Bipolar Disorder

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					                  Bipolar Disorder:
                    an overview




                                       Roy Perlis, MD
                             Bipolar Research Program
Massachusetts General Hospital/Harvard Medical School
 Key points in bipolar disorder
 Costly, common (1%+), treatable
 Defined by recurrent episodes of mania (or
  hypomania) and depression
 Often misdiagnosed
 New treatments FDA-approved, more on
  the way…
 … but older treatments can save lives, too.
                          Case: B.P.
   20 y.o. male college sophomore;
    – Depressive episode, age 16
          Won‟t get out of bed, won‟t go to school
          Resolves after several months without treatment
    – Manic episode, age 20
          No sleep for 1 week – busy with „projects‟
          Agitated, excited, talking rapidly about his „cure for cancer‟
          Convinced his roommates are scheming against him


   What‟s at stake?
    The costs of bipolar disorder

                        LIFE




       8 years          Risk of suicide death
                                                 >>$60 Billion
of effective function   29x general population
   Expectable Course, Untreated
 If onset at age 16, given median rate of recurrence
           by age 30, EXPECT  10 episodes
                              Age
  16             20      22     24 25 26 27 28 29 30


    1             2       3      4   5    6   7   8   9   10

                         Episode Number


(Peak onset age 15-19)
          A common disease
   Prevalence estimated between 1-3%
    – (depends on diagnostic criteria)
 Males=females
 Found across cultures and ethnicities
 Strongly heritable
                   The High Rate of
                    Misdiagnosis
2000 National DMDA Bipolar Survey of 600 bipolar patients:

                     69%
                    Initially                             Most frequent misdiagnosis:
                 Misdiagnosed
                                                           Unipolar depression
                                                                  60%



                     35% were symptomatic for more than
                       10 years before correct diagnosis
                                                                          10+ years

    National Depressive and Manic-Depressive Association (NDMDA), Constituent Survey. 2001; Chicago, IL.
    Hirschfeld RMA, et al. J Clin Psychiatry. 2003;64:161-174.
                    Screening
   The Mood Disorder Questionnaire:
    – 13 yes/no questions


   Available at:
    www.dbsalliance.org/questionnaire/screening_intro.asp
                    Diagnosis

   There are no clinically useful lab tests which make
    a diagnosis of bipolar disorder
    – blood tests: normal
    – CT/MRI: normal*
    – EEG: normal


   Thus, diagnosis rests on clinical evaluation –
    ideally by a psychiatrist or psychologist!
      AGE OF SYMPTOM ONSET
        NDMDA Survey N=500
            LISH et     al, J. Aff. Dis 1994
30%
                         28%

20%

                                                    16%
                 14%                15%
10%        12%
                                            9%
      5%

      <5   5-9   10-14   15-19      20-24   25-29   30+
                     Years of age
NDMDA Survey: Initial Symptoms
  of Bipolar Disorder (N = 500)
    Symptom                                         %

    Depressed mood/hopelessness                     33
    Mania/hyperactivity                             32
    Lack of sleep                                   24
    Mood swings                                     13
    Anger/irritability                                9
    Delusions/paranoia                                9

NDMDA = National Depressive and Manic-Depressive Association.
Lish et al. J Affect Disord. 1994;31:281-94.
                                     Marcus Unwellby, M.D.
        DEA # __________          Massachusetts General Hospital
                                        Boston, MA 02114
        Name _________________                                      Date __________



                              Mania DSM IV
       7 days or more of elevated or irritable mood


                          DIGFAST
                                                                                  M.D.

                                                 F – Fast thoughts (Flight of ideas)
D - Distractible
                                                 A – Active (or agitation)
I – Injudicious (impulsive)
                                                 S – Decreased need for sleep
G - Grandiose
                                                 T – Talking fast
                              Adapted from William Falk, M.D.
            Questions for Detecting
                 Hypomania
   Do you have days of energy or ideas that come
    and go abruptly?
   On those days of energy, are you productive?
    Creative? Feel unconquerable? Convinced of your
    self-worth, talents abilities? Positive about the
    future? Talkative? Distinctly more social?
    Irritable?
   On those days of energy, do your thoughts feel as
    if they‟re racing?
Manning JS, et al. Arch Fam Med. 1998;6:63-71.
            Questions for Detecting
                 Hypomania
   At these times, do you need less sleep? Continue
    to be productive?
   How many consecutive days does this period of
    increased energy and change in mood last?
   Do others notice the change in your mood or
    energy level?




