Integrative Management of Bipolar Disorder General Practice Psychotherapy Association Annual Conference April, 2009 Toronto James Lake M.D. 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 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 – 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; hypo- mania 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 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 SJW- only 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 anti- arrhythmic 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 Rx- refractory 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. (Natural Medicines Comprehensive Database)

General resources APA CAM Caucus ( A Clinical Manual of Complementary and Alternative Treatments in Mental Health, eds. Lake and Spiegel, American Psychiatric Press, Inc., January, Textbook of Integrative Mental Health Care, Lake, Thieme Medical Publishers, September, NORTON book