Diagnosis and Psychopharmacological
Treatment of Major Depressive Disorder
Dr. James K. Rustad, M.D.
Copyright © 2011. All Rights Reserved.
Presentation Overview
 Definitions of Major Depressive Episode
and Major Depressive Disorder
 Suicide risk assessment: SAD PERSONS
 Pathophysiology and Neurobiology of
Depression
Psychopharmacological Treatment of MDD
 Monoamine Oxidase Inhibitors (MAOIs )
 Tricyclic Antidepressants (TCAs)
 Selective serotonin reuptake inhibitors (SSRIs)
 Serotonin norepinephrine reuptake inhibitors (SNRIs)
 Norepinephrine dopamine reuptake inhibitor (NDRI)
Bupropion)
 Alpha-two antagonist (Mirtazapine)
 Serotonin antagonist/reuptake inhibitor (SARI: Trazodone)
 Combination and Augmentation Strategies for TreatmentResistant Depression
Major Depressive Episode
from DSM-IV TR (4th edition), 2000.
 A. Five (or more) of the following symptoms have been present during the
same 2-week period and represent a change from previous functioning; at least
one of the symptoms is either (1) depressed mood or (2) loss of interest or
pleasure. Note: Do note include symptoms that are clearly due to a general
medical condition, or mood-incongruent delusions or hallucinations.
(1) depressed mood 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). Note: In children and adolescents, can be irritable mood.
(2) markedly diminished interest or pleasure in all, or almost all, activities most
of the day, nearly every day (as indicated by either subjective account or
observation made by others)
(3) significant weight loss when not dieting or weight gain (e.g., a change of
more than 5% of body weight in a month), or decrease or increase in appetite
nearly every day. Note: In children, consider failure to make expected weight
gains.
(4) insomnia or hypersomnia nearly every day
Major Depressive Episode
from DSM-IV TR (4th edition), 2000.
 (5) psychomotor agitation or retardation nearly every day (observable by
others, not merely subjective feelings of restlessness or being slowed
down)
(6) fatigue or loss of energy nearly every day
(7) feelings of worthlessness or excessive or inappropriate guilt (which may
be delusional) nearly every day (not merely self-reproach or guilt about
being sick)
(8) diminished ability to think or concentrate, or indecisiveness, nearly
every day (either by subjective account or as observed by others)
(9) recurrent thoughts of death (not just fear of dying), recurrent suicidal
ideation without a specific plan, or a suicide attempt or a specific plan for
committing suicide
Major Depressive Episode
from DSM-IV TR (4th edition), 2000.
 B. The symptoms do not meet criteria for a Mixed Episode.
C. The symptoms cause clinically significant distress or
impairment in social, occupational, or other important areas of
functioning.
D. The symptoms are not due to the direct physiological effects
of a substance (e.g., a drug of abuse, a medication) or a general
medical condition (e.g., hypothyroidism).
E. The symptoms are not better accounted for by Bereavement,
i.e., after the loss of a loved one, the symptoms persist for longer
than 2 months or are characterized by marked functional
impairment, morbid preoccupation with worthlessness, suicidal
ideation, psychotic symptoms, or psychomotor retardation.
Major Depressive Disorder, Single Episode
from DSM-IV TR (4th edition), 2000.
 A. Presence of a single Major Depressive Episode
 B. The Major Depressive Episode is not better accounted for by
Schizoaffective Disorder and is not superimposed on
Schizophrenia, Schizophreniform Disorder, Delusional Disorder,
or Psychotic Disorder Not Otherwise Specified.
 C. There has never been a Manic Episode, a Mixed Episode, or a
Hypomanic Episode. Note: This exclusion does not apply if all
the manic-like, mixed-like, or hypomanic-like episodes are
substance or treatment induced or are due to the direct
physiological effects of a general medical condition.
Major Depressive Disorder, Recurrent
from DSM-IV TR (4th edition), 2000.
 A. Presence of two or more Major Depressive Episodes.
 Note: To be considered separate episodes, there must be an interval of
at least 2 consecutive months in which criteria are not met for a Major
Depressive Episode.
 B. The Major Depressive Episodes are not better accounted for by
Schizoaffective Disorder and are not superimposed on Schizophrenia,
Schizophreniform Disorder, Delusional Disorder, or Psychotic Disorder
Not Otherwise Specified.
 C. There has never been a Manic Episode, a Mixed Episode, or a
Hypomanic Episode. Note: This exclusion does not apply if all the
manic-like, mixed-like, or hypomanic-like episodes are substance or
treatment induced or are due to the direct physiological effects or a
general medical condition.