Manning JS, et al. Arch Fam Med. 1998;6:63-71.
            Questions for Detecting
                 Hypomania
   During these “up” times, do you do things that you
    later regret? Make plans you find impossible to
    complete? Take on tasks that you later suddenly
    lose interest in?
   Are you particularly more depressed or lethargic
    immediately before or after these periods of
    energy? Does it feel like you “crash”? Does your
    body seem as if made of lead? Do you need
    excessive sleep?
Manning JS, et al. Arch Fam Med. 1998;6:63-71.
 On average, bipolar patients spent
about 1/3 of their time with symptoms
            of depression
                                          Mood states
                                          Euthymia
                                          Depression
                                          Dysthymia
                                          Subsyndromal
                                          Elevated
                                          Cycling



              -NIMH Collab Depression Study - Judd et al, Archives 6/2002
Beyond mania and depression
   A marathon, not a sprint!
                      Case: B.P.
   20 y.o. male college sophomore;
    – Depressive episode, age 16 (no treatment)
    – First manic episode, age 20
          No sleep for 1 week – busy with „projects‟
          Agitated, excited about his „cure for cancer‟
          Convinced his roommates are scheming against him


 Discharged on hospital day 7 on a regimen of
  valproate (divalproex) and olanzapine.
 Arrives (30‟ late) for follow-up appointment and
  announces, “There‟s no way I‟m taking this
  #$%@!”
Most Common
 Reasons for
Discontinuing
 an Effective
 Treatment in
    Bipolar
  Disorder:

Weight Gain,
 Sedation
          STEP-BD: an effectiveness study




“Systematic Treatment Enhancement Program – Bipolar Disorder”

       5000 Bipolar Patients (n>3000 as of 6/1/03)
             100-200 Treating Psychiatrists
                 15 Treatment Centers
         Common Disease Management Model                   P
                                                       E
                                                  T         D
                                              S        B
   BIPOLAR DISORDER:
Standard & Novel Treatments

      Andrew L. Stoll, M.D. © 1998-2003
   Psychopharmacology Research Laboratory
               McLean Hospital
           Harvard Medical School
         Alstoll@mclean.harvard.edu
                617-855-2459


                   2003
                    Bipolar Disorder:
Current or Evolving Concepts of Treatment

  • Polypharmacy is the rule, not the exception
  • Mood Elevating Mood Stabilizers exist:
      – Lamotrigine
      – Some atypical antipsychotic agents
      – Omega-3 fatty acids
  •   “Stabilizing the mood from below”1
  •   Minimizing antidepressant use is now more practical
  •   Tolerability is now as important as efficacy
  •   Nutritional agents have a role
  •   Complementary & Alternative Medicine is here to stay



1Ketter   and Calabrese, 2001
    MOOD STABILIZERS WITH
      CONTROLLED DATA
                    (partial list)
•   chlorpromazine          •   risperidone
•   lithium salts           •   omega-3 fatty acids
•   carbamazepine           •   lamotrigine
•   phosphatidylcholine     •   olanzapine
•   valproate               •   topiramate
•   ECT                     •   magnesium salts
•   Verapamil               •   clozapine
•   L-tryptophan            •   quetiapine
•   hypermetabolic T4       •   ziprasidone
        LITHIUM SALTS
    (Lithobid, Eskalith CR)
   ADVANTAGES               DISADVANTAGES
• Extensive and long use   • Narrow therapeutic
• Acute and chronic          index
  efficacy data            • Renal & thyroid toxicity
• Relative safety in       • Multiple “nuisance”
  Pregnancy                  side-effects
• Moderate                 • Narrow spectrum of
  antidepressant effects     activity
• Demonstrated anti-       • Occasional depression
  suicide effects            induction
                           • Stigma
     DIVALPROEX SODIUM
    (Depakote, Depakote ER)
    ADVANTAGES                  DISADVANTAGES
• Strong acute efficacy     • Nausea (acute)
  data                      • Weight gain (chronic)
• Some long-term data       • “Nuisance” side-effects
• Broad activity            • Possibly less effective for
  spectrum                    pure bipolar depression
• “Loading” doses           • Neural tube defects (5-7%)
  rapidly effective         • Controversy over
• Effective for anxiety &     pancreatitis & polycystic
  migraine                    ovary syndrome
• Less toxic than Li+
             CARBAMAZEPINE
                (Tegretol)
   ADVANTAGES                         DISADVANTAGES
• Strong acute efficacy data        • May lose effectiveness
• Broad activity spectrum             over the long-term
• Possible antidepressant           • Drug interactions
  effects in bipolar disorder                (induction of CYP450 3A3/4)

