The Antidepressants

Eric Levander, MD, MPHUCLA Mood Disorders Research Program

levander@ucla.edu

Objectives• Appropriately prescribe medications for depression.• Manage the patient with depression from diagnosis, through

treatment, to a goal of remission.• Understand the uses of psychotherapy for treatment of

depression.

You have just started your medicine rotation inyour first year of residency in the outpatientcontinuity clinics. You have just started noticing acurious pattern.

Your current patient is an overweight 50-year-oldwoman with NIDDM, who is here for a follow-upappointment for a workup for fatigue. Her lastresident had ordered a CBC, Chem-7, B12 and TSH.All are normal except for an elevated blood sugar of221. On further questioning it seems she oftenforgets to take her medications, feels like she has noenergy and feels “blah” most of the time, and has ahard time falling asleep.

What information can help you appropriately diagnose andtreat this woman?

What pathophysiological mechanisms could be at play?

Depression:The Cost to Society

• Major health problem in the U.S.• 18 million office visits/yr• 100 million prescriptions/yr• “Clinical paradox” -- only 1 of 3 patients

accurately diagnosed• Economic costs: $44 billion/yr• Lifetime prevalence: 17 %• 8 million cases of major depressive disorder per

year

Top 10 Treatment ClassesRank US Sales ($ x 106)1. Statins 11,2912. PPI 10,2433. SSRI/ SNRI 9,8614. Antipsychotics 5,3745. Erythropoietan 5,1256. Cox-2 Inhibitor 4,7087. CCB 4,6008. Seizure meds 4,5599. Antihistamine 4,33810. ACEI 3,760

IMS Health Data, 2002

Depression:Psychopharmacology

Monoamine NeurotransmitterDeficiency Hypothesis• Serotonin (5-HT)• Norepinephrine (NE)• Dopamine (D)

Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder

Depression:Psychopharmacology

Action dependent on location and subtypeSerotonin:• Headquartered in raphe nucleus• 13 different subtypes

– pre-synaptic 5HT-1A, 1D– post-synaptic 5HT-1A, 1D, 2A, 2C, 3, 4

Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder, 2000

Antidepressants: Mechanism ofAction

Serotonergic cell bodies headquartered inraphe nucleus with projections to:

• Frontal cortex -- mood• Basal ganglia -- obsessive/comp (5HT-2A)• Limbic area -- anxiety and panic (2A, 2C)• Spinal column -- sexual response• GI tract -- motility (5HT-3 & -4)• Hypothalmus -- sleep, vomit (5HT-3)• Sleep center (5HT-2A)

Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder, 2000

Depression:Psychopharmacology

Receptor subtypes and locationNorepinephrine:• 10 different subtypes, alpha-1 & 2 and beta-1• Projections

– frontal cortex (mood),– limbic area (emotions, energy)– brainstem (blood pressure)

Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder, 2000

Depression:Psychopharmacology

Dopamine:• 5 different subtypes of receptors• Not well-characterized

Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder, 2000

Depression:Key Receptors

Post-synaptic receptors5HT-2A: activation results in depression, anxiety,insomnia

Pre-synaptic receptors:5HT-1A & -1D; α-2 NE: release ofneurotransmitter

Stahl, Essential Psychopharmacology of Depression and Bipolar Disorder, 2000

• You ask your patient about several othersymptoms of depression. She starts cryingand reports sadness, passive suicidalideations, late insomnia with terriblesadness in the morning, guilt and recent tenpound weight loss.

• What medication would you start her on?• What side effects might she expect?

Depression Management

Pharmacotherapy:• Proven effectiveness in patients with Major Depressive Disorder Dysthymia

ACP-ASIM Position Paper, Ann Intern Med 2000;132:738); Williams, JAMA2000;284:1519; Barrett et al, J Fam Pract 2001;50:405

Antidepressant Therapy• SSRI• Bupropion• SNRIs: Duloxetine, Venlafaxine• Mirtazapine• Nefazodone• Cyclics: tricyclics and tetracyclics (maprotiline,

amoxapine)

• MAOI: phenelzine (Nardil), tranylcypromine (Parnate),isocarboxacid (Marplan)

Which AD toStart?