Major Depressive Disorder, Recurrent
from DSM-IV TR (4th edition), 2000.
 Specify (for current or most recent episode):
Severity/Psychotic/Remission Specifiers
Chronic
With Catatonic Features
With Atypical Features
With Melancholic Features
With Postpartum Onset
 Specify
Longitudinal Course Specifiers (With and
Without Interepisode Recovery)
With Seasonal Pattern
Phases of Depression: Recovery is the goal!
 Acute phase: 6-12 weeks
 Continuation phase: 4-9
months
 Maintenance phase: 1 or
more years
Stahl, Essential
Psychopharmacology of
Depression and Bipolar
Disorder 2000.
Risk factors for Chronicity
 Prior history of multiple episodes: 50-85% of patients
will have more than one episode and likelihood of
additional episodes increases with each one
 Persistent Dysthymic Symptoms
 Comorbidity
Recurrence
 After first episode MDD, 50-60% chance of having
second episode
 After second episode, 70% chance of having third
 After third episode, 90% chance of having fourth
 Recurrence more likely if patients not treated to
Remission during given episode
Poor prognostic factors
 Psychotic/catatonic presentations
 Positive family history
 Death of near relative or partner/spouse
 Presence of disabled spouse
 Concurrent medical/psychiatric illness
 Substance abuse
Family history
 Depression is 1.5 to 3-fold times more common in
patients with 1st degree relative who suffers from the
disorder
 In twin studies, monozygotic twins have two-fold
greater concordance rates (50-70%) for MDD than
dizygotic twins (20-25%)
Suicide Risk Asssesment
Patterson et al., Psychosomatics 1983.
Proposed Model of Depression (from Mayberg, 1997)
 Limbic-Cortical Dysregulation
 Attentional and Cognitive Features of Illness: Dorsal Compartment
(neocortical and midline limbic elements: DLPFC, dorsal anterior
cingulate, inferior parietal cortex, striatum). Symptoms: Apathy,
Psychomotor Slowing, Impaired selective/directed attention and
executive function. Hypo-functioning in Depression.
 Vegetative/Somatic Aspects of Illness: sleep, appetite, libido,
endocrine. Ventral Compartment (paralimbic cortical, subcortical and
brainstem regions: HPA axis, insula, subgenual cingulate, and
brainstem). Over-active in depression.
 Rostral Cingulate: important regulatory role in overall network
facilitating interactions between dorsal and ventral components.
Manji et al., Nature
Medicine 2001.
5-HTT Gene Polymorphism
Caspi et al., 2003.
 Why do stressful experiences lead to depression in some people
but not in others?
 Individual’s response to environmental insults moderated by
genetic makeup.
 In a prospective-longitudinal study of a representative birth
cohort, a functional polymorphism in the promoter region of the
serotonin transporter (5-HTT) gene was found to moderate
influence of stressful life events on depression.
 Individuals with one or two copies of short allele of 5-HTT
promoter polymorphism exhibited more depressive symptoms,
diagnosable depression, and suicidality in relation to stressful
life events than individuals homozygous for long allele.
5-HTT Gene Polymorphism
Caspi et al., 2003.
Sleep Neurophysiology
 Decreased REM latency, increased REM density,
decreased non-REM sleep in 40% of outpatients and
80% of inpatients with MDD
Manji et al., Nature
Medicine 2001.
Neuroendocrine factors
 Hypothalamic-pituitary-adrenal
(HPA) axis implicated by
observations that severely
depressed patients fail to
suppress corticotrophinreleasing factor (CRF) and
serum cortisol in response to
dexamethasone challenge
(“suppression test”) and CSF
samples of depressed patients
contain increased CRF
concentrations.
Endocrine Review: Cushing Syndrome
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Hypercortisolism
Central obesity
Muscle wasting
Proximal muscle weakness
(difficulty getting up from
chair, going up stairs)
Easy bruisability
Moon facies
Buffalo hump
Weight gain
Hirsutism, hyperglycemia
 Screening: 24 hour urine
free Cortisol
Dexamethasone Suppression Test
 A normal result: decrease in cortisol levels upon
administration of low-dose dexamethasone.
 Results indicative of Cushing's Disease (Pituitary
adenoma causing increased ACTH production)
involve no change in cortisol on low-dose
dexamethasone, but inhibition of cortisol on highdose dexamethasone.
 If the cortisol levels are unchanged by low- and highdose dexamethasone then other causes of Cushing's
Syndrome must be considered with further work-up
needed.