• Long history of use               • Blood dyscrasias
• No weight gain                    • Narrow therapeutic index
                                    • Acute side-effects
  Usage: 200 mg BID initially. Gradually titrate to 300-400 mg
  BID, then check serum level. Titrate to highest tolerated dosage
  within therapeutic range. Due to CYP450 autoinduction, the
  dosage may have to be increased in several weeks.
                       TRILEPTAL
                     (Oxcarbazepine)
     ADVANTAGES                                    DRAWBACKS
•   Carbamazepine-like action              •   Limited data in bipolar disorder
•   More rapid dose titration possible     •   Drug interaction risk still present
•   FDA approved anti-epileptic                 – Reduced effectiveness of low-
     – Used in Europe since 1990                  dose oral contraceptives
•   Milder adverse effect profile than     •   Carbamazepine-like adverse effects
    carbamazepine                               – ~ 1/3 the incidence
     – Less bone marrow and liver               – dizziness, somnolence, diplopia
        effects                            •   Hyponatremia (low sodium)
     – Less drowsiness                          – higher incidence (~ 2.5%) than
•   No labs required (except for sodium)          carbamazepine
•   Fewer drug interactions.                    – Usually not clinically significant
                                                  unless very low
                                                – Correct slowly to prevent
                                                  neurological complications



      Schachter et al. Neurology 1999;52:732-737.
                     LAMOTRIGINE
                       (Lamictal)
ADVANTAGES                                      DISADVANTAGES
•   Controlled data (N > 1300)              •   Slow dosage titration limits
     –   Bipolar depression 1                   acute utility
     –   Rapid-cycling3
     –   Prophylaxis                        •   Skin issues
     –   Bipolar I and II                        – High rate of benign skin
     –   Unipolar depression                       rashes (~10%)
•   Very well-tolerated                          – Fear of Stevens-Johnson
     – No weight gain                              syndrome (SJS)
     – No labs; No sedation                      – Increased SJS only if dosed
     – No cognitive “dulling”                      too aggressively.
•   Neuroprotective                         •   Valproate will double
     – Blocks glutamatergic Na+                 Lamictal serum levels
       channels


1Calabrese  et al. J Clin Psychiatry 1999;60:79-88.
2Ichimet al. Ann Clin Psychiatry 2000;12:5-10.
3Calabrese et al. J Clin Psychiatry 2000;61:841-850.
LAMOTRIGINE & SKIN RASH
    Safe Management
 • Patient education
 • Warn patients not to change soaps, laundry detergents,
   OTC products, unusual foods, etc. - during 1st 6 weeks of
   lamotrigine titration
 • Assess rash (severity, location, features)
 • Discontinue if:
        a. Rash is severe, painful, or rapidly evolving
        b. Any blistering
        c. Systemic symptoms
        d. Mucous membrane involvement
 • Early Dermatology consultation if unsure
                 Lamotrigine and
                 Women’s Health
   •   No menstrual effects.
   •   No risk of PCO.
   •   No weight gain.
   •   No other neuroendocrine or other cosmetic effects.
   •   No interference with oral contraceptives metabolism
   •   No cognitive side-effects.
   •   Appears safe in pregnancy (registry data)1.


1MassachusettsGeneral Hospital. AED Pregnancy Registry
1-888-233-2334 or 1-888-AED-AED4 (Toll free)
Is “Polypharmacy” a Bad Thing?
 • YES
   – Poorly done polypharmacy may be ineffective and unsafe.
 • NO
   – Appropriate polypharmacy can be life-changing or even life-saving:

        • ENHANCED EFFICACY:
            – Improves the chance of a full syndromic recovery
            – Improves the chance of a full functional recovery
            – Can speed the time to response
        • IMPROVED TOLERABILITY & SAFETY:
            – Additive or synergistic effects of the proper combination
              permit lower dosages, leading to:
            – Reduction of side-effects
            – Lessened risk of toxicity
 Why is Polypharmacy Now So Common
         and Widely Accepted?