Depression ManagementPharmacotherapy:• 50 to 70% effective

• Selection factors: prior response to agent anticipated side effects concomitant illness potential for drug interactions family history of response patient desire cost

Antidepressants:Therapeutic Action

ACTION TCA BUPRO SSRI VNLFX NFZD MRTZP

NE reuptake inhibition + + 0 ++ + 05-HT reuptake inhibition ++ 0 +++ ++ + 0Dopamine reuptake inhibition 0 + 0 0 0 0alpha-2 NE receptor blockade 0 0 0 0 0 ++5HT-2A receptor blockade + 0 0 0 ++ ++

TCA = Amitriptyline Vnlfx = VenlafaxineBupro = Bupropion Nfzd = NefazadoneSert = Sertraline Mrtzp = Mirtazapine

Not All SSRI’s Are Equal

Depression:Guide to Use of ADs

• Start at low initial dose, titrate up to targetdose over 5 to 10 days

• At 4 weeks, if no or partial response andside effects tolerable, increase dose; if sideeffects intolerable or no response, switchAD or add adjunctive Rx

• Full therapeutic effect may not be evidentfor 4 to 6 weeks

SSRIs• 1st line therapy -- ease in prescribing and superior

side effect profile• Fluoxetine, sertraline, paroxetine, fluvoxamine,

citalopram, escitalopram– All have similar side effects and efficacy; but failure with

one doesn’t mean failure on another• Side effects: nausea*, H/A*, insomnia*,

anxiety/agitation*, sedation, sexual dysfunction(desire, arousal, orgasm)

* May resolve themselves after 10-14 days

SSRIs

• Young patients, on no other medications,no problem…

• Older patients, with poly-pharmacy, becareful, there is a lot to keep track of …

Fluoxetine

• AM dosing: activating• qd dosing, though may give divided• Response in 2 to 4 wks• T ½: 9 days for metabolite

– !! MAO-I: wait 5-6 wks prior to starting• Response to as low as 5 mg/d• Can cause akathesia

Fluoxetine: Pregnancy

• Most data for depression in pregnancy:fluoxetine– 128 women 10-80 mg (mean 25.8 mg) no

difference of malformations c/w TCA and withnonteratogenic drugs

– Higher non-significant miscarriage rate (13.5vs. 12.2 v. 6.8) ? If from drugs vs. depression

More SSRI

• Sertraline– More GI (Nausea, diarrhea, upper GI)– Less activating– May be good for nursing moms

• Paroxetine– Possible less manic flips– Most anticholinergic: constipation, sedation– Most risk of weight gain– Withdrawal– P450 2D6: Watch with Warfarin

More SSRI

• Citalopram/ Escitalopram– Most selective SSRI– Fewest drug-drug interactions

• Fluvoxamine– Approved for OCD only– High rates of nausea and vomiting compared

with other SSRI– Inhibits P450 1A2, 2C9, and 3A4

SSRIs: Half-Lives

• Fluoxetine 1-4 daysNorfluoxetine 7-9 days

• Sertraline 26 hours– Less active metabolite 70 hours

• Paroxetine 21 hours• Fluvoxamine 16 hours• Citalopram 35 hours

Antidepressants and Suicide• Antidepressants: black box warning for < 18• Pooled analyses for PC-drug trials in kids of 9

drugs (> 4400 patients)– greater risk of adverse events representing suicidal

behavior or thinking in 1st months of treatment– average risk on drug: 4%, placebo risk: 2%

• JAMA, 2004– non-significant risk for suicidality increased in

fluoxetine, paroxetine in English patient registry of159,810 patients

– 15 adolescent suicides, none on any drug.

