Transcript Integrative Management of Bipolar Disorder Toronto GPPA

Integrative Management of Bipolar
Disorder
General Practice Psychotherapy Association
Annual Conference
24-25 April, 2009
Toronto
James Lake M.D.
www.IntegrativeMentalHealth.net o
The burden of bipolar disorder
• 1% of U.S. adults fulfill criteria for the DSM-IV
diagnosis of Bipolar disorder
• Recurrent manic episodes linked with
progressive deterioration in functioning
• Two thirds dx’d with BD unemployed but most
have attended college (WHO Report 2001)
• 25% of Bipolar I pts attempt suicide, 15%
eventually succeed.
Integrative Management of Bipolar
Disorder
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Etiology
Definitions
Diagnosis
Assessment
Treatment
Case vignette
Etiology
• First-degree relatives significantly
more likely to develop BD than the
population
• Identical twins have 70%
concordance rate
• Fraternal twins have 15%
concordance rate (Gurling 1995)
Etiology
• Decreased expression of RNA coding for
mitochondrial proteins causes
dysregulation of CNS energy metabolism
especially hippocampus (Konradi 2004)
• Both phases of BD may be manifestations
of chronic folate deficiency (Hasanah
1997)
Defining Bipolar Disorder
Symptom type, severity and duration
Mania may include
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pressured speech
racing thoughts
euphoric or irritable mood
Agitation
inflated self-esteem
Distractibility
excessive or inappropriate involvement in pleasurable
activities
– increased goal-directed activity
– diminished need for sleep
– psychosis.
Dx criteria for Mania
• Elevated or irritable mood
• lasts at least one week
• Accompanied by at least three of above
symptoms
• Causes significant social or occupational
impairment
• Cannot be explained by substance abuse or
medical problem
Dx criteria for hypomania
• Elevated or irritable mood
• Persists at least 4 days
• Together with 3 or more of above
symptoms
• Medical problems and substance abuse
ruled out
• Functioning not severely impaired
Bipolar variants
Pose Dx and Rx problems
Bipolar I vs Bipolar II
• One or more manic episodes sufficient to dx BD I
but most BD I patients have had many manic
episodes
• Previous depressive episode not required to dx
BD I
• At least one hypo-manic episode and one
depressive episode sufficient to dx BD II
• Moderate or severe depressive episodes
alternate with manic symptoms in BD I and BD II
“Mixed” mania and “rapid cycling”
• “Mixed” mania dx’d when mania and
depressed mood occur during same episode
• “Rapid cycling” requires at least four
complete mood cycles during 12-month
period
• Depressive sx three times more often than
mania, five times more often than rapid
cycling or mixed episodes (Judd 2002)
Cyclothymic Disorder
• Mild variant of BD
• Dx requires multiple hypo-manic and
depressive episodes
• Over two-year period
• Absence of manic, mixed or severe depressive
episodes
• Medical problems/substance abuse ruled out
• Absence of severe impairment
Making a diagnosis
Clarifying history and identifying
underlying factors
Diagnosis
• Based on personal and family history and
mental status examination
• Sometimes difficult to differentiate
between transient mania or hypo-mania
and acute agitation caused by other
factors
• Longitudinal history clarifies pattern of
mood changes
Dx Difficulties
• Euphoric, agitated or irritable pt may not
disclose psychotic episodes or mood sx related
to drug abuse
• Extreme mood swings in personality disorders,
especially BPD resemble variants of BD
Dx difficulties
• “Rapid cycling” dx’d as mood disorder or
personality disorder depending on
training
• Definitive dx of BD II and Cyclothymic DO
problematic because criteria overlap with
other disorders eg: MDD, Schizoaffective
Disorder, personality disorders
Assessment
Of patients complaining of mania or
mood swings
Conventional Assessment
• Lab studies (eg. TFTs, urinary tox screen)
rule out medical problems or substance
abuse causing or exacerbating sx
• Brain imaging studies rule out
neurological problems (eg. CVA (right
frontal), multiple sclerosis, seizure
disorders)
Assessment—folate deficiency
• Folic acid deficiency common in manic
patients (Coppen 1986)
• Chronic folate deficiency interferes with
serotonin synthesis
• Manic pts often have low RBC folic acid levels
but normal serum levels (Lee 1992; Hasanah
1997)
• Chronic folate deficiency in both phases
(McKeon 1991).