• Greater numbers and varieties of drugs and
  supplements available.
• Steadily growing knowledge about the risks and
  benefits of specific combinations.
• Accumulating data indicating the poor prognosis and
  outcome of inadequately treated illness.
• Higher consumer education and expectations for
  improved outcome.
• Big Pharma PR and advertising
                PHOTOTHERAPY
             ADVANTAGES                                         DRAWBACKS
•   Controlled data in SAD patients.                   •   Expensive.
•   Plausible neurochemical mechanism.                 •   Compliance sometimes
•   Well-tolerated; Energizing.                            difficult.
•   High patient acceptance.                                – 20-60 minutes per day
•   No ocular damage with quality boxes.                        required.
•   Possible dampening of seasonal                          – A.M. light best.
    mood shifts if used year-round?                    •   Eye strain and headaches.
•   Finances                                           •   Possible induction of
     – Light boxes now more affordable.                    hypomania and cycling.
     – some insurers are paying.

•   10,000 lux box at ~18-22”.
•   Face the direction of the box. Look at the box as often as you desire, or read, etc.
•   20-60” per day, preferably in the a.m.
•   Many brands available:
     – Alaska Northern Lights: 1-800-880-6953 or Northern Lights (Montreal):
A traditional diet in the Arctic regions of North America provides
     15-19 grams/day of EPA + DHA (omega-3 fatty acids ).

In the U.S. < 1 gram/day of omega-3 fatty acids are consumed
   GENERAL HEALTH BENEFITS
    OF OMEGA-3 FATTY ACIDS
• Cardiac
   – Reduced incidence of MI
   – Improved survival if MI
• Gastrointestinal
   – Improvement in Crohn’s disease & ulcerative colitis
   –  corticosteroid use in inflammatory bowel disease
• Rheumatology
   – Improvement in rheumatoid arthritis symptoms
   –  corticosteroid use in rheumatoid arthritis
• Renal
   – IgA nephropathy
   – Improved outcome in renal transplant
• Neuropsychiatric
   –   Mood disorders
   –   Schizophrenia
   –   ADHD
   –   Dementia prevention
   Omega-3 Fatty Acids:
AREAS OF ACTIVE RESEARCH
•   Bipolar disorder
•   Unipolar depression
•   Schizophrenia
•   Borderline personality disorder
•   Post-partum depression
•   ADHD
•   Autism spectrum disorders
•   Other developmental neuropsychiatric disorders
     POSSIBLE MECHANISMS OF
     ACTION OF OMEGA-3 FATTY
    ACIDS IN BIPOLAR DISORDER

•    2nd-messenger generation in PI system.
•   Anti-kindling effects.
•   Blockade of calcium channels.
•   Inhibition of PKC.
•   Altered receptor function.
•   Altered CNS cytokine function.
•   Altered arachadonic acid (n6) pathways.
 OMEGA-3 FATTY ACIDS IN
   BIPOLAR DISORDER:
      Study Design
• Double-blind placebo-controlled 4-month trial
• N = 30 bipolar outpatients (mostly Type I)
• All subjects had mania/hypomania within past 1 year
• Randomized to 9.6 g/day omega-3 vs. placebo (olive oil)
• Concomitant meds left unchanged
• N = 8 entered study on no other drug therapy
• Main outcome measures:
   Recurrence or lack of response
   SCID Status at end of trial
    OMEGA-3 IN BIPOLAR DISORDER:
          Survival Analysis

          100                         omega-3
                                        N = 14
           80
 Number of
  patients 60
remaining in
 study (%) 40                          olive oil
                                         N = 16
                  p = 0.002
           20   (Mantel-Cox)


                 20    40        60     80        100   120
                               Time (days)
   OMEGA-3 FATTY ACID MONOTHERAPY:
             Survival Curve
                                               omega-3
           100
                                                 N=4
            80


Cumulative 60
Survival (%)
             40
                                                olive oil
                    p = 0.04
            20    (Mantel-Cox)                    N=4



                   20    40        60     80    100         120
                                 Time (days)
        OMEGA-3 FATTY ACIDS in
        UNIPOLAR DEPRESSION
              Direct Evidence of Efficacy
    • 4 double-blind, placebo-controlled trials
        –    DHA in unipolar depression (ineffective)1
        –    EPA monotherapy in unipolar depression2
        –    EPA add-on in recurrent unipolar depression3
        –    EPA + DHA (3:2) in unipolar depression4


