Pharmacologic Treatment of Depression. Ten Leading Causes of Disability in the World Type of Disability Cost (in DALYs) Cumulative % of Cost Unipolar.

Pharmacologic Pharmacologic Treatment of Treatment of DepressionDepression

Ten Leading Causes of Ten Leading Causes of Disability in the WorldDisability in the World

Type of DisabilityType of Disability Cost (in Cost (in DALYs)DALYs)

CumulativCumulative %e %

of Costof Cost

Unipolar major depressionUnipolar major depression 42,97242,972 10.310.3

TuberculosisTuberculosis 19,67319,673 14.914.9

Road traffic accidentsRoad traffic accidents 19,62519,625 19.619.6

Alcohol useAlcohol use 14,84814,848 23.223.2

Self-inflicted injuriesSelf-inflicted injuries 14,64514,645 26.726.7

Bipolar DisorderBipolar Disorder 13,18913,189 29.829.8

WarWar 13,13413,134 32.932.9

ViolenceViolence 12,95512,955 36.036.0

SchizophreniaSchizophrenia 12,54212,542 39.039.0

Iron deficiency anemiaIron deficiency anemia 12,51112,511 42.042.0

Antidepressants - Antidepressants - HistoryHistory

19581958Monoamine oxidase inhibitors (MAOIs)Monoamine oxidase inhibitors (MAOIs) 1958 Tricyclics (TCA’s)1958 Tricyclics (TCA’s) 19821982Trazodone (Deseryl)Trazodone (Deseryl) 19881988Fluoxetine (Prozac)Fluoxetine (Prozac) 19891989Bupropion (Wellbutrin)Bupropion (Wellbutrin) 19941994Nefazodone (Serzone)Nefazodone (Serzone) 19941994Venlafaxine (Effexor)Venlafaxine (Effexor) 1996 1996 Mirtazapine (Remeron)Mirtazapine (Remeron)

Treatment Response Treatment Response CategoriesCategories

STATESTATE OBJECTIVE OBJECTIVE CRITERIONCRITERION

CLINICAL CLINICAL STATUSSTATUS

PREVALENCPREVALENCE IN RCTSE IN RCTS

RemissioRemissionn

HAM-D HAM-D ≤ 7≤ 7 No residual No residual psychopathologypsychopathology

~ 40%~ 40%

ResponseResponse ≥ ≥ 50% 50% decrease in decrease in HAM-D without HAM-D without remission remission

Substantially Substantially improved, but with improved, but with residual sxsresidual sxs

~ 25%~ 25%

Partial Partial responseresponse

25%-50% 25%-50% decrease in decrease in HAM-D HAM-D

Mild-moderate Mild-moderate improvementimprovement

~ 10%~ 10%

NonresponsNonresponsee

< 25% < 25% decrease decrease

in HAM-Din HAM-D

No clinically No clinically meaningful meaningful responseresponse

~ 25%~ 25%

Efficacy vs Efficacy vs EffectivenessEffectiveness

Fig. 1. Survival analysis of weeks to major depressive episode relapse (MDE): comparing patients with unipolar major depressive disorder who recovered from intake MDE with residual subsyndromal depressive symptoms vs. asymptomatic status. Wilcoxon Chi Square Test of Difference=47.96;

P<0.0001.

Why Is Achieving Why Is Achieving Remission Important?Remission Important?

