pharmacologic treatment of depression and anxiety joseph bryer, m.d. march 28, 2014

Pharmacologic Treatment of Depression and Anxiety

Joseph Bryer, M.D.March 28, 2014

©Joseph Bryer MD, Depression and Anxiety

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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


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Disclosure: Not financially supported by

pharmaceutical industry Some of what will be described is OFF-

LABEL. consult manufacturer’s package insert!


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First Principles: A syndrome is a collection of signs

and symptoms often occurring together, indicating a disease or illness


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First Principles: In general, successful pharmacologic

treatment rests on recognizing and treating psychiatric syndromes rather than individual symptoms


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First Principles: Arrive at a diagnosis before initiating

treatment, and draw conclusions about effectiveness only after adequate dosage and duration of treatment


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“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


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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)


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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)


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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


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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


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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!


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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


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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


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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


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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


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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


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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.


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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)


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Obsessive Compulsive Disorder

Repetitive, intrusive, unwanted thoughts/images (obsessions) or behaviors (compulsions) that the individual is unable to stop, and that interfere with functioning


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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


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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


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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


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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


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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)


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Serotonin-specific re-uptake inhibitors (SSRI) fluoxetine (Prozac®), sertraline (Zoloft®), paroxetine (Paxil®), fluvoxamine (Luvox®), citalopram (Celexa®), escitalopram (Lexapro®), vilazodone (Viibryd®), clomipramine* (Anafranil®)


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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


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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


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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


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SSRI Side Effects Rare but significant:

hyponatremia, increased bleeding time


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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


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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


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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)


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Serotonin/Norepinephrine Re-uptake Inhibitors (SNRI) venlafaxine (Effexor® immediate

release, Effexor XR®) duloxetine (Cymbalta®) desvenlafaxine (Pristiq®) levomilnacipran (Fetzima®)


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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)


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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


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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


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SNRI Side Effects Rare but significant:

hyponatremia increased bleeding time


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SNRI Discontinuation Symptoms frequent momentary dizziness shock-like sensations (“brain zaps”) tearfulness irritability fatigue


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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)


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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


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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


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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


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Miscellaneous Antidepressants trazodone (Desyrel®)

mostly used for sleep (25-150 mg HS), since

usually too sedating at antidepressant doses (300-600 mg HS)


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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


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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


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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


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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


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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


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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®])


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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


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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


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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


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Benzodiazepines for Anxiety Syndromes or Symptoms potential discontinuation/withdrawal:

rebound anxiety states persistent anxiety tremor insomnia autonomic instability seizure withdrawal delirium


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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


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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


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Pharmacologic Treatment of Anxiety Syndromes and Symptoms

Generalized Anxiety Disorder: SSRI, SNRI, buspirone Benzodiazepines may be necessary, but

last choice given chronicity of symptoms


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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


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Obsessive Compulsive Disorder: SSRI often titrating to higher doses and longer

durations


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Post-Traumatic Stress Disorder: SSRI helpful but psychotherapy as, or more, important

Social Anxiety Disorder: SSRI, therapy

Acute Anxiety Disorder: short course of benzos, support

pharmacologic treatment of depression and anxiety joseph bryer, m.d. march 28, 2014

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