Download Depression in Primary Care

Depression in Primary Care
Chirag V Desai MD
Chirag V Desai MD, LLC
8823 San Jose Blvd, Suite 303
Jacksonville, FL 32217
Learning Objectives:
• Upon completion of this activity, participants should be able to:
1. Define and describe the different forms of depressive
disorders.
2. Choose proper assessment methods and identify
current FDA approved medication interventions to treat
depressive disorders
Depression in Primary Care
• Depression is the most common psychiatric disorder in the general
population
• Most common mental health condition in patients seen in primary
care
• Two-thirds of primary care patients with depression present with
somatic symptoms (ie, headache, back problems, or chronic pain),
making detection of depression more difficult
DSM-V Criteria
• A major depressive syndrome or episode manifests with five or more of the following symptoms,
present most of the day nearly every day for a minimum of two consecutive weeks. At least one
symptom is either depressed mood or loss of interest or pleasure.
• Depressed mood
• Loss of interest or pleasure in most or all activities
• Insomnia or hypersomnia
• Change in appetite or weight
• Psychomotor retardation or agitation
• Low energy
• Poor concentration
• Thoughts of worthlessness or guilt
• Recurrent thoughts about death or suicide, or a suicide attempt
Biological Basis of Depression:
Monoamine Hypothesis
Norepinephrine
Serotonin
Dopamine
Brain-Derived Neurotrophic Factor (BDNF)
Neurogenesis, synaptogenesis, neuronal resilience
Under stress, the BDNF gene is repressed
Sustains viability of neurons
Epidemiology: Depression
Prevalence
14% lifetime prevalence
(unipolar depression)1
Impact
2nd leading cause of disability in
the US2, suicide, impairment
Gender ratio
2x female
Risk Factors
Family hx Depression (G x E)
Substance use
Comorbidity
Anxiety, ADHD, Substance Use
Disorders
Future
Recurrent depression
30-70% relapse in 1-2yrs
1 – Kessler et al, 2011; 2 – US Burden of Disease Collaborators, 2013.
Flavors of
1
Depression
• Polarity: Unipolar vs. bipolar
• Symptom-based specifiers:
Melancholic (25-30%)
severe
Atypical (<40%)
Main Symptom
lack of mood reactivity
OR anhedonia
+ Mood reactivity
Additional
features
3: ↓app/wt, ↓ Sleep,
worse AM mood,
despair
2: ↑ app/wt, ↑ Sleep,
Leaden paralysis,
IP rejection sensitivity
Other
Treatment-resistance
Women, SA, young;
Use of MAOIs
1 – Thase ME, 2013.
“Flavors” Continued
Anxious (up to 40%)
Psychotic (15-20% of
severe)
Symptoms
2: restlessness, tension, poor
C (worry),
fears: losing control,
something bad will happen
Delusions, hallucinations
Features
Poorer outcomes with
pharmacotherapy
high recurrence,
hospitalizations, longer
episodes, impairment
Treatment
Adjunctive pharmacotherapy,
CBT
Treatment w/
antipsychotics, ECT
Onset-based subgroups
• Seasonal affective Disorder
• Associated w/ inc. latitude, women
• Different treatment: buproprion1, bright light therapy
• Peripartum onset
•
•
•
•
Non psychotic depression : 13% of women who deliver
Recurrence rates up to 50% in subsequent preganancies2
Includes pregnancy and post-partum period
Treatment: Antidepressants (FDA Class C), CBT
1 – Westrin A, Lam RW. 2007; 2- O’Hara 1996.
Screening Instruments:
• PHQ-9: scored 0 to 27, with scores ≥10 indicating a possible
depressive disorder. It has a sensitivity of 88 percent and specificity of
88 percent.
• PHQ-2: Comprised of the 1st two questions of PHQ-9:
• During the last month, have you often been bothered by feeling down,
depressed, or hopeless?
• During the last month, have you often been bothered by having little interest
or pleasure in doing things?
Screening Instruments:
• Beck Depression Inventory for Primary Care:
• 7 item modified inventory adapted from the 21 item full BDI-II
• 4 point cutoff for identifying MDD
• 97 percent sensitivity and 99 percent specificity for identifying major
depression
• Unfortunately, only available by license requiring a fee which limits broader
use
Medical Factors to Consider:
Other conditions can exhibit similar behaviors as major depression such
as:
Hypothyroidism
Cushing disease
Substance Abuse
Medication : OCP, Steroids, Interferon, Beta blockers (Propanolol).
