoms with one probable exception (panic
disorder), usually helpful at reducing anxiety symptoms, not syndromes
one exception to above: they may exacerbate confusion in some delirious states, and consequently worsen anxiety
generally highly effective managing anxiety as symptom, but non-specific
©Joseph Bryer MD, Depression and Anxiety
57
Benzodiazepines for Anxiety Syndromes or Symptoms side effects include potential for
dependence/diversion, sedation, neuromotor impairment, interact with alcohol, potential for serious withdrawal syndromes
most to least sedating: diazepam, clonazepam, lorazepam, alprazolam
longest to shortest half-life: diazepam, clonazepam, lorazepam/alprazolam
©Joseph Bryer MD, Depression and Anxiety
58
Benzodiazepines for Anxiety Syndromes or Symptoms potential discontinuation/withdrawal:
rebound anxiety states persistent anxiety tremor insomnia autonomic instability seizure withdrawal delirium
©Joseph Bryer MD, Depression and Anxiety
59
Buspirone for Anxiety Syndromes or Symptoms binds to 5-HT type 1A serotonin receptors.
Buspirone also binds at dopamine type 2 (DA2) receptors. The net result is that serotonergic activity is suppressed while noradrenergic and dopaminergic cell firing is enhanced.
Clinically, this is associated with anti-anxiety effects and, probably, antidepressant augmenting effects. No or limited discontinuation symptoms
©Joseph Bryer MD, Depression and Anxiety
60
Gabapentin, Pregabalin for Anxiety Syndromes or Symptoms Neurontin®, Lyrica® effects mediated via
GABA system, with pain-relieving, anticonvulsant and anxiolytic effects
Tend to be sedating
©Joseph Bryer MD, Depression and Anxiety
61
Pharmacologic Treatment of Anxiety Syndromes and Symptoms
Generalized Anxiety Disorder: SSRI, SNRI, buspirone Benzodiazepines may be necessary, but
last choice given chronicity of symptoms
©Joseph Bryer MD, Depression and Anxiety
62
Pharmacologic Treatment of Anxiety Syndromes and Symptoms Panic Disorder: SSRI or SNRI, initially
AT LOW DOSE to start titration. Benzos may have a larger role here,
especially early in treatment
©Joseph Bryer MD, Depression and Anxiety
63
Pharmacologic Treatment of Anxiety Syndromes and Symptoms
Obsessive Compulsive Disorder: SSRI often titrating to higher doses and longer
durations