Major Depression and Treatments

1
Major Depression and Treatments

• David Mischoulon, MD, PhD
• Depression Clinical and Research Program
• Massachusetts General Hospital
• Harvard Medical School

2
Goals

• Understand principles in choosing antidepressant
  medications
• Know about specific antidepressants
• Understand safety considerations
• drug-drug interactions
• side effects
• toxicities
• Other considerations/special cases

3
Depression vs. Unhappiness

• People may describe themselves as depressed, but
  not have significant depressive symptoms
• Situational factors should be considered
• Therapy/counseling may be a good first line of
  treatment
• Antidepressant medications are for specific
  symptoms!

4
How to Choose an Antidepressant

• Safety
• risk of toxicity, overdose, interactions
• Tolerability
• side effects
• Efficacy
• which antidepressant for which patient?

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Safety

• Wide therapeutic index (safest)
• Effexor, Serzone, Remeron, SSRIs
• Narrow therapeutic index (less safe)
• Tricyclics, MAOIs, Wellbutrin, Trazodone
• Know suicide risk
• give less than one week supply if serious risk
• use safer antidepressants

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Safety

• Metabolism
• usually in the liver
• Seizure threshold decrease
• Wellbutrin TCA SSRI, MAOI
• Interactions with other medications
• Cytochrome P450 enzymes

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Tolerability

• Discuss side effects in advance
• tiredness, agitation, stomach upset, headache,
  dizziness, lightheadedness, dry mouth, weight
  gain, sexual problems
• Many side effects clear up in a few days!
• ask your doctor about this
• If you are older start low, go slow!

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Efficacy

• All can take between 2-4 weeks to work
• some need up to 12 weeks for full response
• All have roughly the same efficacy
• 50-70 response rate, 12-15 partial response
• Choice of drug based on
• side effect profile
• subtype of depression, associated symptoms
• suicide risk

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What is Cytochrome P450?

• An enzyme in the liver that breaks down many
  medications
• Some medications interfere with these enzymes and
  may increase or decrease activity of other drugs
• Examples all SSRIs block Cyt P450 2D6, which
  metabolizes TCAs
• so if combining TCA and SSRI, we give lower dose
  of TCA

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Selective Serotonin Reuptake Inhibitors (SSRIs)

• Generally the first line of treatment
• Prozac (Fluoxetine) 20-80mg/day
• Paxil (Paroxetine) 20-50mg/day
• Zoloft (Sertraline) 25-200mg/day
• Luvox (Fluvoxamine) 50-300mg/day
• may need to take 2-3 times a day
• Celexa (Citalopram) 20-50mg qd
• Lexapro (Escitalopram) 10-40mg/day

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SSRIs

• Advantages
• well tolerated
• fewer anticholinergic/cardiac sfx,
• less risk of withdrawal
• no labs needed
• good for elderly
• safe in overdose
• once a day dosing
• can increase or discontinue rapidly

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SSRIs

• Disadvantages
• sexual problems, headaches, stomach upset,
  agitation
• Serotonin syndrome tachycardia, HTN, fever,
  sweating, ocular oscillation, myoclonus ?
  confusion, convulsions, coma ? death.
• DO NOT MIX WITH MAOIs
• If combining with TCA, use low dose TCA

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Atypical Antidepressants

• Usually the second line of treatment, when SSRIs
  fail, but increasingly used as first line
• Wellbutrin (bupropion)
• Effexor (venlafaxine)
• Desyrel (trazodone)
• Serzone (nefazodone)
• Remeron (mirtazepine)

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Wellbutrin (Bupropion)

• Amphetamine-related
• may have stimulant properties
• blocks various neurotransmitters
• Taken 2-3 times a day
• start at 75-100mg twice daily ? 300-450mg/day
  maximum
• SR/XL form may permit once a day dosing
• start at 100-150mg/day

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Wellbutrin (Bupropion)

• Risk of seizure 0.4 in general, but can
  increase to 4 with higher doses, so
• no dose 150mg (200mg OK if SR form)
• no more than 400-450mg/day
• do NOT give to anorexics or bulimics
• No sexual side effects
• may even improve sexual function!
• good for elderly patients

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Effexor (Venlafaxine)

• Has SSRI and TCA activity
• Similar side effect profile to SSRIs
• Can cause increase in diastolic BP
• Withdrawal can be a problem
• Starting dose 37.5mg/day ? 100-300mg/day

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Desyrel (Trazodone)

• Too sedating for daytime use
• Better as a sleep aid, 50-600mg at bedtime
• May cause prolonged erection (priapism)
• REM suppressor
• Good if nightmares present, e.g. in PTSD
• Dont combine with MAOI

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Serzone (Nefazodone)

• Related to Trazodone, but
• No priapism!
• Less sedating during the day
• Good for anxious depression
• Risk of liver toxicity
• Usually requires dosing on 2-3X/day basis
• Begin 100mg 2X/day ? 300-600mg/day
• eventually can go to bedtime dosing

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Remeron (Mirtazapine)

• Good for insomnia
• Relatively less stomach upset
• Weight gain and sedation are common, especially
  at lower doses
• Best for the patient with poor appetite, poor
  sleep
• Typical doses 15-45mg at bedtime

