Bipolar Disorder:  Challenges & Horizons        Prof. Hisham Ramy  Professor of Psychiatry (ASU)   Consultant Psychiatrist...
‫‪Salah Jaheen‬‬‫ساعات أقوم‬           ‫بمبى بمبى‬‫الصبح قلبى‬               ‫الحياة‬       ‫حزين‬               ‫بقى‬    ...
Historical Aspects   Hippocrates
Historical AspectsAretaeus of Cappadocia
Historical Aspects    Avicenna
Historical Aspects  Robert Burton
Historical Aspects   The French
Historical Aspects    Kraepelin
Historical AspectsLeonard & Angst
Historical Aspects     Akiskal
Challenges       What is Bipolar Disorder ?• It is a spectrum of   The DSM-IV affective episodes     categorizes it into: ...
Challenges DSM-IV-TR: Complex Disorder Five types of episodes: Four subtypes Four severity levels Three course specifi...
Challenges           Complex Disorder Bipolar spectrum:    Bipolar I: Depression &mania    Bipolar II: Depression & hypom...
The flavours of bipolar spectrum 1                       Adapted from Akiskal & Pinto 1999
The bipolar spectrum 2Hyperthymic                     ‘Bipolar IV’                          Depressive mixed state ‘IV ½’ ...
Sigmund FreudMania is nothing but a reaction formation to Depression
Challenges• Prevalence: NCSR 2005  • Bipolar I: 2%  • Bipolar II: 1.5%  • Cyclothymia: 0.5%  • Bipolar Spectrum: 6%
Age of Onset                                                           Age <15 years                                      ...
Time spent in episodes        Patients with bipolar disorder regularly switch between mania and depression,               ...
Psychiatric comorbidity                  100      93%                   80                                      71%       ...
Prevalence and impact of bipolar             disorder in the workplace (NCS-R)                                            ...
Impact of bipolar disorder on patients’ lives Onset is usually during late adolescence and early adulthood, a time at whic...
Mortality in bipolar disorder                                      35                                                 Untr...
Personal tragedies: Van GoghBorn in 1853 July 1890, at the ageof 37, he walked intothe fields and shothimself in the chest...
Personal Tragedies: Hemingwayborn on July 21,1899Several suicideattempts1961 shot himself.
Personal Tragedies: Vivian LeihBorn in 1913Throughout herpossession by thatuncannily evilmonster, manicdepression, with it...
Bipolar disorder:                  an under-recognised mood disorder                                                      ...
The magnitude of the problem    High Rate of Misdiagnosis 600 bipolar patients:                                           ...
Prior diagnoses in bipolar patients       Depression                                         60%       Anxiety disorder   ...
The international BRIDGE study (Younget al, 2009),• sample of 5,600 patients with a major depressive    episode•   evaluat...
What is the Solution???
Improving Recognition Utilize family or other collateral informants Assess longitudinal factors       Determine age of f...
Identifying features of bipolar                    depression            Family history of BD in a first-degree relative ...
Identifying features of bipolar                    depression            Early age of onset of major depressive episode  ...
Symptoms of mania during a bipolar depressive            episodeIn the NIMH* Systematic Treatment Enhancement Program for ...
Mood Disorder Questionnaire (MDQ)           Brief, self-report screening instrument           Contains 13 questions on m...
Hypomania Checklist (HCL-32)             Self-rating questionnaire             Core of the instrument consists of a       ...
Bipolar Spectrum Diagnostic Scale                    (BSDS)                 Self-reporting questionnaire                 C...
Graphing the longitudinal course of                    bipolar disease            Collect retrospective patient’s course ...
Graphing the prospective course of                    mood disorders                                                      ...
Treatment aims in bipolar             disorder   Short term           Long term                     - prevention of- contr...
Treatment challenges in bipolar disorder                      Bipolar disorder is often unrecognisedInitial diagnosis     ...
IntroductionPlan.Goals.Place.Tools.
InputPatient.Informant.Records.Research.
GoalsShort term: Remission. Decrease risks.Long term: Maintain Remission. Good quality of life.
GoalsBipolar disorder is characterised by recurrent episodes of major disturbance        at the two ‘poles’ of mood distur...
PlaceHome (outpatient).Day hospital.Hospital.
ToolsPharmacotherapy.Psychosocial treatment.ECT.Others.