Residual symptoms put patients at high risk Residual symptoms put patients at high risk of relapse and recurrenceof relapse and recurrence– Patients with residual symptoms after Patients with residual symptoms after

medication treatment are 3.5 times more medication treatment are 3.5 times more likely to relapse compared to those fully likely to relapse compared to those fully recovered (Judd et al, 1998)recovered (Judd et al, 1998)

– This risk is greater than the risk associated This risk is greater than the risk associated with having with having ≥ 3 prior depressive episodes≥ 3 prior depressive episodes

– Similar finding exists after response to Similar finding exists after response to cognitive therapycognitive therapy

Major DepressionMajor Depression

•Syndromal classification with Syndromal classification with disturbances of mood, disturbances of mood, neurovegetative and cognitive neurovegetative and cognitive functioningfunctioning

Major DepressionMajor Depression

At least 5 of the following symptoms At least 5 of the following symptoms present for at least 2 weeks (either present for at least 2 weeks (either #1 or #2 #1 or #2 mustmust be present): be present):

1) depressed mood1) depressed mood

2) anhedonia – loss of interest or 2) anhedonia – loss of interest or pleasurepleasure

3) change in appetite3) change in appetite

4) sleep disturbance4) sleep disturbance

Major DepressionMajor Depression

5) psychomotor retardation or 5) psychomotor retardation or agitation agitation

6) decreased energy6) decreased energy

7) feeling of worthlessness or 7) feeling of worthlessness or inappropriate guiltinappropriate guilt

8) diminished ability to think or 8) diminished ability to think or concentrateconcentrate

9) recurrent thoughts of death or 9) recurrent thoughts of death or suicidal suicidal ideationideation

Major DepressionMajor Depression•Symptoms cause marked distress Symptoms cause marked distress

and/or and/or impairment in social or occupational impairment in social or occupational functioning.functioning.

•No evidence of medical or substance-No evidence of medical or substance-induced etiology for the patient’s induced etiology for the patient’s symptoms.symptoms.

•Symptoms are not due to a normal Symptoms are not due to a normal reaction to the death of a loved one.reaction to the death of a loved one.

Special Diagnostic Special Diagnostic ConsiderationsConsiderations

BereavementBereavement Late life onsetLate life onset SubtypesSubtypes Cluster B personality disordersCluster B personality disorders

Bereavement and Bereavement and Late Life DepressionLate Life Depression

•25 – 35% of widows/widowers meet 25 – 35% of widows/widowers meet diagnostic criteria for major diagnostic criteria for major depressive disorder at 2 months.depressive disorder at 2 months.

•~15% of widows/widowers meet ~15% of widows/widowers meet diagnostic criteria for major diagnostic criteria for major depressive disorder at one year.depressive disorder at one year.

•This figure remains stable This figure remains stable throughout the second year.throughout the second year.

Subtypes of DepressionSubtypes of Depression

•AtypicalAtypicalReverse neurovegetative Reverse neurovegetative symptomssymptoms

Mood reactivityMood reactivityHypersensitivity to rejectionHypersensitivity to rejectionMAO-I’s and SSRI’s are more MAO-I’s and SSRI’s are more effective treatmentseffective treatments

Subtypes of DepressionSubtypes of Depression

Psychotic (~10% of all MDD)Psychotic (~10% of all MDD)•Delusions common, may Delusions common, may have hallucinationshave hallucinations

•Delusions usually mood Delusions usually mood congruentcongruent

•Combined antidepressant Combined antidepressant and antipsychotic therapy or and antipsychotic therapy or ECT is necessaryECT is necessary

Subtypes of DepressionSubtypes of Depression

MelancholicMelancholic•No mood reactivityNo mood reactivity•AnhedoniaAnhedonia•Prominent neurovegetative Prominent neurovegetative disturbancedisturbance

•More likely to respond to More likely to respond to biological treatmentsbiological treatments

Subtypes of DepressionSubtypes of Depression

CatatonicCatatonic•Motoric immobility Motoric immobility (catalepsy)(catalepsy)

•MutismMutism•Ecolalia or echopraxiaEcolalia or echopraxia

What is the course What is the course of antidepressant of antidepressant response?response?