Dexamethasone (continued)
ACTH
Cortisol
Interpretation
Undetectable or low
Not suppressed by low or
high doses.
Adrenal Cushing
syndrome. Adrenal mass
requires surgery.
Normal to elevated
Not suppressed by low or
high doses.
Ectopic ACTH.
Chest/Abdominal CT.
Mostly small cell lung
carcinoma. Surgery or
Ketoconazole if not a
surgical candidate.
Normal to elevated
Not suppressed by low,
suppressed by high dose.
Pituitary MRI to confirm
Pituitary Cushing
syndrome (Cushing’s
Disease)
Serotonin Synthesis
Tryptophan
Converted by:
Tryptophan Hydroxylase
5-hydroxytryptophan
Converted by:
Amino acid Decarboxylase
Serotonin
Breaks down to 5-HIAA
(5-Hydroxyindoleacetic acid)
Stahl and Wise,
CNS Spectrums
2008.
Dopamine Metabolism Steps
Phenylalanine
Phenylalanine
Hydroxylase
Tyrosine
Tyrosine
Hydroxylase
(rate-limiting)
DOPA
DOPA
Decarboxylase
Dopamine
Dopamine
Beta
Hydroxylase
Epinephrine
Phenylamine NMethyltransferase
Norepinephrine
Stahl and Wise,
CNS Spectrums
2008.
Stahl and Wise,
CNS Spectrums
2008
Desensitization of Neurotransmitter Receptors
Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder 2000.
 Amount of NT changes relatively rapidly after
antidepressant introduced.
 Clinical effect is delayed, as is desensitization, or down
regulation, of neurotransmitter receptors.
 Temporal correlation of clinical effects with changes in
receptor sensitivity has given rise to hypothesis that
changes in neurotransmitter receptor sensitivity may
mediate clinical effects of antidepressant drugs
(including tolerance to acute side effects of
medications).
Monoaminergic Effects of Common ADs
Stahl et. al., Prim Care
Companion J Clin
Psychiatry 2004.
MAOIs
Stahl and Felker, CNS Spectrums 2008.
 Brain MAO-A must be inhibited for antidepressant
efficacy to occur. This is the form of MAO that
metabolizes 5-HT and NE.
 MAO-A, along with MAO-B, also metabolizes DA, but
inhibition of MAO-A alone does not appear to lead to
robust increases in brain DA levels since MAO-B can
still metabolize DA.
MAOIs
Stahl and Felker, CNS Spectrums 2008.
 In the presence of a large amount of DA derived from
administration of a large dose of its precursor
levodopa, selective MAO-B inhibition is sufficient to
boost DA action in the brain.
 Two MAOIs, selegiline and rasagiline, when
administered orally in doses selective for inhibition of
MAO-B, are approved for use in patients with
Parkinson’s disease, but not effective at these selective
MAO-B doses as antidepressants.
MAOIs
Stahl and Felker, CNS Spectrums 2008.
 Perhaps most important role of MAO-B in
psychopharmacology is when it is inhibited
simultaneously with MAO-A. In that case, there is
robust triple monoaminergic boost of DA as well as 5HT and NE. Theoretically would provide most
powerful antidepressant efficacy across range of
depressive symptoms.
 MAO-A plus B inhibition is one of the few therapeutic
strategies available to increase DA in depression and,
therefore, to treat refractory symptoms of diminished
positive affect (theoretically) linked to DA deficiency.
MAOIs
Stahl and Felker, CNS Spectrums 2008.
 Reversible inhibitors of monoamine (RIMAs) have
potential of providing MAO-A inhibition with
decreased risk of a tyramine reaction.
 If someone taking a RIMA eats aged cheese high in
tyramine, as the tyramine is absorbed it will release
NE; however, this released NE will chase the reversible
inhibitor off the MAO-A enzyme, reactivating MAO-A
in the intestine, liver, and sympathomimetic neurons,
allowing destruction of the dangerous amines.
Phenelzine (Nardil, Nardelzine)
 Initial 45 mg/day in 3 divided doses; increase to 60-90
mg/day; after desired therapeutic effect achieved
clinician should lower the dose as far as possible.
Tranylcypromine (Parnate)
 Initial 30 mg/day in divided doses; after 2 weeks
increase daily dose by 10 mg every 1-3 weeks; max. 60
mg/day.
Isocarboxazid (Marplan)
 Initial 10 mg twice a day; increase daily dose by 10 mg
every 2-4 days; dosed 2-4 times/day; max. 60 mg/day.
