Integrative Management of Bipolar Disorder Saybrook Residential Conference May 12-13, 2009

6. Integrative Management of Bipolar DisorderSaybrookResidential ConferenceMay 12-13, 2009 James Lake M.D.www.IntegrativeMentalHealth.net o

7. 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’dwith BD unemployed but most have attended college (WHO Report 2001) • 25% of Bipolar I pts attempt suicide, 15% eventually succeed.

8. Integrative Management of Bipolar Disorder • Etiology • Definitions • Diagnosis • Assessment • Treatment • Case vignette

9. 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)

10. 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)

11. Defining Bipolar Disorder Symptom type, severity and duration

12. 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.

13. 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

14. 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

15. Bipolar variants Pose Dx and Rx problems

16. 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

17. “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)

18. 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

20. Making a diagnosis Clarifying history and identifying underlying factors

21. 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

22. Dx Difficulties • Euphoric, agitated or irritable pt may not disclose psychotic episodes or mood sxrelated to drug abuse • Extreme mood swings in personality disorders, especially BPD resemble variants of BD

23. 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

24. Assessment Of patients complaining of mania or mood swings

25. 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)

26. Assessment—folate deficiency • Folic acid deficiency common in manic patients (Coppen1986) • 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).

27. 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)

28. 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

29. 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

30. 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)

31. 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

32. 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 sxrapidly normalized • Using VAS to identify Rx that restored energetic balance resulted in cost savings (Ackerman 1989).

34. Treatment

35. 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 • Lamotrigineand valproate significantly reduced risk of depressive relapses. Discontinuation due to AEs 100% higher with lithium compared to valproate and lamotrigine

36. 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)

37. 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).

38. Conventional Rx Unresolved issues and limitations

39. 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)

40. 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

41. 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)

43. CAM and Integrative Rx What the evidence suggests

44. 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)

45. 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

46. 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

47. 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

48. 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)

49. Omega-3 fatty acids—safety issues • case report of hypomania induced by high doses of omega-3 fatty acids (Kinrys2000) • 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

50. 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).