Why a temporal delay Why a temporal delay for maximal for maximal therapeutic benefittherapeutic benefit

-adrenergic receptor down--adrenergic receptor down-regulationregulation

5-HT5-HT22 receptor down-regulation receptor down-regulation

Tricyclic Tricyclic Antidepressants Antidepressants (TCAs)(TCAs) Characteristic three-ring nucleus Characteristic three-ring nucleus

Clinical effectsClinical effects Normalization of mood and resolution of Normalization of mood and resolution of

neurovegetative symptomsneurovegetative symptoms Biochemical effectsBiochemical effects

Inhibit monoamine uptake at nerve Inhibit monoamine uptake at nerve terminalsterminals

May potentiate action of drugs that cause May potentiate action of drugs that cause neurotransmitter releaseneurotransmitter release

Temporal delay of weeks for clinical effects, Temporal delay of weeks for clinical effects, although biochemical effects are immediatealthough biochemical effects are immediate

Mechanism of action of Mechanism of action of TCAsTCAs

“Tertiary” TCAs Inhibit 5-HT uptakeimipramine (weaker inhibition of NE uptake)amitriptyline

clomipramine

“Secondary” TCAs Inhibit NE uptakedesipramine (weaker inhibition of 5-HT uptake)nortriptyline

TCA Metabolism

N

CH3H3C

N

N

CH3H3C

N

N

CH3H

N

CH3H

nortriptyline

imipramine

amitriptyline

desipramine

tertiary amines secondary amines

In vivo action of TCAsIn vivo action of TCAs

If one administers a tertiary TCA there is always both the tertiaryand the secondary amine in thecirculation

If one administers a secondary TCA there is only the secondary amine in the circulation.

Neuropharmacology of Neuropharmacology of TCAsTCAs Inhibit monoamine uptake (NE and 5-Inhibit monoamine uptake (NE and 5-

HT)HT)

Muscarinic cholinergic antagonismMuscarinic cholinergic antagonism

HH11 histamine antagonism histamine antagonism

11-adrenergic antagonism-adrenergic antagonism

Tricyclics-Tricyclics-Contraindications Contraindications QTc greater than 450 msec QTc greater than 450 msec Conditions worsened by Conditions worsened by

muscarinic blockade (eg muscarinic blockade (eg myasthenia gravis, BPH)myasthenia gravis, BPH)

pre-existing orthostatic pre-existing orthostatic hypotensionhypotension

Seizure disorderSeizure disorder

Side effect profile of Side effect profile of TCAsTCAs Dry mouthDry mouth ConstipationConstipation DizzinessDizziness TachycardiaTachycardia Urinary retentionUrinary retention Impaired sexual funtionImpaired sexual funtion Orthostatic hypotensionOrthostatic hypotension

Low therapeutic index Low therapeutic index of TCAsof TCAs Cardiotoxicity: resulting from combination of:Cardiotoxicity: resulting from combination of:

Conduction defects, arrhythmiasConduction defects, arrhythmias DeliriumDelirium

Potentiation of effects of other sedating drugsPotentiation of effects of other sedating drugs ConsequencesConsequences

suicidesuicide requires care in prescribingrequires care in prescribing monitoring drugs that might have monitoring drugs that might have

synergistic effects on monoamine functionsynergistic effects on monoamine function

Monoamine Oxidase Monoamine Oxidase Inhibitors (MAOIs)Inhibitors (MAOIs)

Irreversibly inhibit monoamine Irreversibly inhibit monoamine oxidase enzymesoxidase enzymes

Effective for major depression, Effective for major depression, panic disorder, social phobiapanic disorder, social phobia

Drug interactions and dietary Drug interactions and dietary restrictions limit userestrictions limit use

Biochemistry of MAOBiochemistry of MAO

Occurs as two isoenzymesOccurs as two isoenzymes MAO-A – MAO-A –

• Oxidizes norepinephrine, Oxidizes norepinephrine, serotonin, tyramineserotonin, tyramine