1Marangell   et al. DHA in unipolar major depression. Presented at ISSFAL,
Tsukuba, Japan 2000.
2Peet et al. EPA for unipolar major depression. Abstr Biol Psychiatry. 2001.
3Nemets et al. Addition of omega-3 fatty acid to maintenance medication
treatment for recurrent unipolar depressive disorder. Am J Psychiatry.
2002;159:477-9.
4Su et al. Omega-3 fatty acids in major depressive disorder: a preliminary
double-blind placebo-controlled trial. Eur Neuropsychopharmacol.
                                                FISH CONSUMPTION AND MAJOR
   Annual Prevalence of Major depression (%)
                                               DEPRESSION AROUND THE WORLD
                                                         New Zealand (5.8%)
                                                                 Canada
                                                              (5.2%)
                                                                                                        r = -0.84
                                                                     France (4.5%)                    p < 0.005
                                                W. Germany (5.0%)




                                                        USA (3.0%)            Puerto Rico
                                                                                (3.0%)
                                                                                                 Korea (2.3%)



                                                                                   Taiwan (0.8%)
                                                                                                                  Japan (0.12%)
                                                        20     40        60         80     100       120         140   160
                                                   Apparent Per Capita Seafood Consumption (lbs/year)
Adapted from: Hibbeln JR. Lancet
OMEGA-3 FATTY ACID DEPLETION
   IN POST-PARTUM WOMEN

•   After 1 child: Low DHA
•   After 2 children: Lower DHA
•   After 3 children: Lowest DHA
•   Triplets > twins:
•   Triplets:
•   Lactation: At 16 weeks, decreased DHA
         FISH CONSUMPTION AND
        POSTPARTUM DEPRESSION
        South Africa (24.5%)
 25      Brazil (24.1%)

      UAR (18.0%)
 20              Germany (20.0%)                22 countries
                       Australia (18.6%)
                     New Zealand (17.4%)
    Netherlands UK (14.4%)
 15                       Italy (15.0%)
     (14.0%)
            Israel (12.4%)  Canada  Spain (13.6%)
                               (12.7%)
 10    Ireland (11.0%)
                                 
                      USA (11.5%) France (11.0%)
                   
             Switzerland          Sweden (9.0%)
               (10.2%)
 5
                                   
                        Chile (5.5%)                 Hong Kong (5.5%)

 2.5                         
                      Malaysia (3.0%)                               Japan (2.0%)
                                         Singapore (0.5%)
            20         40      60         80      100        120     140     160
              Apparent Per Capita Seafood Consumption (lbs/year)
Hibbeln 1999
   IDEAL CHARACTERISTICS OF
     A FISH OIL SUPPLEMENT
• Maximum concentration
    – >90% now available
• No heavy metal or organic carcinogens
    – Any concentrated fish oil (> 50%) is convincingly safe
• No fishy aftertaste, smell, or “repeat”
    – Mitigated by encapsulating under nitrogen to minimize
      oxidation
• EPA >> DHA
    – Virtually all the data points to EPA as the active ingredient

Locke CA, Stoll AL. World Rev Nutr. 2001
    OMEGA-3 FATTY ACIDS
        Usage Guide
• Fish oil usually preferred over flaxseed oil.
• Calculate dosage based on EPA content.
   – Start dosage: 1 gram/day EPA x 3-5 days.
   – Usual dosage: 2-5 grams/day EPA
   – Dosage schedule: Typically BID (qd or TID OK)
• Antioxidant vitamins are required:
   – Vitamin E 400-800 IU/day
   – Vitamin C 250-500 mg/day
        Omega-3 Fatty Acids:
            Side-Effects and Safety

• No known toxicity
   – Arctic peoples ingest 15-20 g/d of EPA + DHA
   – Heavy metals & organic carcinogens in fish (not fish oil)
• Weight neutral or weight loss.
• GI side-effects are the only common complaint
   – Fishy aftertaste (“repeat”)
   – Nausea
   – Loose stools or diarrhea
• Only a theoretical risk of increased bleeding
          Omega-3 Fatty Acids:
                   Drug Interactions