Seligiline Transdermal System (EMSAM)
 Initial 6 mg/24 hours;
can increase by 3 mg/ 24
hours every 2 weeks.
 Maximum dose generally
12 mg/24 hours.
Moclobemide (Aurorix, Arima, Manerix)
 RIMA
 At higher doses,
 Initial 300 mg/day in 3
moclobemide also
inhibits MAO-B.
 Taking moclobemide
after meals may
minimize chances of
interactions with
tyramine.
divided doses after a
meal; increase dose
gradually; maximum
dose generally 600
mg/day; minimum dose
generally 150 mg/day.
Tertiary Amines
 Clomipramine
(Anafranil)
 Imipramine (Tofranil)
 Trimipramine
(Surmontil)
 Amitriptyline (Elavil)
 Doxepin (Sinequan)
 Two methyl groups at the
end of the side chain.
Clomipramine (Anafranil)
 FDA Approved for OCD.
 Dose: Initial 25 mg/day;
increase over 2 weeks to
100 mg/day to achieve
desired therapeutic
efficacy; max. dose
generally 250 mg/day.
 2D6 and 1A2 substrate.
 Monitoring of plasma
drug levels!
Imipramine (Tofranil)
 Initial dosing: Initial 25
mg/day at bedtime;
increase by 25 mg every 3-7
days.
 Usual therapeutic dose: 75100 mg/day once daily or in
divided doses; gradually
increase daily dose until
desired efficacy is
achieved.
 Max dose 300 mg/day
 2D6 and 1A2 substrate.
 Monitoring of plasma drug
levels!
 Metabolized to active
metabolite, desipramine,
by demethylation via
CYP450 1A2.
Trimipramine (Surmontil)
 Initial dosing: 25 mg/day at
bedtime; increase by 75 mg
every 3-7 days.
 Usual therapeutic dose: 75
mg/day in divided doses;
increase to 150 mg/day to
achieve desired efficacy.
 Maximum 200 mg/day
(hospitalized patients may
receive up to 300 mg/day).
 Substrate for CYP450 2D6, 2C19,
and 2C9. Half-life approx. 7-23
hrs.
Amitriptyline (Elavil)
 Initial dosing: 25 mg/day
at bedtime; increase by
25 mg every 3-7 days.
 Usual therapeutic dose:
75 mg/day in divided
doses; increase to 150
mg/day until desired
efficacy is achieved.
 Maximum 300 mg/day.
 2D6 and 1A2 substrate
Doxepin (Sinequan)
 Initial dosing: 25 mg/day at
bedtime; increase by 25 mg
every 3-7 days.
 Usual therapeutic dose: 75
mg/day; increase gradually
until desired efficacy
achieved; can be dosed
once a day at bedtime or
divided doses.
 Max dose: 300 mg/day.
 Substrate for 2D6, half-life
approx. 8-24 hours.
Secondary Amines
 Desipramine
(Norpramin, Pertofrane)
 Nortriptyline (Aventyl,
Pamelor)
 Protriptyline (Vivactil)
 More potent in blocking
the norepinephrine
transporter.
Desipramine (Norpramin)
 Initial dosing: 25 mg/day at
bedtime; increase by 25 mg
every 3-7 days.
 Usual therapeutic dose: 75
mg/day once daily or in
divided doses; gradually
increase dose to achieve
desired efficacy.
 Max. dose 300 mg/day.
 2D6/1A2 substrate. Halflife approx. 24 hours.
Active metabolite of
imipramine.
 Monitoring of plasma drug
levels!
Nortriptyline (Pamelor)
 Initial dosing: 10-25
mg/day at bedtime;
increase by 25 mg every 3-7
days; can be dosed once
daily or in divided doses
(max. 300 mg/day).
 2D6 substrate
 Nortriptyline is the active
metabolite of
Amitryptyline, formed by
demethylation via 1A2.
 Half-life approx. 36 hours.
 Monitoring of plasma drug
level well studied.
Protriptyline (Triptil, Vivactil)
 Initial dosing: 15 mg/day
in divided doses;
increase morning dose as
needed; maximum dose
60 mg/day.
 2D6 substrate
 Half-life approx. 74
hours.
Amoxapine (Ascendin)
 Derived from
neuroleptic loxapine.
 Potent NRI
 Blocks postsynaptic
dopamine receptors (has
anti-psychotic activity)
 2D6 substrate
 Half-life of parent drug 8
hours and active
metabolites 24 hours.
 Initial dosing: 25 mg/day split 2-
3 times/day; increase gradually
to 100 mg total either in split
doses 2-3 times/day or single
bedtime dose to achieve desired
efficacy. Max. 400 mg/day
(inpatient: 600).