MAO-B MAO-B selective for dopamine selective for dopamine metabolismmetabolism

Dietary and Drug Dietary and Drug InteractionsInteractions Increased stores of catecholamines sensitize Increased stores of catecholamines sensitize

patients to effects of sympathomimeticspatients to effects of sympathomimetics Accumulation of tyramine (sympathomimetic) = Accumulation of tyramine (sympathomimetic) =

high risk of hypertensive reactions to dietary high risk of hypertensive reactions to dietary tyraminetyramine requires dietary restrictionsrequires dietary restrictions

Interactions with other sympathomimetic drugsInteractions with other sympathomimetic drugs AntidepressantsAntidepressants OTC cold remediesOTC cold remedies

• phenylpropanolaminephenylpropanolamine MeperidineMeperidine L-dopa L-dopa

Examples of MAOIsExamples of MAOIs Irreversible, non-selective MAOIsIrreversible, non-selective MAOIs

phenelzine phenelzine isocarboxazidisocarboxazid tranylcypromine tranylcypromine

SSelective MAO-Belective MAO-B inhibitors inhibitors deprenyl deprenyl (selegiline)(selegiline) loses its specificity for MAO-B in antidepressant loses its specificity for MAO-B in antidepressant

dosesdoses Reversible monoamine oxidase inhibitors Reversible monoamine oxidase inhibitors

(RIMAs)(RIMAs) Moclobemide – not approvedMoclobemide – not approved Appears to be relatively free of food/drug Appears to be relatively free of food/drug

interactionsinteractions

Serotonin syndromeSerotonin syndrome

Evoked by interaction between serotonergic Evoked by interaction between serotonergic agentsagents e.g., SSRIs and MAOIse.g., SSRIs and MAOIs Combination of increased stores plus inhibition Combination of increased stores plus inhibition

of reuptake after releaseof reuptake after release SymptomsSymptoms

HyperthermiaHyperthermia Muscle rigidityMuscle rigidity MyoclonusMyoclonus Rapid changes in mental status and vital signsRapid changes in mental status and vital signs

Can be lethalCan be lethal

Selective Serotonin Selective Serotonin Uptake InhibitorsUptake Inhibitors(SSRIs)(SSRIs)

Currently marketed medicationsCurrently marketed medications fluoxetine (Prozac).fluoxetine (Prozac). sertraline (Zoloft).sertraline (Zoloft). paroxetine (Paxil)paroxetine (Paxil) fluvoxamine (Luvox)fluvoxamine (Luvox) citalopram (Celexa)citalopram (Celexa) escitalopram (Lexapro)escitalopram (Lexapro)

Selectively inhibit 5-HT (not NE) uptakeSelectively inhibit 5-HT (not NE) uptake Differ from TCAs by having little affinity for Differ from TCAs by having little affinity for

muscarinic, as well as many other neuroreceptorsmuscarinic, as well as many other neuroreceptors

Selective Serotonin Selective Serotonin Uptake InhibitorsUptake Inhibitors(SSRIs)(SSRIs)

Much higher therapeutic index than Much higher therapeutic index than TCAs or MAO-I’sTCAs or MAO-I’s

Much better tolerated in early Much better tolerated in early therapytherapy

Equal or almost equal in efficacy to Equal or almost equal in efficacy to TCAsTCAs

Side effects associated Side effects associated with SSRIswith SSRIs

NauseaNausea Sexual dysfunctionSexual dysfunction

Delayed Delayed ejaculation/anorgasmiaejaculation/anorgasmia

AnxietyAnxiety InsomniaInsomnia

Selective Norepinephrine-Selective Norepinephrine-Serotonin Reuptake Serotonin Reuptake InhibitorsInhibitors

VVenlafaxine (Effexor)enlafaxine (Effexor) Duloxetine Duloxetine (Cymbalta)(Cymbalta): : relatively devoid of relatively devoid of

antihistaminergic, anticholinergic, antihistaminergic, anticholinergic, and antiadrenergic propertiesand antiadrenergic properties

nonselectivenonselective inhibitor of both NE and inhibitor of both NE and 5-HT uptake.5-HT uptake.