SSRI’s and Suicide

• What to do?– Follow your patients closely!– Rule out bipolar disorder– Look for increasing agitation or panic attacks

Serotonin Syndrome• combination of mental, neurologic, and autonomic

findings• Symptoms: changes in mental status, myoclonus,

rigidity, autonomic instability, fever, tachycardia,diarrhea, flushing, elevated WBC, CK

• Rarely, rhabdomyolysis, arrhythmias and death• Stop meds!• Hydrate!• IV lorazepam, ? dantrolene

Bodner et al, Neurology 1995;45:219

Discontinuing SerotonergicAntidepressants

• Taper by 20% every 1 to 2 weeks*• Too rapid tapering FLUSH

F: flu-like symptoms, nauseaL: light-headedness, dizzinessU: uneasiness, rebound mood/anxietyS: sleep disturbanceH: headaches & dysesthesia

Watch for in venlafaxine and paroxetinePreskorn, Clinical Cornerstones* Except for fluoxetine

Switching Antidepressants

• Within class vs. across class• Studies show 50% response to 2nd SSRI

– Poor methodology• Standard practice: Try 1 or 2 SSRIs before

switching class

Venlafaxine

• Less than 150mg acts as a simple SSRI• 150 –300 mg SNRI• > 300 mg possible dopamine• SE: similar to standard SSRI’s (including

sexual side effects) except also worry aboutblood pressure and discontinuation

• Some controversy about whether moreefficacious than SSRI’s

Case Study

Your patient calls one day to complain ofnausea and lightheadedness. You have hercheck her blood pressure and drink somewater.

You are shortly paged from the ER. Yourpatient has seized. What went wrong?

SSRI and Hyponatremia• All SSRI’s are associated with SIADH• Mechanism may be via increased vasopressin secretion• Average age of patients is over 70• Some reported risk factors: advanced age, female gender,

concomitant use of medications known to cause SIADH orhyponatremia, and, possibly, higher doses

• Usually occurs within 2 wks of initiation, although ¼present more than 3 months after starting on SSRI therapy.

Case Study

Her depression improves, but three monthsinto treatment she reports sexualdysfunction with reduced libido andanorgasmia.

What are your options for managing thisproblem?

Management ofSexual Dysfunction

• Watchful waiting• Reduce dose• Drug holiday• Bupropion• Buspirone 15 to 30 mg BID• Sildenafil 50 to 100 mg

Sexual Dysfunction (con’t)• Cyproheptadine** (5HT-2A antagonist):

4 to 16 mg qhs• Yohimbine** (α-2 adrenoreceptor

antagonist): 5.4 mg before prn or 5.4 mgTID

• Gingko biloba**: 60 to 240 mg/d

** all anecdotal

Sexual Dysfunction (con’t)Switch to a antidepressant with a lesser

potential for causing sexual dysfunction: mirtazapine nefazodone bupropion

Case Study

Your patient returns for a follow-upappointment. She reports that her mood isback to normal, her libido has improved,but she is still having almost nightlyproblems with middle insomnia.

What options do you have?

Management of Insomnia• Ensure good sleep hygiene• Take medication in AM• Add trazodone 50 to 200 mg qhs• Consider buspirone 10 to 20 mg

BID/TID, if anxiety• Zolpidem, zaleplon• Switch to more sedating AD

Bupropion

• Structurally related to amphetamine• Start SR: 100 mg BID or XL 150 qam• SE: agitation, restlessness, insomnia,

anxiety, GI, rarely rash• Seizures: (0.4%), mostly in patients with

bulimia, seizure history or above 450 mg• Good for anergic, hyperphagic, no libido

patients who smoke

Trazadone

• Acts as a 5HT2 antagonist• Also worry about mCPP• Rapid onset, short half life• Antidepressant doses from 400-600• Great for insomnia• Watch for sedation, hypotension, nausea,

and of course, priapism

Nefazodone• Like trazadone but not as sedating, no priapism,

and has a 1/250,000 patient-year risk of liverfailure

• 5-HT2 serotonin blocker• SE: headache, dry mouth, dizziness, nausea, and

above 450 mg palinopsia. Doesn’t effect sex• Effective doses are > 450 mg• mCPP (major metabolite) induced anxiety in 5-

10% with p450 deficiency in 2D6• Potent 3A4 inhibitor• Start at 50 mg a day and advance slowly!