Maprotiline (Ludiomil)
 Identical side chain to secondary
amines (potently blocks
norepinephrine transmitter).
 2D6 substrate, 51 hr. mean half
life, peak plasma concentration
8-24 hours.
 Initial 25 mg/day at bedtime;
increase by 25 mg every 3-7 days.
 Usual therapeutic dose: 75
mg/day; after 2 weeks increase
dose gradually by 25 mg/day to
achieve desired efficacy; max.
generally 225 mg/day.
Tricyclics: Potentially Fatal in Overdose!
 Anticholinergic effects: altered mental status (e.g., agitation, confusion,
lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation),
fever
 Cardiac effects: hypertension (early /transient, should not be treated),
tachycardia, orthostasis and hypotension, arrhythmias (such as ventricular
tachycardia and ventricular fibrillation, most serious consequence)/ECG





changes (prolonged QRS, QT and PR intervals)
CNS: syncope, seizure (convulsions), coma, myoclonus, hyperreflexia
Pulmonary effects: hypoventilation (resulting from CNS depression)
Gastrointestinal effects: decreased (or absent) bowel sounds
Metabolic Acidosis
Treatment: Supportive with ICU Monitoring. Role for Sodium Bicarbonate:
Tricyclics are highly protein bound, become less bound in more acidic
conditions. By reversing acidosis, protein binding increases /bioavailability
decreases. Alternative explanation: sodium load helps reverse Na+ channel
blocking effects of TCA.
Fluoxetine (Prozac)
 FDA approved for: MDD, OCD, Premenstrual
dysphoric disorder, Bulimia nervosa, Panic disorder,
Bipolar depression (in combination with olanzapine
[Symbyax])
 5HT2C antagonism could contribute to agitation,
anxiety, undesirable activation (especially early in
treatment)
 Initial dose 20 mg/day, wait a few weeks to assess drug
effects before increasing.
 Maximum dose generally 80 mg/day.
Fluoxetine (Prozac)
 Active metabolite (norfluoxetine) has 2 weeks half-life
 Parent drug has 2-3 day half life
 Inhibitor of CYP450 2D6 and 3A4
 May displace highly protein bound drugs such as
Warfarin
Paroxetine (Paxil and Paxil CR*)
 FDA Approved for: MDD *, OCD, Panic Disorder *, Social

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Anxiety Disorder *, PTSD, GAD, PMDD (only CR)
Mild anticholinergic actions, may have mild
norepinephrine reuptake blockade
MDD dose 20-50 mg/day (25-62.5 CR)
Higher dose for anxiety disorders
Dosage increments: increase by 50% once a week to achieve
desired therapeutic efficacy.
Withdrawal effects: many patients tolerate 50% dose
reduction for 3 days then another 50% reduction for three
days, then stop.
Half life: 24 hours
Inhibits CYP450 2D6, may displace warfarin
Sertraline (Zoloft)
 FDA approved: MDD,
PMDD, Panic disorder,
PTSD, Social anxiety
disorder, OCD
 Some ability to block
dopamine reuptake
pump
 Mild antagonist actions
at sigma receptors
 Generally does not
elevate prolactin
Sertraline (Zoloft)
 Dosage: 50 mg/day
 May increase weekly to max of 200 mg/day
 Parent drug has 22-36 hour half-life, metabolite half-
life 62-104 hours
 Inhibits 2D6 and 3A4 (weakly at low doses)
Fluvoxamine (Fluvox)
 FDA approved for OCD
 Has antagonist properties at sigma 1 receptors – may
explain potential advantages in psychotic depression
and delusional depression
 Dosage range 100-300 mg/day for OCD: initial 50
mg/day then increase every 4-7 days
 Parent drug has 9-28 hour half-life
 Inhibits 3A4, 1A2, 2C9/2C19
Enantiomers
Burke and Kratochvil, Prim Care Companion J Clin Psychiatry 2004.