SSRI’s and Effect on CYP450
• SSRIs inhibit P450 (CYP1A2, CYP3A4, CYP 2D6)
• Can increase levels of anti-arrhythmics, β-blockers, antihistamines,
and Ca2+ channel blockers
• e.g. CYP2D6 inhibition by fluoxetine, paroxetine, sertraline (weak) may cause
metoprolol and carvedilol accumulation and bradycardia
• e.g. CYP2C19 inhibition by fluoxetine inhibits clopidogrel’s effect by inhibiting
conversion to active metabolite
• Escitalopram and citalopram (1A2,2D6,2C19) weak inhibitors
Tricyclic Antidepressants
• Relatively safe in short term use for stable ischemic heart disease,
prior MI or CHF
• Orthostatic hypotension is very common
• Nortriptyline is thought to be safest in CHF due to minimal effect on
orthostasis and ejection fraction
• All TCA’s have quinidine like anti-arrhythmic properties that delay
cardiac conduction, increase HR and prolong QTc
Descriptors of Medication Effect:
Response – 50% reduction in symptoms
Remission – all symptoms removed
Recovery – 6 to 12 months of remission
Relapse – worsens before remission
Recurrence – worsens months after recovery
Mechanism of Action
• Currently still do not have a complete and adequate explanation of
how antidepressants work
• Some block monoamine reuptake
• Others block alpha-2 receptors
• Still others block monoamine oxidase
• Direct vs indirect effects on neurotransmitters
Antidepressant Types:
Selective Serotonin Reuptake Inhibitor (SSRI)
Monoamine Oxidase Inhibitor (MAOI)
Tricyclic Antidepressant (TCA)
Serotonin/Norepinephrine Uptake Inhibitor (SNRI)
Norepinephrine/Dopamine Uptake Inhibitor (NDRI)
Noradrenergic/Specific Serotonergic AD (NaSSA)
Serotonin Antagonist Reuptake Inhibitor (SARI)
Receptor Subtypes:
5HT1A – Anxiolytic & Antidepressant
5HT2A – Anxiety, Insomnia, OCD, Libido
5HT2C – Anxiety & Weight loss
5HT3 – GI problems & Nausea
5HT1D – blockade of 5HT release
Selective Serotonin Reuptake Inhibitors
fluoxetine (Prozac)
paroxetine (Paxil)
sertraline (Zoloft)
citalopram (Celexa)
escitalopram (Lexapro)
Chemical Structure
First-line treatments for:
Major depressive disorder (MDD)
Panic disorder (PD)
Obsessive-compulsive disorder (OCD)
Social anxiety
Posttraumatic stress disorder (PTSD)
Bulimia
Generalized anxiety disorder (GAD)
Premenstrual dysphoric disorder (PMDD)
FDA Indications:
MDD (approved for all except fluvoxamine)
PD (approved for fluoxetine, paroxetine, and sertraline)
OCD (approved for all except citalopram and escitalopram)
Social Anxiety (approved for sertraline and paroxetine)
FDA Indications Cont’d
PTSD (approved for sertraline and paroxetine)
Bulimia (approved for fluoxetine)
GAD (approved for paroxetine and escitalopram)
PMDD (approved for fluoxetine [Sarafem only], paroxetine [controlled
release only], and sertraline)
Adverse Effects:
Most common side effects
Nausea, diarrhea, headache
Decreased libido
Delayed/Inability for orgasm
“Serotonin Syndrome”
Hyperpyrexia, myoclonus, mental status changes,
seizures, arrhythmias, delirium
Drug Interactions:
Increase TCA levels (paroxetine, fluoxetine)
Increase carbamazepine, phenytoin (paroxetine)
Increase haloperidol, olanzapine, risperidone (paroxetine)
MAOI (contraindicated): serotonin syndrome
Smoking decreases many psychotropic levels
Serotonin/Norepinephrine Reuptake Inhibitors
venlafaxine (Effexor)
duloxetine (Cymbalta)
desvenlafaxine (Pristiq)
Chemical Structure
Venlafaxine (Effexor)
Blocks reuptake of serotonin, norepinephine, (and to a lesser extent, dopamine)
First-line monotherapy for MDD
Activating at high doses
Can elevate blood pressure at higher doses
Some efficacy for PTSD that failed SSRI
Treatment of chronic pain conditions
Duloxetine (Cymbalta)
Blocks serotonin and norepinephine
More potent norepinephrine reuptake inhibitor (NRI) compared to venlafaxine