Mirtazapine

• 5-HT2A and 5-HT2C receptor antagonistand alpha2 autoreceptor antagonist (alsoantihistamine and 5HT3.

• SE: sedation, weight gain, neutropenia,agranulocytosis

TCA• Still useful

– ? If more helpful for melancholic depression• Prior to starting

– ECG in anyone > 40 or known cardiac hx– Avoid in anyone with BBB, QTc > 450 msec

• Tertiary amine TCA’s have more potent 5-HTreuptake inhibition– More side effects that secondary amines

• Secondary amine TCA’s are more potent NEreuptake inhibitors– Desipramine and protriptyline: more activating– Nortriptyline: least orthostatic hypotension

TCAs• 2nd line therapy• Side effects: anticholinergic (dry mouth, constipation,

urinary retention, blurred vision, confusion & hallucinationrisk in elderly); orthostatic hypotension: antihistamine(sedation, weight gain); less a problem with desipramine &nortriptyline

• Low therapeutic index• Remember that amoxapine can cause EPS

TCA’s

• Starting doses– Nortriptyline: Twice as potent as other TCA’s:

25 mg qhs for 3-4 days and increase by 25-50mg q 3-4 days. Target 75-100 mg for bloodlevel of 50-150 ng/ml. Therapeutic window.

– Desipramine: 25-50 mg qam for 3-4 days andincrease by 25-50 mg q 3-4 days. Blood level >125 ng/ml. Max 300 mg

Your patient suffers a relapse of depressionafter several medication trials. Now, insteadof insomnia, she is sleeping 16 hour days andgaining weight. She tells you that theslightest comment from a friend may makeher start sobbing. She also says that she cansometimes perk up quickly. What would youdo now?

Depression Rx:Switching Antidepressants

Required washout times:• Fluoxetine to MAOI 5 wks• Other SSRI to MAOI 2 wks• MAOI to non-MAOI 2 wks

MAOIs

• Uncommonly used• Dietary restrictions

– avoid tyramine-containing food/drinks– aged cheese; EtOH: beer, red wine; fish: anchovies,

cured, herring, dried; meats: smoked, cured, salami,liver; yeast products: marmite

• Side effects– dizziness, orthostasis, weight gain, sleep disturbances,

sexual dysfunction, edema• Drug interactions:

– Avoid non-NSAIDs, cold medications

MAO-I’s

• Phenelzine (Nardil) is more studied but more sideeffects – Weight gain, anticholinergic, more hepatoticity– Start 15 mg BID to TID, advance by 15 mg q wk to 45-

60 mg a day• Tranylcypromine (Parnate)

– Fewer side effects except for insomnia (can use abenzo)

– Start 10 mg BID to TID, advance by 10 mg q wk to 30-40 mg a day

Your patient pages you at 11 pm one Saturdaynight complaining of severe headache,

sweating, and heart palpitations. She hadeaten some Marmite and Caviar at a party.

What should you do?

Hypertensive Crisis:

• A HTN Crisis involves diastolic BP > 120-130 AND end-organ damage– Pentolamine 5 mg IV– Avoid: Nifedipine: patients should go to an ER!

• Avoid β blocker as may worsenhypertension

Antidepressant Actions:Adverse Effects

Bupropion: dose-dependent seizure risk

Venlafaxine: dose-dependent elevation in BP Sweating

Duloxetine: BP, LFT’s

Mirtazapine: sedation, weight gain

Nefazadone: Liver Failure

Trazadone: priapism

SSRI’s: SIADH, especially in elderly Bruxism

Residual Symptoms and RelapsePaykel et al, Psychol Med 1995;25:1171

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Months Between Remission & Relapse

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residual sxs no symptoms

Your colleagues notice your success with thispatient, and recall that you are a psychiatric resident.