• No known interactions with psychotropic drugs.
• Adverse interactions with blood thinners very unlikely:
   – Only a theoretical risk of increased bleeding
   – EPA only partially inhibits platelet aggregation via a transient
     eicosanoid effect
   – Aspirin inhibits platelets fully and irreversibly
   – No well-documented cases of bleeding have ever been reported.
   – A recent review of the literature revealed no bleeding episodes in
     >15,000 subjects in clinical trials of omega-3s
       Product Comparison Chart
Of Some Examples of Omega-3 Fatty Acids

Brand              Omega-3          EPA to DHA     aftertaste
                   concentration       ratio

OmegaBrite1        > 90%                7:1           +/-

Omega-7002         60-70%               3:2            ++

Nordic Naturals3     50%                3:2           +++

MaxEPA4             > 30%               3:2          ++++



1Omega   Natural Health, Inc. www.omegabrite.com
2Solgar Vitamin Co. Retail
3Nordic Naturals. www.nordicnaturals.com
4General Nutrition Centers. Retail
OmegaBrite

Supplement Facts
Serving Size: 3 capsules
                                Amount Per Serving         % Daily Value
Calories                              15
Calories from fat                     15
Total fat                              1.5 g                   2%*
Polyunsaturated fat                    1.5 g                                   1125 mg
Cholesterol                            0g                      0%*             ÷ 3
Vitamin E (as d-a-tocopherol)          3 IU                    11%
                                                                                  375 mg EPA
EPA (eicosapentanoic acid)           1,125 mg                                 (per 500 mg capsule)
DHA (docosahexanoic acid)             165 mg                   
Other omega-3 fatty acids               90 mg                  
Omega-6 fatty acids                     60 mg                  
Other fatty acids                       60 mg                  

*Percent Daily Values are based on a 2,000 calorie diet.
Daily value not established.                                      Distributed by Omega Natural health
Ingredients: fish oil, gelatin, glycerin                           Waltham, MA 02451
and vitamin E (as d-a-tocopherol).                                 www.omegabrite.com
    TERRESTRIAL SOURCES
   OF OMEGA-3 FATTY ACIDS
   •   Flaxmeal or flaxseed oil
   •   Perilla Oil
   •   Chia
   •   Borage seed oil
   •   Hemp oil: Too much omega-6 (n6:n3 = 4:1)
   •   Wild game
   •   Omega-3 enriched eggs1,2,3


1Lewis  et al. Enriched eggs as a source of n-3 polyunsaturated fatty
acids for humans. Poult Sci 2000;79:971-4.
2Three omega-3 enriched eggs = 1 serving fatty fish.
3The Country Hen. Box 333, Hubbardston, MA 01452
www.countryhen.com
                 FLAX OIL
             (a-Linolenic acid)
        Advantages                             Drawbacks
• More palatable than              • No controlled data in
  fish oil                           neuropsychiatric disorders
• Native flax oil more             • May cause more manic
  concentrated than                  switch than fish oil
  native fish oil                  • Limited conversion to
                                     longer chain omega-3
• May be used in
  recipes (but not as a
  frying oil)

Usage: 1 tablespoon (~7 g of ALA) qd-TID or use capsules.
Omega-3 dosage with flax oil should be the same or higher as
that used for fish oil, due to the incomplete conversion of ALA
        FLAXSEED TOXICITY?
• Inexplicable link to prostate cancer:
    – At least 4 epidemiological studies associated ALA content
      of blood with elevated rates of prostate cancer.1-4
    – In vitro data also suggests ALA promotes prostate cancer.5
    – Omega-6 fatty acids also promote tumorigenesis.5
    – Adequate EPA inhibits tumorigenesis.5
• The seed husks of flaxseeds (also lima & cassava beans)
  contain cyanogen, which is converted thiocyanate.
  Thiocyanate inhibits iodine uptake by thyroid, possibly
  leading to goiter. Cyanogen is destroyed during cooking.
  Flaxseed oil is free of cyanogen.6
1Giovannucci    et al. J Natl Cancer Inst 1993;85:1571-1579.
2Godley et al. Cancer Epidemiol Biomarkers Prev 1996;5:889-895.
3Harvei et al. Int J Cancer 1997;71:545-551
4De Stefani et al. Cancer Epidemiol Biomarkers Prev 2000;9:335-338.
5Pandalai et al. Anticancer Res 1996;16:815-820.
6Simopoulos A. 1999
   IS FISH STILL A GOOD SOURCE OF
               OMEGA-3?