Evidence based ToolsPharmacotherapy & ECTProdrome Detection: Perry and colleaguesPsycho education: Colom and colleaguesCog...
DrugsChoice.Dose.Duration.
Psychosocial      TreatmentChoice.Duration.Setting.Frequency.
TypesAncient Treatments  exorcism,  caged like animals,  beaten, burned, castrated,  mutilated, blood replaced  with an...
Cognitive Behaviour Therapy (CBT)The main assumption behind CBT is thatpsychological difficulties depend on howpeople thin...
Psycho educationInformation (counselling).EE management.Medication management.Support.
Compliance EnhancementInformation.Schedule.Life chart.Models.Therapeutic alliance.
OthersProdrome Detection:Perry and colleaguesInterpersonal and Social RhythmTherapy (IPSRT) :Frank and colleagues
ECTIndications.Frequency.Number.Procedures.
Electroconvulsive Therapy (ECT)
ECT – EfficacyGold standard for treatment of MDD  Response rate 70-90% compared to  40-60% with pharmacotherapyHighly effi...
ECT - ProcedurePre-procedure – NPO, flumazenilPerformed in ECT suite, bedside or ICUInduction with rapidly acting anesthet...
ECT – SafetyMortality rate depends on medical comorbidity  Healthy individual: 1:10,000 mortality  Risk / benefit assessme...
Mood StabilizersLithiumValproateCarbamazepineLamotrigineTopiramate (not effective)Gabapentin (not effective)Atypical Antip...
IdeallyThe ideal treatment for bipolardisorder would achieve moodstabilisation by effectivelytreating mania and depression...
Mood Stabilizer “Must show efficacy in the treatment of acute mania and/or depression and the prophylaxis of subsequent ma...
The Evolution of Therapies for                   Bipolar Disorder1940       1950         1960      1970        1980     19...
Drug Response             Dependent on 3 Variables:                       2. Drug Concentration      3. Patient   1. Affin...
The Perfect Mood Stabilizer                    A L ousy Mood Stabilizer   Efficacy in              Efficacy in       Effic...
The Perfect Mood Stabilizer                       A L ousy Mood Stabilizer   Efficacy in                  Efficacy in     ...
FDA-approved treatments                            Mania   Mixed         Maintenance             Depression               ...
LithiumFirst medication to be found effective in Txof maniaNarrow therapeutic indexIndications:  Acute mania  Maintenance ...
Slide 74     Lithium – Mechanism           of ActionMechanism unknown Inhibits alpha unit of G- proteins coupled to cAMP, ...
Lithium - Pharmacology Dosed to a serum therapeutic range of0.6 – 1.2 mEq/L Usual dosage: 900 – 1200 mg / day Excreted unc...
Lithium        - Adverse EffectsNeurological – dysphoria, lack of creativity, slowedreaction times, memory difficulty, tre...
Lithium ToxicityCharacterized by  1.2 – 1.5 mEq/L: tremor, ataxia, diarrhea, nausea  1.5 – 2 mEq/L : increased risk of sei...
Lithium   - TeratogenicityEbstein’s Anomaly Malformation of tricuspid valve Can be mild to severe Associated with first tr...
Valproate (Depakine)Indications  Acute mania  Maintenance / prophylaxis of bipolar d/o  More effective than Li in rapid cy...
Valproate –         Mechanism of ActionIncreases the inhibitory neurotransmitterGABA by:  Inhibiting catabolism of GABA  I...
Valproate - PharmacologyMetabolized by liver90% plasma protein boundAnticonvulsant serum level:  50 -100 mcg/mLBlood level...
Valproate – Adverse             EventsGastrointestinal (nausea, dyspepsia,vomiting, diarrhea)Neurological (sedation, ataxi...
Valproate – Severe            Adverse EventsFatal hepatotoxicity (~2.6 in 100,000),hemorrhagic pancreatitis,agranulocytosi...
Carbamazepine (Tegretol)Indications:  Drug of choice for Tx of psychiatric Sx  associated with complex – partial Sz  Mood ...
Carbamazepine - Pharmacology   Inhibits voltage-dependent sodium    channels   70-80% protein bound   Induces its own m...
Carbamazepine – Adverse EventsDose related –      Non-dose related –  Double/blurred      Agranulocytosis (1  vision      ...