Assessment—QEEG mapping
• Abnormal EEG more common in mania than
depressed mood (Hughes 1999)
• Depressed mood, psychosis and acute mania
have distinctive patterns of brain electrical
activity on QEEG mapping
• Specific abnormal findings predict differential
response rates to different classes of mood
stabilizers or antipsychotics (Small 1999)
Assessment—QEEG
• Non-medicated manic pts have lower EEG
amplitudes in left anterior and temporal
regions (Small 1998)
• Non-responders more likely to have diffuse
theta at baseline and higher amplitudes in left
temporo-parietal regions
• Acutely manic inpatients who respond to
mood stabilizers more often have left sided
abnormalities
Assessment--GABA
• PCRT found high serum GABA levels predicted
improved response of mania to divalproex but
not lithium (Petty 1996)
• GABA levels normalized with response to Rx
treatment
• Serum GABA levels might clarify Rx planning in
patients who do not respond to conventional
mood stabilizers
Assessment—HVA
• High pre-treatment serum HVA levels
predicted improved response of acute mania
or psychosis to lower doses of typical
antipsychotics including haloperidol (eg,
5mg/day) (Chou 2000)
• Low pre-treatment HVA levels suggest need
for higher dosing strategies of typical
antipsychotics (eg up to 25mg/day)
Assessment—HVA
• Higher HVA levels may reflect higher
turnover of CAN dopamine and lower
effective doses of conventional
(dopamine-blocking) antipsychotics
• Unknown whether findings generalize to
atypical antipsychotics or other
medication classes
Assessment—VAS
• Case report: VAS reflex useful when evaluating
rapidly cycling mood changes poorly responsive
to conventional Rx
• VAS reflex identified appropriate Rx regimen
including: L-tryptophan 22g, vitamin C 10g,
acupuncture for energetic imbalance
• Previously non-responsive sx rapidly normalized
• Using VAS to identify Rx that restored energetic
balance resulted in cost savings (Ackerman 1989).
Treatment
Conventional Rx
• Conventional Rx address specific sx (mood stabilizers,
antidepressants, antipsychotics, sedative-hypnotics)
• Systematic review of PCRTs of mood stabilizers in BD
revealed markedly differing efficacy and tolerability for
different Rx (Smith et al. 2007)
• Lithium and olanzapine most effective for reducing
manic relapses
• Lamotrigine and valproate significantly reduced risk of
depressive relapses. Discontinuation due to AEs 100%
higher with lithium compared to valproate and
lamotrigine
Conventional Rx
• Debate over antidepressants in BD because of
mania risk, but many BD patients use to control
depressive mood swings
• Combining antidepressant and mood stabilizer
reduces mania risk
• Mania induction risk significantly less with SSRIs
and other more recently introduced
antidepressants (Salvi et al. 2007)
• Combining “atypical” antipsychotics and mood
stabilizers more effective than mono-therapies
for acute mania (Scherk et al 2007)
Conventional Rx—TMS
• TMS may have beneficial effects similar to ECT
with markedly lower AE risk
• Repetitive TMS of left pre-frontal cortex may be
effective Rx of depressive phase of BD; no reports
of mania induction in stable pts (Nahas 2003)
• Early findings of TMS for mania promising,
especially right prefrontal stimulation (Grisaru
1998) however RCTs using sham TMS highly
inconsistent (Kaptsan 2003).