 Stereoisomers have same chemical structure but
different spatial arrangement of substituent groups
around chiral center (e.g. carbon atom)
 Enantiomers = non-superimposable mirror image (like
R and L hand)
 Rotate plane-polarized light (+/−) by equal amounts
but in opposite directions
Citalopram (Celexa)
 FDA approved for Depression
 Mild antagonist actions at H1 histamine receptors
 Inactive R entantiomer may interfere with therapeutic
actions of active S enantiomer at serotonin reuptake
pumps
 Initial dose 20 mg/day, increase 20 mg/day weekly
until desired efficacy. Max usually 60 mg/day
Escitalopram (Lexapro)
 10 mg of escitalopram may be comparable in efficacy
to 40 mg of citalopram with fewer side effects
 Mean terminal half-life 27-32 hours
 Steady-state plasma concentrations achieved within 1
week
 No significant actions on CYP450 enzymes
Venlafaxine (Effexor XR)
 SNRI FDA Approved for Depression, GAD, Social
Phobia, Panic disorder
 Usual dose: 75-225 mg/day (start at 37.5 mg once daily
for a week, if tolerated increase by 75 mg every four
days until desired efficacy reached.
 Max dose generally 375 mg/day.
 Withdrawal symptoms upon discontinuation: taper
down slowly!
Duloxetine (Cymbalta)
 SNRI FDA approved for MDD, DPNP
 Initial 40 mg/day in 1-2 doses; can increase to 60
mg/day if necessary; max. 120 mg/day
 Elimination half-life 12 hours
 Metabolized mainly by 2D6 and 1A2
 Inhibits 2D6 (clinically significant)
Desvenlafaxine (Pristiq)
 SNRI FDA approved for
depression, usual dose
50 mg/day
 Unique feature:
Metabolism primarily by
conjugation in the liver
and, to a lesser extent,
oxidative metabolism
(independent of CYP
2D6)
Bupropion Extended Release
(Wellbutrin XL)
 NDRI FDA approved for MDD (Bupropion, Bupropion SR and
Bupropion XL) and Nicotine Addiction (Bupropion SR)
 Usual adult target dose for Wellbutrin XL is 300 mg/day (given once
daily in the morning). Dosing should begin at 150 mg/day given as a
single daily dose. If 150-mg initial dose is adequately tolerated, an
increase to the target dose (300-mg/day), given as once daily, may be
made as early as day 4 of dosing. Should be an interval of at least 24
hours between successive doses.
 Max dose: 450 mg/day
 Inhibits 2D6
Mirtazapine (Remeron)
 Alpha 2 antagonist; NaSSA (noradrenaline and specific serotonergic





agent); dual serotonin and norepinephrine agent.
FDA approved for MDD, usual dosage 15-45 mg.day
Blocks alpha 2 adrenergic presynaptic receptor (increase NE
neurotransmission)
Blocks alpha 2 adrenergic presynaptic receptor on serotonin neurons,
increasing serotonin transmission
Blocks 5HT2A (anxiolytic, sleep restoring, no sexual dysfunction),
5HT2C (anxiolytic, side effect of weight gain) and 5HT3 (no GI
problems or nausea) serotonin receptors and H1 receptors (anxiolytic,
weight gain, drowsiness)
Half-life 20-40 hours
Trazodone (Desyrel)




SARI (serotonin 2 antagonist/reuptake inhibitor)
FDA approved for depression
Metabolized by 3A4
Bi-phasic half-life; first phase 3-6 hours and second phase
5-9 hours
 For depression monotherapy, initial 150 mg/day in divided
doses; can increase every 3-4 days by 50 mg/day as needed;
max. 400 mg/day (outpatient) or 600 mg/day (inpatient)
split into two daily doses
 For insomnia, initial 25-50 mg at bedtime; increase as
tolerated usually to 50-100 mg/day
Trazodone ER (Oleptro)
 Recommended starting dose
of Oleptro is 150 mg once
daily in adults. Dose may be
increased by 75 mg/day every
three days (i.e., start 225 mg
on therapy Day 4). Maximum
daily dose should not exceed
375 mg.
Stahl et. al., Prim Care
Companion J Clin
Psychiatry 2004.
Serotonin Syndrome
 Clinical triad of abnormalities:
 Cognitive effects: agitation, headache,hypomania,
mental confusion, hallucinations, coma
 Autonomic effects: sweating, shivering,
hyperthermia, hypertension, tachycardia, nausea,
diarrhea
 Somatic effects: tremor, myoclonus (muscle
twitching), hyperreflexia (as manifested by clonus)
 Treatment: stop the offending agent! Supportive care and treat
hyperthermia/autonomic instability. Benzodiazepines for
myoclonus and agitation. Role for cyproheptadine.
Suicidality and Anti-depressant use
 FDA Black Box warning:
Suicidality and
Antidepressant use in
adolescents (under 19) and
young adults (19-24).
Antidepressant Discontinuation and Risk of Suicide Attempt
Valuck et al., JCP 2009.