Carbamazepine – Adverse EventsTeratogenicity - in 1st trimester,increased incidence of neural tubedefects (1-4%), reduced ...
Lamotrigine (Lamictal)Indications:  Bipolar depression  Maintenance Tx of bipolar d/o  Refractory partial Sz  Pain d/oMech...
Lamotrigine - PharmacologyModerate protein bindingInitial daily dose: 25mg /day  Increase weekly to maintenance dose of  7...
Lamotrigine – Adverse EventsRash in 10% of patientsRequires discontinuation because ofrisk of progression to Stevens-Johns...
Atypical Antipsychotics    Olanzapine 5-20mg daily    Risperidone 1-6mg range daily    Quetiapine dose range 300-600mg dai...
Medication approved for bipolardepression MonotherapyLithiumOlanzapine/fluxetineQuetiapineLamotrigine
Drug Specificity:            Comparative Receptor Binding Profiles                 Quetiapine                             ...
Rationale-based Pharmacotherapy   Important Principles                                                                    ...
Binding Affinities for Atypical Antipsychotics                and Tricyclic Antidepressants for Norepinephrine            ...
Drugs are not enoughProdrome Detection: Perry and colleaguesPsycho education: Colom and colleagues3. Cognitive Therapy: La...
AntidepressantsAppropriate use and effectiveness iscontroversialAntidepressant-induced mania in 20-40% withall antidepress...
AntidepressantsConflicting evidence for efficacy againstdepressive relapse:  Protective?:     Altshuler L, et al¹ (retrosp...
AntidepressantsNo benefit?:  Frankle WG, et al¹ (retrospective, 50 pts, 30  weeks):     No difference in length of depress...
Initiation of sustained ultradian cycling during       unopposed antidepressant treatment in a bipolar II       female. 30...
FUTURE DIRECTIONS
Brain Affection
Brain Affection
Brain affection
Structural Changes With BPD Progression:    Episodes Are Associated With Brain Tissue LossPrefrontal Cortex↓ Left inferior...
HPA Axis Dysregulation                           in Bipolar Disorder     HPA axis hyperactivity prominent in BPD     Sig...
Anterior Limbic NetworksThalamus (MD)                                              Cerebellar                             ...
Future treatmentBifeprunoxPramipexolelicarbazepineGLYT1 (glycine transporter) inhibitorGlycine site specific NMDA modulato...
THANK YOU
Bipolar abbassia
Bipolar abbassia
Bipolar abbassia
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Bipolar abbassia

  1. 1. Bipolar Disorder: Challenges & Horizons Prof. Hisham Ramy Professor of Psychiatry (ASU) Consultant Psychiatrist (UK) Secretary GeneralNational Mental Health Commission
  2. 2. ‫‪Salah Jaheen‬‬‫ساعات أقوم‬ ‫بمبى بمبى‬‫الصبح قلبى‬ ‫الحياة‬ ‫حزين‬ ‫بقى‬ ‫أطل بره‬ ‫لونها‬ ‫الباب‬ ‫بمبى‬ ‫ياخدنى‬ ‫و انا جنبك‬ ‫الحنين‬ ‫وانت‬ ‫اللى لقيته‬ ‫جنبى‬ ‫ضاع‬ ‫واللى‬ ‫بوسة‬
  3. 3. Historical Aspects Hippocrates
  4. 4. Historical AspectsAretaeus of Cappadocia
  5. 5. Historical Aspects Avicenna
  6. 6. Historical Aspects Robert Burton
  7. 7. Historical Aspects The French
  8. 8. Historical Aspects Kraepelin
  9. 9. Historical AspectsLeonard & Angst
  10. 10. Historical Aspects Akiskal
  11. 11. Challenges What is Bipolar Disorder ?• It is a spectrum of The DSM-IV affective episodes categorizes it into: including: Bipolar I Disorder Major depressive episode Bipolar II Disorder Manic episode Cyclothymia Mixed episode Bipolar N.O.S. Hypomanic episode 5. Unspecified
  12. 12. Challenges DSM-IV-TR: Complex Disorder Five types of episodes: Four subtypes Four severity levels Three course specifiers  With or without inter-episode recovery  Seasonal pattern  Rapid cyclingE American Psychiatric Association. (2000). Diagnostic and StatisticalManual of Mental Disorders-Fourth Edition-Text Revision. Washington, DC:Author.