Conventional Rx
Unresolved issues and limitations
Conventional Rx—limitations
• Only half of conventional Rx used to treat BD
supported by strong evidence (Boschert 2004)
• Half of all BD pts who take mood stabilizers as
maintenance therapy do not experience good sx
control or refuse to take medications (Fleck et al.,
2005)
• Widely used Rx protocols combine lithium with
antidepressants however systematic review
found only modest improvements in outcomes
(Ghaemi 2001)
Conventional Rx—limitations
• 50% of BD pts discontinue Rx
because of AEs: tremor, weight gain,
elevated liver enzymes
• High relapse rate in BD pts on
maintenance mood stabilizers
Conventional Rx—limitations
• Over two thirds of BD pts receive no Rx for
manic or depressive symptoms during active
phase of illness
• Debate over prevalence of BD vs MDD—less
severe mania sx often unreported; hypomania resembles agitation in MDD
• Failure to confirm mania hx often leads to
false dx of MDD and inappropriate Rx
(Benazzi 1997)
CAM and Integrative Rx
What the evidence suggests
Integrative Rx of Bipolar Disorder—
Defining the context
• Biological, psychological and social causes of
mania and depressive mood swings evaluated
in context of pt’s unique history
• High percentage of individuals dx’d with BD
use CAM together with prescription Rx
however weak evidence for safety and efficacy
of most non-conventional treatments (Ernst
2003; Dennehy 2004)
Integrative Rx—basic considerations
• Mental health professionals and CAM
practitioners should be familiar with evidence
for CAM Rx choices to give best advice
• Most appropriate integrative Rx determined
by sx type and severity, co-morbid medical or
psychiatric disorders, prev Rx and response,
preferences, cost and availability
Non-conventional Rx
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Omega-3 EFAs
Proprietary nutrient formula
Branch-chained amino acid drink
Adding choline to lithium
Trace lithium
Trace magnesium
St. John’s wort plus bright light in SAD
K+ supplementation for lithium AEs
Omega-3 fatty acids
• 4-mo PCRT 30 BD pts treated with Omega-3s
(9.6gm/d) vs placebo while continuing mood
stabilizers (Stoll 1999)
• Omega-3 group remained in remission
significantly longer than placebo
• Pts taking Omega-3 fatty acids only remained
in remission significantly longer than placebo
group
Omega-3 fatty acids
• 4 mo PCRT 121 rapid cycling or depressed BD
pts treated with EPA (6g/day) together with
mood stabilizers did not improve over placebo
(Keck et al. 2002)
• Some pts taking EPA in combination with
Lithium carbonate report improvements in
psoriasis presumably caused by a general
deficiency in Omega-3s or AE of lithium
(Akkerhuis 2003)
Omega-3 fatty acids—safety issues
• case report of hypomania induced by
high doses of omega-3 fatty acids (Kinrys
2000)
• Rare cases of increased bleeding times,
but not increased risk of bleeding, in pts
taking aspirin or anti-coagulants
• Omega-3s should be regarded as viable
Rx of mania and bipolar illness
Proprietary nutrient formula
• Proprietary nutrient formula containing 36
separate constituents significantly reduces mania,
depressed mood and psychosis in individuals dx’d
with BD when taken together with conventional
mood stabilizing medications (Popper 2001;
Kaplan 2001).
• Mechanism may involve correction of metabolic
errors that predispose some individuals to
become symptomatic when micronutrients
deficient in the diet (Kaplan 2001).
Proprietary nutrient formula
• First series took 32 capsules daily in four
divided doses over 6 mos. 11 pts were
able to reduce mood stabilizers by half
while improving clinically
• Second series 13 out of 19 BD pts who
took formula remained stable after
discontinuing mood stabilizers (Simmons
2003)
Proprietary nutrient formula
• Three pts resumed mood stabilizers because
of recurring mania
• 11 of 19 patients in the series who elected to
discontinue mood stabilizers while taking the
formula remained stable more than one year
• Four patients discontinued Rx because of GI
side effects including nausea and diarrhea
Proprietary nutrient formula (NOTE:
confirm details with Kaplan)
• Two PCRTs on-going in U.S. and Canada to
determine most efficacious nutrients, simplify
Rx and minimize AE risk
• Protocol starts with 6 capsules TID then 3
capsules TID after two months
• Large prospective studies needed to clarify
whether formula alone is beneficial alone or
as adjuvant
Proprietary multi-ingredient formula—
safety concerns
• Micronutrient-medication interactions require
gradual dose reductions (Popper 2001)
• Monitoring for AEs (specify) when starting
formula to minimize toxicity risk
• Lowering doses of mood stabilizers too rapidly
risks sx worsening while maintaining
medications at their therapeutic doses may
cause toxicity
Branch-chained amino acids
Branch-chained amino acid drink
• Certain branch-chain amino acids
resulting in acute tyrosine depletion may
improve acute mania (Barrett 2004).