 Retrospective, Nested Case-Control Study
 After adjusting for confounding due to depression severity,
comorbidities and other medications, antidepressant use showed
protective effect for suicide attempt (OR = 0.62, P < .001).
 Antidepressant Discontinuation had a significant risk for suicide
attempt compared to prior therapy (OR = 1.61, P < .05).
 Antidepressant initiation had highest risk for suicide attempt
(OR = 3.42, P < .05), followed by titration (titration up, OR =
2.62 and down, OR = 2.19; P < .05).
 Recommendation: patients should be closely monitored during
these periods!
Thase et al.,
Depression and Anxiety 2000.
Strategies for Treatment-Resistant Depression
Nelson, JCP 2007.
Switching
Combination or Augmentation
 Advantages: improved
 Combination: add another
compliance, reduced
medication cost, fewer drug
interactions
antidepressant, typically from
different class
 Augmentation: add second
pharmacologic agent not
generally used as
antidepressant, such as T3
(Cytomel)
 Advantages: rapid response,
No titration necessary, initial
improvements maintained
Strategies for Treatment-Resistant Depression
Nelson, JCP 2007.
 Bridging: addition of 2nd agent to enhance response. If
patient does well: first medication withdrawn and
continue patient on second medication.
Papakostas, CNS Spectrums 2009.
Heroic Combos
from Stahl’s Essential Psychopharmacology, 2009.
 1: High dose venlaxafine + mirtazapine = California rocket
fuel
2: High dose venlaxafine + NDRI (bupropion)
3: High dose venlaxafine + NRI (selective reboxetine or a
nonselective TCA such as desipramine, maprotilene,
nortriptyline, or protriptyline)
4: High dose venlaxafine + stimulant (e.g. d-amphetamine,
methylphenidate, phentermine, or diethylpropion
could also include direct-acting dopamine agonists such as
pramipexole)
Heroic Combos
from Stahl’s Essential Psychopharmacology, 2009.
 5: Venlaxafine + SARI
6: Mirtazapine + SSRI
7: Mirtazapine + NRI
(reboxetine)
8: Mirtazapine + NDRI
(bupropion)
9: Mirtazapine + stimulant
 10: SSRI + NRI (selective
reboxetine)
11: SSRI + NDRI (bupropion)
12: SSRI + stimulant
13: SARI + NDRI (bupropion)
Aronson et al., Arch. Gen. Psychiatry 1996.
Aronson et al., Arch. Gen. Psychiatry 1996.
Lithium Augmentation
Bauer et al., Canadian Journal of Psychiatry 2003.
Lithium Augmentation
Bauer et al., Canadian Journal of Psychiatry 2003.
Lithium Augmentation
Bauer et al., Canadian Journal of Psychiatry, 2003.
Modafanil (Provigil)
Stahl, JCP 2002.
 Neurotransmitters (hypocretin 1
and 2, orexin A and B) in lateral
hypothalamus mediate aspects
of sleep and arousal.
 Modafanil increases neuronal
activity in wake promoting
hypothalamic neurons and
decreases activity in sleep
promoting neurons.
 Dosage: 100 mg/day to 200
mg/day
Former NBA player Eric “Sleepy” Floyd
Modafanil (Provigil)
 Rare cases of SJS (Stevens
Johnson Syndrome), TEN (Toxic
Epidermal Necrolysis), DRESS
(Drug Rash with Eosinophilia
and Systemic Symptoms).
Discontinue medication at first
sign of rash.
 Rare cases of multi-organ
hypersensitivity.
Former NBA player Eric “Sleepy” Floyd
References
 American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders DSM-IV-TR Fourth Edition (Text Revision). American
Psychiatric Publishing, Inc.; 4th edition (June 2000).
 Aronson R., Offman H.J., Joffe R.T., Naylor D. Triiodothyronine Augmentation
in the Treatment of Refractory Depression: A Meta-Analysis. Arch Gen
Psychiatry 53: 842-848, 1996.
 Bauer M., Adli M., Baethge C., Berghofer A., Sasse J., Heinz A., Bschor T.
Lithium Augmentation Therapy in Refractory Depression: Clinical Evidence
and Neurobiological Mechanisms. Can J Psychiatry 48, 440-448, 2003.
 Burke W.J., Kratochvil C.J., Stereoisomers in Psychiatry: The Case of
Escitalopram. Prim Care Companion J Clin Psychiatry 4: 20-24, 2002.
 Caspi A., Sugden K., Moffitt T.E., Taylor A., Craig I.W., Harrington H., McClay
J., Mill J., Martin J., Braithwaite A., Poulton R. Influence of Life Stress on
Depression: Moderation by a Polymorphism in the 5-HTT Gene. Science 301:
386-389, 2003.