  13. 13. Challenges Complex Disorder Bipolar spectrum: Bipolar I: Depression &mania Bipolar II: Depression & hypomania Bipolar II-½: Depression & cyclothymic temp. Bipolar III: Depression & manic switch. Bipolar III-½: Depression & mood swings &SUD. Bipolar IV: Depression & FH &/ or hyperthymia.
  14. 14. The flavours of bipolar spectrum 1 Adapted from Akiskal & Pinto 1999
  15. 15. The bipolar spectrum 2Hyperthymic ‘Bipolar IV’ Depressive mixed state ‘IV ½’ Highly recurrent depression ‘bipolar V’ Adapted from Akiskal & Pinto 1999
  16. 16. Sigmund FreudMania is nothing but a reaction formation to Depression
  17. 17. Challenges• Prevalence: NCSR 2005 • Bipolar I: 2% • Bipolar II: 1.5% • Cyclothymia: 0.5% • Bipolar Spectrum: 6%
  18. 18. Age of Onset Age <15 years 33%Age ≥20 years 39% Age 15–19 years 27% Hirschfeld RM, et al. J Clin Psychiatry 2003;64:161-174
  19. 19. Time spent in episodes Patients with bipolar disorder regularly switch between mania and depression, and the amount of time in each state can vary Percentage time spent in each state of bipolar disorder 6% 3% 32% 36% 48% 53% 9% No symptoms 13% BP I, n=146, m=12.8 years1 Manic / hypomanic BP I, n=405, m=1 year3 Depressive 2% Mixed / rapid cycling 2% 37% 47% 50% 51% 1 2 1% 10% BP II, n=86, m=13.4 years2 BP II, n=102, m=1 year31 Judd et al. Arch Gen Psychiatry 2002;59:530-7 m, mood diaries2 Judd et al. Arch Gen Psychiatry 2003;60:261-93 Kupka et al. Bipolar Disord 2007;9:531-5
  20. 20. Psychiatric comorbidity 100 93% 80 71% 61% 59% Patients (%) 60 41% 40 29% 20 0 Any Any Alcohol Drug Conduct Adult anxiety substance dependence dependence antisocial behaviourKessler RC, et al. Psychol Med 1997;27:1079-1089
  21. 21. Prevalence and impact of bipolar disorder in the workplace (NCS-R) p<0.05 The annual lost human capital due to bipolar disorder is larger 49.5 than that due to major depression 31.9 6.4% 3.1% Bipolar I or II Major depression Bipolar I or II Major depression Prevalence in the workplace Annual lost days per ill workerKessler RC, et al. Arch Gen Psychiatry 2005;62:590-592National Comorbidity Survey Replication (NCS-R)
  22. 22. Impact of bipolar disorder on patients’ lives Onset is usually during late adolescence and early adulthood, a time at which individuals are establishing their careers and building long-term relationships Healthy life Reduced by 12 years Working life Reduced by 14 years Life expectancy Reduced by 9 years Employment problems Twice as common Divorce / separation Twice as common Results for patients developing bipolar disorder in their mid-20s Coryell et al 1993; Scott 1995
  23. 23. Mortality in bipolar disorder 35 Untreated Treated 30 * 25 20 Standardised mortality ratio 15 10 5 * * * * 0 Cancer Vascular Accident Suicide Other Total or diseases intoxication causes 220 bipolar inpatients followed up for 22 years or more *p<0.001 vs treated patientsAngst F, et al. J Affect Disord 2002;68:167-181
  24. 24. Personal tragedies: Van GoghBorn in 1853 July 1890, at the ageof 37, he walked intothe fields and shothimself in the chestwith a revolverHis last words "Latristesse dureratoujours"
  25. 25. Personal Tragedies: Hemingwayborn on July 21,1899Several suicideattempts1961 shot himself.