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Tricyclic Antidepressants

• Amitriptyline (Elavil)--used for sedation or to
  increase appetite
• Nortriptyline (Pamelor)-- Inverted U
  pharmacokinetics, therapeutic window
• Imipramine (Tofranil)--used for panic disorder
• Desipramine (Norpramin)
• Clomipramine (Anafranil)--used for OCD

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Tricyclic Antidepressants

• Less favored today due to side effect profile
• Advantages
• safety in pregnancy
• may be better for severe depression
• Disadvantages
• cardiovascular sfx, orthostatic hypotension,
  sedation
• CAN BE DEADLY IN OVERDOSE

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Tricyclic Antidepressants

• Check EKG if
• patient older than 40, or has conduction disease
• watch out for QRS 0.1sec
• Dosing/Discontinuation must be slow
• Best to use one dose at bedtime (divide if sfx)
• withdrawal flu-like symptoms
• Increase by 50mg every 3-4 days

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Monoamine Oxidase Inhibitors (MAOI)

• Used less often because of side effects and diet
  issues
• Good for atypical depression, panic, social
  phobia, last resort, post-ECT
• Orthostatic hypotension, sedation
• Can be deadly in combination with Tyramine-rich
  foods
• special diet needed

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Monoamine Oxidase Inhibitors (MAOI)

• Dont mix with
• SSRIs, Clomipramine, Buspar
• switch from Prozac to MAOI 5 week washout
• other SSRIs or TCA to MAOI 2 week washout
• Demerol
• Epinephrine
• Local anesthetics
• Dextromethorphan

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Tyramine Reaction

• Tyramine increases norepinephrine production
• Increases blood pressure
• Hypertensive crisis
• occipital headache
• death rate is low (0.01-0.02)
• risk of stroke is significant

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Tyramine Reaction

• Treatment
• Nifedipine 5mg sublingual (antihypertensive)
• Regitine 5mg IV (alpha blocker)
• Thorazine 50-100mg by mouth or intramuscular
  injection

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Natural Remedies

• Patients often use them without informing their
  physician
• always ask!
• Examples
• St. Johns Wort, DHEA, DHA, PEA, Omega-3, Kava,
  Black Cohosh, Chaste Tree Berry, homeopathic
  remedies, Ginkgo, Valerian, Melatonin, Vitamins

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St. Johns Wort
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St. Johns Wort

• Derived from Hypericum Perforatum
• Most popular remedy in the world!
• Appears effective for milder depression
• Benign side effect profile
• worst side effect is phototoxicity
• Adverse interactions with other drugs can be
  fatal
• Should not be mixed with SSRIs
• 900-1800mg/day is recommended dose

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SJW Drug-Drug Interactions

• Warfarin
• Cyclosporin
• Oral contraceptives
• Theophylline
• Fenprocoumon
• Digoxin
• Indinavir
• Camptosar

• Hyperforin induces CYP-3A4 expression
• Reduced therapeutic activity
• Caution required in
• HIV patients
• Cancer patients
• Transplant recipients

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A Warning about Natural Remedies

• There are limited research data on them
• Effectiveness compared to conventional
  medications (and to placebo) is still unclear
• Safety issues also unclear
• Preparations may vary in strength/purity
• Buyer Beware!

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Sexual Side Effect Management

• TELL YOUR DOCTOR!
• SSRIs are the worst offenders
• Is it a side effect or a worsening of depressive
  symptoms?
• Avoid decreasing the dose
• depressive symptoms may worsen
• Various options, with variable results

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Sexual Side Effect Management

• Yohimbine 2.7-5.4mg 3X/day as needed
• Cyproheptadine 4-8mg/day
• Amantadine 100-200 mg/day
• Wellbutrin 75mg-150mg/day
• Buspar 5mg 3X/day
• Trazodone 100-200mg/day
• Viagra 25-100mg one hour before sex
• If all else fails, switch to another agent!

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During Pregnancy

• There are limited data regarding safety of
  antidepressants during pregnancy
• Tricyclics have the longest track record for
  safety
• Emerging data support safety of SSRIs
• Perinatal psychiatry consult is a good idea

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If a Medication is Ineffective

• Increase dose (SSRIs are easier to tolerate)
• Augment with other agents
• Lithium, thyroid, stimulants, Buspar
• Add a second antidepressant
• one of another class
• Switch to another antidepressant
• preferably one of another class

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Once Remission is Attained

• Stay on antidepressant for at least 6 months to
  one year post remission (longer if history of
  recurrence or severe depression)
• Monitor for symptoms of recurrence
• Taper antidepressant slowly (over 1-3 weeks,
  depending on dose)

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Psychotherapies

• May be sole treatment or used in combination with
  antidepressants
• Research suggests combination may be best for
  major depression
• Psychodynamic therapy
• Cognitive-Behavioral Therapy (CBT)
• Interpersonal Therapy (IPT)
• Supportive Therapy

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Conclusions

• Know the signs and symptoms of depression
• Seek help if you believe you are depressed
• Depression is treatable!