They have started to curbside you with all sorts ofquestions. First they ask what other diagnoses they

can treat.

Uses for Antidepressants

• Depression• Minor Depression• Dysthymia• PMDD• Anxiety Disorders• Panic• PTSD• OCD

• Eating Disorders• Social Phobia• Trichotillomania• Body Dismorphic

Disorder• Chronic pain• Premature Ejaculation• ADHD

Response

• 50 % fully recover• 30-40% some improvement• 10-15% no improvement

– Worse among anxiety disorder, substance abusedisorder, personality disorder, or psychoticdisordered patients

Why do patients fail to get better

• Inadequate drug dosage• Inadequate length of drug trial• Wrong diagnosis• Comorbid Disorder• Compliance• Patient does not respond to medication

Common General MedicalCauses of Depression

• Drug Induced• Drug Use

– EtOH– Benzos– Coke/crank

• Metabolic– Thyroid– Cushing– Ca/Na– Diabetes

• Neurologic– Stroke– Hematoma– MS– PD– Dementia– Syphilis

• Nutritional• B12• Pancreatic CA• Viral: Mono, Flu

Selected Antidepressants for Use in Depression

Generic Trade name Initial Dose Target Dose Step-up Dose

SSRI

Citalopram Celexa 20 mg/d 20 mg/d 40 mg/d

Fluoxetine Prozax 20 mg q am 20 mg q am 40-60 mg q am

Fluvoxamine Luvox 50 mg qhs 100-150 mg/d 200-300 mg/d

Paroxetine Paxil 20 mg/d 20 mg/d 50 mg/d

Sertraline Zoloft 50 mg/d 100 mg q am 150-200mg q am

TCA

Amitriptyline Elavil 25 mg qhs 100 mg qhs 150 mg qhs

Doxepin Sinequan 25 mg qhs 100 mg qhs 150-200 mg qhs

Imipramine Tofranil 25 mg qhs 100 mg qhs 150-200 mg qhs

Desipramine Norpramin 25 mg qam 100 mg qam 300 mg qam

Nortriptyline Pamelor 25 mg qhs 75 mg Qhs 150 mg qhs

Miscellaneous

Venlafaxime Effexor 37.5 mg BID 75 mg BID 100-150 mg BID

Effexor XR 37.5 mg/d 75-150/d 225 mg/d

Duloxetine Cymbalta 40 mg 60 mg TBD

Mirtazapine Remeron 15 mg qhs 30 mg qhs 45 mg qhs

Bupropion Wellbutrin 75 mg BID 150 mg BID 150 mg TID

Adjunctive Agents:Advantages vs. Disadvantages

• Advantages– Minimize relapse as

change rx– Capacity to provide

specificneurotransmitter effect

• Disadvantages– Pharmacokinetic

interactions– Additive side effects– Regimen complexity

leading to poorcompliance

Depression Rx:Augmentation Strategies

• Lithium 600 mg/d• Thyroid hormones: T3 25-50 mcg/d• Combination• Stimulants: methyphenidate, d-

amphetamine, modafinil• Pindolol (5 HT1A antagonist) - 2.5 mg TID

1st LineAugmentation Strategies

Drug Data PopularityLithium *** *T3 (Cytomel) ** *Combinations * ***Stimulants * **Pindolol * 0

Case Study

Your patient begins to complain ofexcessive sedation, constipation,orthostatic dizziness and a dry mouth. Youhad started her on fluoxetine one monthearlier. You also recall that she has beenon amitriptyline 50 mg a day for diabeticneuropathy.