First-line monotherapy for MDD
Approved for Peripheral Neuropathy
May treat stress urinary incontinence
Desmethylvenlafaxine (Pristiq)
Major metabolite of venlafaxine
More potent reuptake inhibitor of norepinephrine
Only approved for MDD
Appears to be effective to treat vasomotor symptoms from menopause
50mg initiation/final dose
Not metabolized by P-450 and thought to have less drug-drug interaction
Indications:
MDD (Effexor XR, duloxetine, desvenlafaxine)
GAD (approved for Effexor XR and duloxetine)
Social anxiety disorder (approved for Effexor XR)
Neuropathic pain (approved for duloxetine)
Fibromyalgia (approved for duloxetine)
Safety
Fatal overdoses with venlafaxine are exceedingly rare
No reported fatal overdoses of duloxetine
10 g or more resulted in seizures and serotonin syndrome
Desvenlafaxine overdoses associated with arrhythmias, serotonin
syndrome, rhabdomyolysis (often in combination with other drugs)
NORADRENERGIC-DOPAMINERGIC
ANTIDEPRESSANT
• Bupropion (Wellbutrin)
Chemical Structure
Indications:
First-line monotherapy or augmentation for mild to moderate
depression
Smoking cessation (Zyban)
Treatment of seasonal affective disorder
Appears to be effective in the treatment of ADHD
Not effective in the treatment of anxiety disorders
Factors to Consider:
Relatively safe in overdose
Completed suicides due to underlying seizure disorder
Counteract sexual dysfunction
EtOH abuse/Eating Disorders
Lower doses for liver and kidney problems
Factors to Consider:
Serious drug interactions are uncommon
Drugs that lowers the seizure threshold such as clozapine and
clomipramine should be used cautiously or avoided
MAOI and bupropion is contraindicated as greater risk of hypertensive
crisis
Avoid if dependent on alcohol or benzodiazepines
Tricyclic Antidepressants:
imipramine (Tofranil)
amitriptyline (Elavil)
clomipramine (Anafranil)
desipramine (Norpramin)
nortripyline (Pamelor)
Chemical Structure
Indications:
Second- or third-line agents for MDD
Panic disorder
OCD (FDA approved for clomipramine)
Pain syndromes
Migraine prophylaxis
Enuresis (FDA approved for imipramine)
Mechanism of Action:
Block Serotonin reuptake
Block Norepinephrine reuptake
Block alpha1 adrenergic receptors
Block H1 histamine receptors
Block muscarinic cholinergic receptors
Adverse Effects:
Dry mouth, urinary retention, constipation, confusion, blurred vision,
tachycardia
Weight gain
Sedation
Sexual dysfunction
Orthostasis
Cardiac conduction abnormalities by blocking sodium channels (cardiac
arrest and seizures)
Factors to Consider:
Amitriptyline has a very poor side-effect profile secondary to its
anticholinergic and antihistaminic side effects
Desipramine and nortriptyline have the most favorable side-effect
profiles
Desipramine more stimulating
Amitriptyline more sedating
Drug Interactions:
Anticoagulants: ↑ warfarin levels
Antipsychotics: ↑ TCA and antipsychotic levels
Cimetidine: ↑ TCA levels
Stimulants: ↑ TCA levels
Oral contraceptives: ↑ TCA levels
SSRIs: ↑ TCA levels
Monoamine Oxidase Inhibitors:
Nonselective MAO Inhibitors
phenelzine (Nardil)
tranylcypromine (Parnate)
isocarboxazid (Marplan)
Selective Inhibitor MAO B for treatment of Parkinson’s Disease
Selegiline (Eldepryl)
transdermal (Emsam)
Chemical Structure
Indications:
Third-line agents for MDD (FDA approved for resistant depression)
Social anxiety
Panic disorder
Parkinson's disease (selegiline has FDA approval)
Mechanism of Action:
Irreversible inhibitor of monoamine oxidase A (MAO-A)
Exert effects on norepinephrine and 5-HT
Selective irreversible MAO-B inhibitor
Exert effects on phenylethylamine and dopamine
Adverse Effects:
Weight gain
Orthostasis
Sexual dysfunction
Dry mouth
Insomnia/somnolence
Headache
Factors to Consider:
Potentially lethal in overdose