  26. 26. Personal Tragedies: Vivian LeihBorn in 1913Throughout herpossession by thatuncannily evilmonster, manicdepression, with itsdeadly ever-tightening spirals.Died in 1967
  27. 27. Bipolar disorder: an under-recognised mood disorder 80% of patients that screened positive for bipolar disorder* using the MDQ had not previously been diagnosed as bipolar *type I or II MDQ, mood disorder questionnaireHirschfeld RM, et al. J Clin Psychiatry 2003;64:53-59
  28. 28. The magnitude of the problem High Rate of Misdiagnosis 600 bipolar patients: Most frequent misdiagnosis: Unipolar depression 60% 35% were symptomatic for more than 10 years before correct diagnosis 10+ yearsNational Depressive and Manic-Depressive Association (NDMDA), Constituent Survey. 2001; Chicago, IL.Hirschfeld RMA, et al. J Clin Psychiatry. 2003;64:161-174.
  29. 29. Prior diagnoses in bipolar patients Depression 60% Anxiety disorder 26% Schizophrenia 18% Personality disorders 17% Substance abuse 14% Schizo-affective disorder 11%Hirschfeld RM, et al. J Clin Psychiatry 2003;64:161-174
  30. 30. The international BRIDGE study (Younget al, 2009),• sample of 5,600 patients with a major depressive episode• evaluated: using clinical judgment at entry then using broader systematic assessment to elicit reports of hypomania/mania.• The frequency of bipolar disorder which was 29% at entry based on clinical judgment, 47% by systematic evaluation of hypomania/mania according to the bipolarity specifier (broader definition of bipolar disorder than DSM IV).
  31. 31. What is the Solution???
  32. 32. Improving Recognition Utilize family or other collateral informants Assess longitudinal factors Determine age of first-episode onset Evaluate course to establish quality of inter-episode recovery Evaluate family history Review response prior to treatment Assess common conditions in differential diagnosis History Laboratories Assess common comorbidities Aim to estimate diagnostic confidence Sachs G. FOCUS. 2007;5(1):3-13.
  33. 33. Identifying features of bipolar depression  Family history of BD in a first-degree relative  Antidepressant-induced mania or hypomania  Hyperthymic or cyclothymic temperament  Recurrent major depressive episodes (>3)  Brief major depressive episodes (on average, <3 months)  Atypical depressive symptoms  Psychotic major depressive episodesNassir Ghaemi S et al. Can J Psychiatry 2002;47:125–34.Kaye NS. J Am Board Fam Pract 2005;18:271–281.
  34. 34. Identifying features of bipolar depression  Early age of onset of major depressive episode (<25 years)  Post-partum depression  Seasonality  Rapid on/off pattern, mood lability  Wearing off of antidepressant efficacy (acute but not prophylactic response)  Lack of response to ≥3 antidepressant treatment trials  Mixed depression, (psychomotor agitation, irritability, racing/ crowded thoughts)  Substance abuseNassir Ghaemi S et al. Can J Psychiatry 2002;47:125–134.Kaye NS. J Am Board Fam Pract 2005;18:271–281.
  35. 35. Symptoms of mania during a bipolar depressive episodeIn the NIMH* Systematic Treatment Enhancement Program for BD (NIMH STEP BD), 69% had at least one manic symptom. Most prevalent symptoms: distractibility, racing thoughts, rapid speech, increased activity 60 53.9% Proportion of patients (%) 50 40 ≥4 symptoms 1–3 symptoms 29.9% 30 20 15.8% 8.7% 9.9% 10.7% 9.3% 10 0 d d h s/ iity ty r se se p eec idea hts tib t ivi a vio ea emrea ee sp of oug t r ac ac eh cr c s l ed b In este e t s se d D or s ur igh g t h Di ea r isk lf f Fl cin cr se ed res ra In i gh*NIMH = National Institute of Mental Health ne P HGoldberg JF et al. Am J Psychiatry 2009;166:173–181.
  36. 36. Mood Disorder Questionnaire (MDQ)  Brief, self-report screening instrument  Contains 13 questions on manic symptomatology  Can detect bipolar I but less sensitive for bipolar II  Positive screen if at least 7 symptom items, co- occurrence of at least 2 symptoms and moderate to severe impairment  Available at http://www.dbsalliance.org/pdfs/MDQ.pdfHirschfeld RM et al. Am J Psychiatry 2000;157:1873–1875.
  37. 37. Hypomania Checklist (HCL-32) Self-rating questionnaire Core of the instrument consists of a checklist of 32 hypomanic symptoms Screening tool for hypomania but no difference between bipolar I and II Individuals with a total score of 14 or more are potentially bipolar Available at http://www.psycheducation.org/depression/HCL–32.htmAngst J et al. J Affect Disord 2005;88:217–233.