 Cassano P., Lattanzi L., Soldani F., Navari S., Battistini G., Gemignani A.,
Cassano G.B. Pramipexole in Treatment-Resistant Depression: An Extended
Follow-Up. Depression and Anxiety 20: 131-138, 2004.
References
 Hammad T.A., Laughren T., Racoosin J. Suicidality in Pediatric Patients
treated with antidepressant drugs. Archives of General Psychiatry 63: 332-339,
2006.
 Manji H.K., Drevets W.C., Charney D.S. The cellular neurobiology of
depression. Nature Medicine 7: 541-547, 2001.
 Mayberg H.S. ”Limbic-Cortical Dysregulation: A proposed model of
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Neuropsychiatry of Limbic and Subcortical Disorders (pp. 167-177). American
Psychiatric Press, Inc. Washington, D.C., London, England (1997).
 Nelson J.C., Managing Treatment-Resistant Major Depression. J Clin
Psychiatry 64 (supplement 1): 5-12.
 Nelson J.C., “Tricyclic and Tetracyclic Drugs.” In: Schatzberg A.F. and Nemeroff
C.B., Eds. Textbook of Psychopharmacology, Fourth Edition (pp.263-287).
Washington, D.C: American Psychiatric Publishing, 2009.
 Papakostas G.I., Switching Antidepressants vs. Conventional Augmentation
Strategies. CNS Spectrums 14 (Supplement 4): 11-14, 2009.
 Patterson W.M., Dohn H.H., Bird J., Patterson G.A. Evaluation of suicidal
patients: The SAD PERSONS Scale. Psychosomatics 24: 343-349, 1983.
References
 Rush J.A., Trivedi M.H., Wisniewski S.R., Nierenberg A.A., Stewart J.W.,
Warden D., Niederehe G., Thase M.E., Lavori P.W., Lebowitz B.D., McGrath P.J.,
Rosenbaum J.F., Sackeim H.A., Kupfer D.J., Luther J., Fava M. Acute and
Longer-Term Outcomes in Depressed Outpatients Requiring One or Several
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 Stahl S.M. Essential Psychopharmacology of Depression and Bipolar Disorder.
Cambridge University Press, 2000.
 Stahl S.M., Pradko J.F., Haight B.R., Modell J.G., Rockett C.B., LearnedCoughlin S. A Review of the Neuropharmacology of Buproprion, a Dual
Norepinephine and Dopamine Reuptake Inhibitor. Prim Care Companion J
Clin Psychiatry 6: 159-166, 2004.
 Stahl SM, Essential Psychopharmacology: Neuroscientific Basis and Practical
Applications. Cambridge (UK), Cambridge University Press; Third edition
(2008).
 Stahl S.M. and Felker A. Monoamine Oxidase Inhibitors: A Modern Guide to
an Unrequited Class of Antidepressants. CNS Spectrums 13: 855-70, 2008.
References
 Stahl S.M., Awakening to the Psychopharmacology of Sleep and
Arousal: Novel Neurotransmitters and Wake-Promoting Drugs. J. Clin.
Psychiatry 63: 467-468, 2002.
 Stahl S.M., Selective Histamine H1 antagonism: Novel Hypnotic and
Pharmacologic Actions Challenge Classical Notions of Antihistamines.
CNS Spectrums 13: 1-12, 2008.
 Stahl S.M., Wise D.D. The Potential of a Corticotropin Releasing
Factor-1 Antagonist in Psychiatric Disorders. CNS Spectrums 13: 467483, 2008.
 Stahl S.M., Essential Psychopharmacology: The Prescriber’s Guide
(Antidepressants), Cambridge University Press; 3rd edition, 2009.
References
 Stahl S.M., Mechanism of Action of Trazodone: A Multifunctional
Drug. CNS Spectrums 14: 536-546, 2009.
 Stahl, SM. Enhancing Outcomes from Major Depression: Using
Antidepressant Combination Therapies with Multifunctional
Pharmacologic Mechanisms from the Initiation of Treatment. CNS
Spectrums 15: 79-94, 2010.
 Thase M.E., Friedman E.S., Howland R.H. Venlafaxine and TreatmentResistant Depression. Depression and Anxiety 12 (supplement 1): 5562, 2000.
 Valuck R.J., Orton H.D., Libby A.M. Antidepressant Discontinuation
and Risk of Suicide Attempt: A Retrospective, Nested Case Control
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