Hypertensive crisis
Stroke
Myocardial infarction
Requires 2-3 week wash-out period before switching to another
antidepressant
Dietary Considerations:
Foods to be avoided (tyramine content):
Beer, red wine
Aged cheeses (cottage and cream cheese allowed)
Dry sausage
Fava or Italian green beans
Brewer's yeast
Smoked fish
Liver (beef or chicken)
Drug Interactions:
ß-Blockers: hypotension, bradycardia
Bupropion (contraindicated): hypertensive crisis, seizure
Carbamazepine (contraindicated): hypertensive crisis
Meperidine (contraindicated): serotonin syndrome
Nefazodone: possible serotonin syndrome
Sympathomimetics: hypertensive crisis
SSRIs (contraindicated): serotonin syndrome
TCAs: clomipramine contraindicated
Mirtazapine (contraindicated): hypertensive crisis
SNRIs (contraindicated): serotonin syndrome
Vilazodone HCl (Viibryd)
•
•
•
•
•
•
•
•
SSRI with dual mechanism of action
Blocks serotonin reuptake through the serotonin transporter
Partial agonism of the 5-HT1A presynaptic receptor
FDA indicated for MDD
Thought to decrease the therapeutic lag of traditional SSRI’s
Felt to have less sexual side effects compared to the other SSRI’s
Common adverse effects include diarrhea, nausea, vomiting and headache
should be taken with food because it has 72% bioavailability after a meal
Levomilnacipran (Fetzima)
• Serotonin–norepinephrine reuptake inhibitor (SNRI)
• Levomilnacipran is the enantiomer of milnacipran, approved in Europe for
depression but only for fibromyalgia pain and peripheral neuropathy in the
US
• In theory, levomilnacipran should improve cognitive functions linked to
norepinephrine: concentration and motivation, and in turn, improve social
function
• Potential adverse effects include: increases in heart rate and blood
pressure, and dose-dependent urinary hesitancy and erectile dysfunction
• levomilnacipran is affected by renal function but no dose adjustment
needed in mild renal impairment
Vortioxetine (Trintillex)
• SSRI as well as a 5-HT1A full agonist and 5-HT3 receptor antagonist
• Inhibitory effect on 5-HT7 and 5-HT1D receptors and partial agonism
of 5-HT1B receptors
• Ultimate effect of the multimodal action is an increase in dopamine,
norepinephrine, and acetylcholine activity in the prefrontal cortex
• In theory, this should lead to improvement in cognitive deficits
associated with depression
• Specifically studied for use in the geriatric population
References
American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, 5th ed. Arlington, VA: American Psychiatric Association; 2013.
American Psychiatric Publishing Textbook of Psychopharmacology, 4th edition.
Schatzberg AF, Nemeroff CB (eds); American Psychiatric Publishing, Inc.
Washington, D.C. (2009).
Deardorff WJ, Grossberg GT. A review of the clinical efficacy, safety and tolerability
of the antidepressants vilazodone, levomilnacipran and vortioxetine. Expert
Opin Pharmacother. 2014;15(17):2525-2542
Kessler RC, Ormel J, et al. Development of lifetime comorbidity in the World
Health Organization world mental health surveys. Arch Gen Psychiatry
2011;68:90.
O’Hara MW. Swain AM. Rates and risk of postpartum depression: a meta-analysis.
Int Rev Psychiatry. 1996;8: 37-54
Prescriber’s guide to using 3 new antidepressants: Vilazodone, levomilnacipran,
vortioxetine Current Psychiatry. 2015 February;14(2):28-29, 32-26
Thase ME. The multifactorial presentation of depression in acute care. J Clin
Psychiatry 2013; 74 (suppl 2): 3 – 8.
US Burden of Disease Collaborators. The state of US health, 1990-2010: burden of
diseases, injuries, and risk factors. JAMA 2013; 310:591.
Up To Date: Screening for Depression
Westrim A, Lam RW. Long-term and preventative treatment for seasonal affective
disorder. CNS Drugs. 2007; 21:901-999.