  38. 38. Bipolar Spectrum Diagnostic Scale (BSDS) Self-reporting questionnaire Consists of a descriptive story that captures subtle features of bipolar symptoms and course Equal sensitivity for bipolar I and II/not otherwise specified Optimum threshold for likelihood of bipolar disorder: Score ≥13 Available at http://www.psycheducation.org/depression/BSDS.htmNassir Ghaemi S et al. J Affect Disord 2005;84:273–277.
  39. 39. Graphing the longitudinal course of bipolar disease  Collect retrospective patient’s course of illness  Urge patients to continue this on a prospective basis  Provides a clear picture of the earlier course of illness, the best predictor of the future episode pattern  Clarifies pattern of prior medication responsiveness  Facilitates the recognition of low-level manic symptoms  Encourages the patient’s collaborationPost RM, Altshuler LL. In: Kaplan & Sadock ’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment ofBipolar Disorders. 2009.
  40. 40. Graphing the prospective course of mood disorders Benzodiazepines / Gabapentin MAOI Lamotrigine Antidepressant Atypical Antipsychotics Lithium Carbamazepine / Oxcarbazepine PROSPECTIVE (DAILY) RATINGS Hosp Severe Incapacitated Dysphoric Mania Si = suicide Mania High Moderate Much Low Moderate Some } Difficulty functioning attempt Approximate Dates Mild Not impaired Depression Mild Not impaired Low Moderate Some High Moderate Much } Difficulty functioning Severe Incapacitated SWITCHES SWITCHES PER MONTH PER DAY PA PA (i.e. = 4 = ultra (i.e. ultra – ultra Symptoms Comorbid panic attacks rapid) rapid cycling, or ultradian cycling) Alcohol Substance use (–4 to +4) Impact (3/1) Arrested for speeding (1/15/92) Got married (2/10/90) Promotion (8/23/91) Dog died (6/20/02) Lost job (2/12) All nighter Events Life MAOI = monoamine oxidase inhibitor; PA = panic attack; Si = suicide attemptPost RM, Altshuler LL. In: Kaplan & Sadock ’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment ofBipolar Disorders. 2009.
  41. 41. Treatment aims in bipolar disorder Short term Long term - prevention of- control of acute relapse Managementsymptoms of comorbid - treatment acceptance / conditions adherence Ultimate treatment goal – mood stabilisation Vieta 2005
  42. 42. Treatment challenges in bipolar disorder Bipolar disorder is often unrecognisedInitial diagnosis and undiagnosed Comorbidities Common, can hinder diagnosis Predominant symptomatic phase, Depression can lead to misdiagnosis Need for long-term symptom stability acrossChronic disorder both poles Bipolar I vs bipolar II, rapid cycling, Phenotypes mixed states Evans 2000; Hirschfeld 2003a, 2003b Judd et al 2002, 2003; Citrome 2005; Kupka et al 2007
  43. 43. IntroductionPlan.Goals.Place.Tools.
  44. 44. InputPatient.Informant.Records.Research.
  45. 45. GoalsShort term: Remission. Decrease risks.Long term: Maintain Remission. Good quality of life.
  46. 46. GoalsBipolar disorder is characterised by recurrent episodes of major disturbance at the two ‘poles’ of mood disturbance: mania and depression
  47. 47. PlaceHome (outpatient).Day hospital.Hospital.
  48. 48. ToolsPharmacotherapy.Psychosocial treatment.ECT.Others.
  49. 49. Evidence based ToolsPharmacotherapy & ECTProdrome Detection: Perry and colleaguesPsycho education: Colom and colleaguesCognitive Therapy: Lam and colleagues,Interpersonal and Social Rhythm Therapy(IPSRT) : Frank and colleaguesFamily-Focused Therapy (FFT) and IntegratedFFT/IPSRT: Miklowitz and colleagues
  50. 50. DrugsChoice.Dose.Duration.
  51. 51. Psychosocial TreatmentChoice.Duration.Setting.Frequency.
  52. 52. TypesAncient Treatments  exorcism,  caged like animals,  beaten, burned, castrated, mutilated, blood replaced with animal’s blood
  53. 53. Cognitive Behaviour Therapy (CBT)The main assumption behind CBT is thatpsychological difficulties depend on howpeople think or interpret events (cognitions),how people respond to these events(behaviour), and how it makes them feel(emotions).CBT aims to break the vicious cycle betweenthoughts, feelings and behaviours by helpingpeople to learn more useful ways of thinkingand coping.