• Mixture of amino acids excluding
tyrosine and phenylalanine (the
precursor of tyrosine) may reduce CNS
dopamine in BD pts improving mania and
cognitive functioning (Gijsman 2002)
Branch-chained amino acid drink
• Twenty acutely manic adult inpatients
randomized to tyrosine-free mixture
experienced significant improvements in
mania (McTavish 2001).
• 7-day DBPCT 25 BD pts randomized to
special tyrosine-free amino acid drink
60g/day versus placebo had significant
improvement in mania 6 hrs p. Rx; effects
lasted 6 wks post-Rx (Scarna 2003).
Adding choline to lithium
• Choline is required for biosynthesis of
acetylcholine (Ach); low Ach levels are
known cause of mania (Leiva 1990).
• Case study of Rx-refractory rapid-cycling
BD pts taking lithium—four of six
responded to addition of 2,000-7,200
mg/day free choline (Stoll 1996)
Adding choline to lithium
• Small PCRT found phosphatidylcholine
15gm to 30gm/day reduces severity of
both mania and depressed mood in BD
pts (Stoll 1996)
• Sx recurred when Rx discontinued
Trace lithium supplementation
• Small open study suggests BD I pts with mania
or depressed mood improve with low doses
(50 micrograms/meal) of a natural lithium
preparation (Fierro 1988)
• Responders had undetectable post-Rx serum
Li+ levels
• Large PCRTs needed to replicate findings
Trace magnesium supplementation
• Small pilot study suggests Mg
supplementation 40mEq/day as effective as
lithium in the treatment of rapidly cycling
Bipolar patients (Chouinard 1990).
• Large PCRTs needed to replicate findings
St. John’s wort plus Bright light
exposure
• Open study 169 self-referred pts with SAD
treated with SJW vs SJW combined with daily
am bright light exposure (Wheatley 1999)
• Both groups reported significant
improvements in anxiety and insomnia
• Combined Rx group reported greater
improvement in insomnia compared to SJWonly group
K+ supplementation for Lithium AEs
• Small open study suggests BD I pts who take
potassium 20mEq BID with lithium have fewer
AEs including tremor (Tripuraneni 1990)
• Pending confirmation by large PCRT study K+
supplementation may be effective Rx for BD pts
who don’t tolerate Li+ at therapeutic doses
• Pts with cardiac arrhythmias or on antiarrhythmic medications should consult with their
physicians before considering potassium
Integrative Management
Acute mania and maintenance
Goals of Integrative Rx
• Confirm diagnosis of BD, rule out co-morbid
psychiatric or medical disorders
• Document conventional, CAM and integrative
therapies already tried and response
• Identify core sx of depressed mood, mania,
psychosis, etc. that are focus of clinical attention
• Stabilize as rapidly as possible starting with
conventional or integrative protocols that have
been successful in previous episodes.
Goals of Integrative Rx
• When previous treatments not effective or no
previous similar episode, start with most
validated treatment protocol targeting core
symptom(s).
• Assess pt response, progress to less validated
conventional or integrative Rx with patient’s
informed consent of risks and benefits for all
therapies being considered.
Acute mania
• Priority on safety and rapid stablization often
requires psychiatric hospitalization
• Atypical antipsychotics probably most
effective and efficient Rx of severe mania and
accompanying psychosis; can stabilize within
hours or days
• “Loading” manic pt with mood stabilizer to
rapidly achieve therapeutic serum level is also
effective strategy for managing acute mania
Acute mania
• Omega-3s can be used adjunctively during the
initial stages of treatment and may permit
lower effective doses of mood stabilizers,
reduced incidence of treatment-emergent
AEs, and improved medication adherence
• Branch-chained amino acid drink still
experimental. Large PCRTs needed to replicate
findings before recommending
Treating residual sx and long-term
maintenance
• Residual sx of moderate insomnia and pressured
speech managed using melatonin, improved
sleep hygiene and guided imagery.
• Regular exercise and mind-body practice can
provide a healthy preventative framework for BD
patients.
• Following a period of stabilization doses of
conventional medications may be slowly tapered
in parallel with the gradual introduction of
proprietary nutrient formula.