Adverse effects: GI , Sexual Adverse effects: GI , Sexual dysfunction, hypertension dysfunction, hypertension (venlafaxine)(venlafaxine)

Other antidepressantsOther antidepressants Trazodone Trazodone

mixed 5-HT agonist/antagonistmixed 5-HT agonist/antagonist 1 1 antagonistantagonist• HH11 antagonist antagonist

Nefazodone (Serzone)Nefazodone (Serzone) 5 HT5 HT22 antagonist antagonist

Bupropion (Wellbutrin; Zyban)Bupropion (Wellbutrin; Zyban) Inhibits uptake of DA and NEInhibits uptake of DA and NE antismoking properties probably involves parent antismoking properties probably involves parent

moleculemolecule Lacks sexual side effectsLacks sexual side effects Seizure riskSeizure risk

Mirtazapine (Remeron)Mirtazapine (Remeron) 2 2 antagonistantagonist 5H5H2 2 and 5HTand 5HT33 antagonist antagonist Net effect selective increase in 5HTNet effect selective increase in 5HT1A1A

functionfunction HH11 antagonist antagonist

advantages: sedation, no adverse sexual advantages: sedation, no adverse sexual effectseffects

Antidepressants and Antidepressants and drug interactionsdrug interactions PharmacodynamicPharmacodynamic

– Additive effects with alcohol and other sedating Additive effects with alcohol and other sedating drugsdrugs

– MAOI interactionsMAOI interactions Pharmakokinetic Pharmakokinetic

– Cytochrome P450-2D6 inhibitionCytochrome P450-2D6 inhibition Fluoxetine and paroxetineFluoxetine and paroxetine Increased levels of TCAs, antipsychotics, Increased levels of TCAs, antipsychotics,

warfarinwarfarin– Cytochrome P450-3A4 inhibitionCytochrome P450-3A4 inhibition

Nefazodone and fluvoxamineNefazodone and fluvoxamine Increased levels of terfenadine, astemizole, Increased levels of terfenadine, astemizole,

cisapride – can cause fatal arrhythmiascisapride – can cause fatal arrhythmias

Other uses for antidepressantsOther uses for antidepressants Panic DisorderPanic Disorder Obsessive Compulsive DisorderObsessive Compulsive Disorder

Only the ADs that inhibit serotonin Only the ADs that inhibit serotonin reuptakereuptake

Social PhobiaSocial Phobia Post Traumatic Stress DisorderPost Traumatic Stress Disorder Premenstrual Dysphoric DisorderPremenstrual Dysphoric Disorder Chronic pain syndromesChronic pain syndromes

TreatmentTreatment

CourseCourse One episode – 50% chance of One episode – 50% chance of

reoccurencereoccurence Two episodes – 70% chance of Two episodes – 70% chance of

reoccurencereoccurence Three or more episodes - >90% Three or more episodes - >90%

chance of reoccurence chance of reoccurence

When Do You When Do You Characterize a Response Characterize a Response As Treatment Resistant?As Treatment Resistant?

After a patient has been on an antidepressant at for After a patient has been on an antidepressant at for a reasonable amount of timea reasonable amount of time at at an adequate dosean adequate dose

No commonly accepted time pointNo commonly accepted time point– Most drug trial data comes from 8 week long Most drug trial data comes from 8 week long

studiesstudies– If no onset of response by weeks 4 or 6, there is If no onset of response by weeks 4 or 6, there is

a 73-88% chance of not having onset of response a 73-88% chance of not having onset of response by end of 8 wk trial (Nierenberg et al, 2000), so 4 by end of 8 wk trial (Nierenberg et al, 2000), so 4 weeks is a reasonable point to increase doseweeks is a reasonable point to increase dose

– An An 8-12 week course8-12 week course is consistent with acute is consistent with acute treatment framework and allows patients 8 treatment framework and allows patients 8 weeks at a dose expected to produce responseweeks at a dose expected to produce response