  54. 54. Psycho educationInformation (counselling).EE management.Medication management.Support.
  55. 55. Compliance EnhancementInformation.Schedule.Life chart.Models.Therapeutic alliance.
  56. 56. OthersProdrome Detection:Perry and colleaguesInterpersonal and Social RhythmTherapy (IPSRT) :Frank and colleagues
  57. 57. ECTIndications.Frequency.Number.Procedures.
  58. 58. Electroconvulsive Therapy (ECT)
  59. 59. ECT – EfficacyGold standard for treatment of MDD Response rate 70-90% compared to 40-60% with pharmacotherapyHighly efficacious in Tx of catatoniaand schizophrenia with positive Sx
  60. 60. ECT - ProcedurePre-procedure – NPO, flumazenilPerformed in ECT suite, bedside or ICUInduction with rapidly acting anesthetic(methohexital, ketamine)Paralysis with rapidly acting NM blocker(succinylcholine)Application of electric current to skullGeneralized tonic-clonic SZ (0.5 - 2min)Recovery in 1-2 hours
  61. 61. ECT – SafetyMortality rate depends on medical comorbidity Healthy individual: 1:10,000 mortality Risk / benefit assessment is crucialCommon Side Effects, Temporary: Headache, myalgias Cognitive: anterograde, retrograde amnesia – worse with bilateral electrode placementUncommon / Rare Adverse Events Arrhythmias, MI, CVA, delirium, status epilepticus, prolonged apnea, Tx emergent mania
  62. 62. Mood StabilizersLithiumValproateCarbamazepineLamotrigineTopiramate (not effective)Gabapentin (not effective)Atypical Antipsychotics
  63. 63. IdeallyThe ideal treatment for bipolardisorder would achieve moodstabilisation by effectivelytreating mania and depressionand preventing relapse amongpatients with bipolar I and IIdisorder and rapid cyclers
  64. 64. Mood Stabilizer “Must show efficacy in the treatment of acute mania and/or depression and the prophylaxis of subsequent manic or depressive episodes, not worsen mood symptoms or acute episodes, and not increase the likelihood of an affective switch or cycling.”Expert Consensus Guidelines
  65. 65. The Evolution of Therapies for Bipolar Disorder1940 1950 1960 1970 1980 1990 2000 2002ECT Lithium First-generation Second-generation antipsychotics and antidepressants antipsychotics and antidepressants Clozapine Chlorpromazine* Risperidone+ Trifluoperazine Olanzapine* Fluphenazine Quetiapine+ Thioridazine Ziprasidone+ Haloperidol Aripiprazole+ Mesoridazine Asenipine Anticonvulsants Anticonvulsants Carbamazepine Gabapentin Valproate Lamotrigine TopiramateECT = electroconvulsive therapy Oxcarbazepine
  66. 66. Drug Response Dependent on 3 Variables: 2. Drug Concentration 3. Patient 1. Affinity Absorption Genetics Receptors Distribution Age Enzymes Metabolism DiseaseUptake Pumps Elimination Environment Clinical Response
  67. 67. The Perfect Mood Stabilizer A L ousy Mood Stabilizer Efficacy in Efficacy in Efficacy in Efficacy in Mania Depression Mania DepressionTolerability Safety Tolerability Safety L ithium Divalproex Efficacy in Efficacy in Efficacy in Efficacy in Mania Depression Mania DepressionTolerability Safety Tolerability Safety
  68. 68. The Perfect Mood Stabilizer A L ousy Mood Stabilizer Efficacy in Efficacy in Efficacy in Efficacy in Mania Depression Mania DepressionTolerability Safety Tolerability Safety L amotrigine Olanzapine Efficacy in Efficacy in Efficacy in Efficacy in Mania Depression Mania DepressionTolerability Safety Tolerability Safety
  69. 69. FDA-approved treatments Mania Mixed Maintenance Depression Mania Depression Bipolar I Bipolar IIMood stabiliser Lithium  –  – – – Divalproex DR  – – – – – Divalproex ER   – – – – Carbamazepine ER   – – – –Atypical antipsychotics Risperidone    – – – Olanzapine    – – – Quetiapine       Ziprasidone   – – – – Aripiprazole    – – –Other Lamotrigine – –   – – Olanzapine/fluoxetine – – – –  – Physicians’ Desk Reference 2007