 For the general population, the American Heart Association
recommends at least two 3 oz servings of fatty fish per week.

     •   Anchovies              •   Mackerel
     •   Bluefish               •   Pompano
     •   Herring                •   Salmon
     •   Lake trout             •   Striped Sea Bass


   Source: U.S.D.A., Agricultural Research Service. 2001.
 IS FISH STILL A GOOD SOURCE OF
             OMEGA-3?

• Pollutants, such as Hg, Cd, and PCBs, tend to be higher
  in large, long-lived, predatory fish having more dark meat:
   – Shark, swordfish, king mackerel, and tilefish.
• The FDA has advised pregnant women and young
  children to avoid eating these types of fish:
   – Hg in the meat may harm an unborn baby's developing nervous
     system.
   – These fish contain ~1,000 ppb (parts per billion) of Hg: the FDA
     limit for human consumption
   – Most other fish have about 10-30% of this amount.
• The EPA has advised that fresh-water fish may contain
  more mercury than commercially caught fish:
   – Limit of 1 fresh-water fish meal (~ 6 ounces) per week.
              ConsumerLab.com, LLC.
                                  VITAMINS & MINERALS
    HERBALS                                  Calcium
     Echinacea                                  Iron
    Ginkgo biloba                          Multivitamins
       Ginseng                             Multiminerals
Red clover isoflavones                      Vitamin C
    Saw palmetto                            Vitamin E
  Soy isoflavones
   St. John’s wort     OTHER SUPPLEMENTS
       Valerian
                            Chondroitin
                              CoQ10
                             Creatine
                              Fish oil
                           Glucosamine
                               MSM
                              SAMe
     Journal Summaries

• Currents in Affective Illness
   – 301-320-6915
   – 7000 Carmichael Av, Bethesda, MD 20817
• Biological Therapies In Psychiatry Newsletter
   – <www.btpnews.com>           1-800-700-9589
• Psychiatry Drug Alerts
   – <www.alertpubs.com>         1-973-898-1200
• International Drug Therapy Newsletter
   – Ayd Medical Communications. 1130 E. Cold Spring
      Lane, Baltimore, MD 21239
• The Integrative medicine Consult
   – <www.onemedicine.com> 1-617-641-2300
     USEFUL WEBSITES in
   PSYCHOPHARMACOLOGY
• Medline via “PubMed”
   – <www.ncbi.nlm.nih.gov.entrez>
• NIMH
   – <www.nimh.nih.gov>
• CYP450 info
   – <www.georgetown.edu.departments/pharmacology/clinli
     st.html>
• Pharmaceutical industry: R & D Directions.
   – <www.rddirections.com>
• Evidence-based Psychiatry
   – <www.cebmh.com>
           FINANCIAL DISCLOSURE
                    Andrew L. Stoll, M.D.
  Dir., Psychopharmacology Research Lab., McLean Hospital
  Associate Professor of Psychiatry, Harvard Medical School

• Research Grant support: Abbott Laboratories, Janssen
  Pharmaceutica, Eli Lilly & Co., Solvay Pharmaceuticals, NIH,
  Harvard Medical School, The Stanley Foundation, The Poitras
  Charitable Fund, and the Hirschhorn Foundation.
• Speaker's Bureau: Abbott Laboratories, Astra-Zeneca, Bristol-
  Myers Squibb, Forest Laboratories, Glaxo, Janssen
  Pharmaceutica, Eli Lilly & Co., Organon, Pfizer (Parke-Davis),
  Smith-Kline Beecham, Wyeth-Ayerst.
• Consultant: Abbott Laboratories, Bristol-Myers Squibb, Glaxo,
  Eli Lilly & Co., Pfizer (Parke-Davis), and CX Research, Inc.
• Major Stockholder: None.
• Other: Dr. Stoll has a published a book on omega-3 fatty acids:
  "The Omega-3 Connection" (Simon and Schuster, 2001). His
  wife, Carol A. Locke, M.D. creates nutraceutical products for
  psychiatry and is the Founder and CEO of Omega Natural
  Health, Inc., the maker of OmegaBrite™. (www.omegabrite.com
  1-888-43-OMEGA)

				
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