Maintenance
• Consider SJW + bright light exposure in SAD pt
• Consider choline supplementation + lithium in Rxrefractory rapid cycling pts
• Trace lithium or Mg still experimental—need
large PCRTs to replicate findings before
recommending
• Consider adding K+ to lithium to reduce tremor
(only after pt medically cleared)
• All pts using CAM or integrative protocol should
be closely monitored for recurring mania, AEs
and toxic interactions.
Case Vignette
Presentation
• Lisa is 29 years old, single and unemployed. “I
feel numb inside my head...”
• In the ER she was acutely manic and psychotic
placed on a 5150 and psychiatrically hospitalized
• Further assessment revealed Lisa was paranoid,
internally preoccupied with euphoric mood; she
had not slept for one week; speech was
pressured, thoughts were racing; thought process
was derailed.
Going off medications
• Lisa is dx’d with BD I and started on a mood
stabilizer and an atypical antipsychotic.
• 3 days later she is discharged without acute
manic or psychotic symptoms.
• One month later Lisa discontinues
medications against medical advice “I don’t
want to be on meds all my life…I’ve always
believed in holistic medicine and don’t want
to put poison into my body…”
Relapse
• A friend brings Lisa to an urgent care facility
where she refuses medications but accepts a
referral to a local psychiatrist who practices
integrative medicine
• Lisa is evaluated the 2 days later, assessed as
acutely manic with psychotic symptoms, and
offered Rx plan: lithium carbonate, omega-3
essential fatty acids, B-vitamin complex, and
sedating atypical antipsychotic (at bedtime).
Integrative Rx
• Within 24 hours Lisa’s symptoms have markedly
diminished and there are no sig. AEs.
• Insomnia continues; mood remains mildly
euphoric and speech is pressured.
• Lisa reluctant to accept psychiatrist’s advice to
increase antipsychotic dose
• Remaining time spent on sleep hygiene and
guided imagery before bedtime
• Psychiatrist suggests controlled release melatonin
Follow-up Care
• Two weeks later sleeping consistently improved
and manic sx resolved
• Adherent with all supplements and medications;
serum Li+ level in mid therapeutic range.
• Distressed by hand tremor, requests lithium dose
be reduced and antipsychotic be discontinued;
psychiatrist lowers lithium dose from 1200mg to
900mg but advises continuing antipsychotic at
her current dose one more month then
tapering/discontinuing pending no recurring
symptoms of mania or psychosis.
Follow-up
• Lowering lithium dose resolves tremor and
she continues to take lithium as prescribed.
• Sleeping well and no longer needs to take
melatonin.
• Stable for at least two months and is able to
gradually reduce, then discontinue
antipsychotic while remaining stable on
lithium, vitamins and omega-3 fatty acids.
Follow-up and revised Rx plan
• Recently learned about proprietary nutrient
formula and wishes to DC lithium and start
formula.
• Started yoga practice, exercises almost daily,
continues in psychotherapy with emphasis on
CBT for stress reduction.
• Psychiatrist obtains informed consent to begin
nutrient formula and advises gradually titrating
dose over several weeks while monitoring for
toxic interactions with lithium.
On-going care
• One year after her manic episode Lisa
takes lithium 300mg at bedtime,
antipsychotic PRN to control occasional
recurring manic symptoms, nutrient
formula and omega-3 fatty acids
• She remains euthymic and does not have
AEs to medications or supplements
Resources on Safety
• Bratman, S. & Girman, A.M. (2003). Mosby’s
Handbook of Herbs and Supplements and
their Therapeutic Uses. St. Louis: Mosby, Inc
• Harkness, R. & Bratman, S. (2003) Mosby’s
Handbook of Drug-Herb and Drug-Supplement
Interactions. St. Louis: Mosby, Inc.
• www.naturaldatabase.com (Natural Medicines
Comprehensive Database)
• www.healthnotes.com
General resources
• APA CAM Caucus (www.APACAM.org)
• A Clinical Manual of Complementary and
Alternative Treatments in Mental Health,
eds. Lake and Spiegel, American Psychiatric
Press, Inc., January, 2007.
• Textbook of Integrative Mental Health Care,
Lake, Thieme Medical Publishers, September,
2006.
• NORTON book