Antidepressants andCytochrome P450 Profiles

Moderate to substantialinhibitory effect: Fluoxetine: 2D6, 2C9/10, 2C19 Fluvoxamine: 1A2, 2C19, 3A3/4 Nefazodone: 3A3/4 Paroxetine: 2D6 Venlafaxine, Citalopram, Mirtazapine: none

Preskorn, Clinical Cornerstones 1999;1(4):31

Medications Metabolized by CYP Enzymes(derived from Preskorn, Clin Cornerstones 1999;1(4); Goldberg RJ. Arch Fam Med 1996;5:408; Richelson E, Mayo Clin Proc

1997;72:385; Rothschild A, J Clin Psych 2000;61(suppl 1):28)

Fluoxetine: 2D6, 2C9/10, 2C19; Nefazadone: 3A3/4;Fluvoxamine: 1A2, 2C19, 3A3/4; Paroxetine: 2D6)

CYP enzyme Medications

CYP 1A2 Amitriptyline, imipramine, clozapine, olanzipine, thoridazine, propanolol, tacrine

theophylline, w arfarin

CYP 2C9/10 phenytoin, w arfarin, tolbutamide

CYP 2C19 citalopram. clomipramine, imipramine. mephenytoin, propanolol, diazepam

CYP 2D6 anti-arrhythmics (I.e. encainide,mexiletine, propafenone), anti-psychotics (haloperidol, risperidone,

thioridazine, clozapine), beta-blockers, opiates, SSRI (paroxetine, f luoxetine), bupropion

TCA (desipramine, impipramine, maprotiline, amitriptyline, nortriptyline) venlafaxime, nefazadone

CYP 3A3/4 acetaminophen, anti-arrhythmics (propafenone, quinidine), anti-convulsants (I.e. carbamazepine),

antihistamines (I.e. hismanal, loratidine), anti-psychotics, benzodiazepines (alprazolam, diazepam, etc.)

calcium-channel blockers, macrolide antibiotics, steroids (I.e. estrogen, testosterone, cortisol), tamoxifen

omeprazole, lovastatin, anti-depressants (nefazadone, sertraline, venlafaxime, bupropion, TCA)

How Long Doc?

• Highest risk for relapse among TCA treatedpatients is discontinuation during 1st 16weeks

• Prophylaxis of recurrence has been shownfor as long as 5 years with benefit

• Prophylaxis dose = treatment dose• Severe major depression, suicide attempts,

late life depression, recurrent depression

Depression:Treatment Strategy

• Treat a minimum of 6 to 8 months afterrecovery

• Follow-up visits q 1 to 3 months• When stopping, taper over 2-3 months; if

relapse, treat 3 to 6 more months

Depression:Long-Term Treatment

• Multiple episodes – more than 2-3• Recurrence within one yr of Rx• Double depression (MDD+ dysthymia)• Onset after 60 yrs• Co-morbid anxiety or substance abuse• Co-morbid medical disorders worsened

by depression

Keller MB, et al. Arch Gen Psychiatry. 1992;49:809-816.

Obstacles to AttainingRemission

• Patients and clinicians are satisfied withpartial improvement in symptoms(ie, response but not remission)

• Treatments may not be well tolerated• Under-dosing• Failure to recognize residual symptoms• Continued psychosocial stressors

Depression Rx: ECT

• Effective, safe, life-saving• Consider if:

(1) high risk of suicide(2) rapid physical decline(3) inability to tolerate or benefit from drug Rx(4) history of prior response to ECT(5) patient preference

Depression:Psychotherapy

• Cognitive and behavioral therapy• Interpersonal therapy• Problem-solving therapy• Supportive therapy

Psychotherapy

PROS:• No side effects• “Learning effect” ?

more lasting• Effective• Problem-solving

therapy

CONS:• Time-consuming• Takes longer to work• Not as effective in

more severe MDD• Reimbursement

PsychotherapyMulticenter trial, 12 academic centers, 681subjects with chronic depression• Cognitive-behavioral Rx: 48% response• Nefazodone alone: 48% response• Combined treatment: 73 %

Keller et al (NEJM 2000;342:1462):