  70. 70. LithiumFirst medication to be found effective in Txof maniaNarrow therapeutic indexIndications: Acute mania Maintenance / prophylaxis of bipolar d/o Bipolar depression Schizoaffective d/o, bipolar type
  71. 71. Slide 74 Lithium – Mechanism of ActionMechanism unknown Inhibits alpha unit of G- proteins coupled to cAMP, especially in beta adrenergic receptors This may interfere with neuronal activity occurring in mania PIP inhibition may improve depressive Sx
  72. 72. Lithium - Pharmacology Dosed to a serum therapeutic range of0.6 – 1.2 mEq/L Usual dosage: 900 – 1200 mg / day Excreted unchanged by kidneys
  73. 73. Lithium - Adverse EffectsNeurological – dysphoria, lack of creativity, slowedreaction times, memory difficulty, tremorEndocrine – hypothyroid, hypoparathyroidCardiovascular – sick sinus syndromeRenal – polydypsia, polyuria, nephrogenic diabetesinsipidus; long-term  decreased GFR, nephroticsyndrome, renal insufficiencyDermatological – acne, hair loss, psoriasis, rashGastrointestinal - anorexia, nausea, vomiting,diarrheaMisc – altered carbohydrate metabolism, weightgain, fluid retention
  74. 74. Lithium ToxicityCharacterized by 1.2 – 1.5 mEq/L: tremor, ataxia, diarrhea, nausea 1.5 – 2 mEq/L : increased risk of seizure > 2.5 mEq/L: coma, deathIn elderly or in pts. w/ renal failure, toxicitycan occur within the therapeutic range
  75. 75. Lithium - TeratogenicityEbstein’s Anomaly Malformation of tricuspid valve Can be mild to severe Associated with first trimester use Risk: 1 / 1,000 in Li exposed pregnancies(20x risk general population)
  76. 76. Valproate (Depakine)Indications Acute mania Maintenance / prophylaxis of bipolar d/o More effective than Li in rapid cycling and mixed bipolar states Adjuvant treatment in schizophrenia, schizoaffective disorder GTC / partial Sz, prophylaxis of migraine
  77. 77. Valproate – Mechanism of ActionIncreases the inhibitory neurotransmitterGABA by: Inhibiting catabolism of GABA Increasing release of GABA Increasing GABA b receptor density May improve neuronal responsiveness to GABA All which points to increased seizure control but is unclear how this affects mood disorders
  78. 78. Valproate - PharmacologyMetabolized by liver90% plasma protein boundAnticonvulsant serum level: 50 -100 mcg/mLBlood levels for Tx of mania notestablished but usually the same
  79. 79. Valproate – Adverse EventsGastrointestinal (nausea, dyspepsia,vomiting, diarrhea)Neurological (sedation, ataxia, dysarthria,tremor)Weight gain (up to 44% of patients)Alopecia (3-12% of patients)Transient thrombocytopeniaPersistently elevated transaminasesPCO
  80. 80. Valproate – Severe Adverse EventsFatal hepatotoxicity (~2.6 in 100,000),hemorrhagic pancreatitis,agranulocytosis Monitor LFT’s and CBC on initiation and periodicallyTeratogenicity – 1st trimester useassociated with increased risk of neuraltube defects, craniofacial defects,
  81. 81. Carbamazepine (Tegretol)Indications: Drug of choice for Tx of psychiatric Sx associated with complex – partial Sz Mood stabilization in bipolar disorder Unclear therapeutic range for mood disorders, usually use 8-12 mcg/mL
  82. 82. Carbamazepine - Pharmacology Inhibits voltage-dependent sodium channels 70-80% protein bound Induces its own metabolism (autoinduction), requiring increase in dose after 2-3 weeks
  83. 83. Carbamazepine – Adverse EventsDose related – Non-dose related – Double/blurred Agranulocytosis (1 vision in 125,000) Vertigo Aplastic anemia GI disturbance Hepatic failure (rare) Cognitive Rash impairment Pancreatitis Mild leukopenia
  84. 84. Carbamazepine – Adverse EventsTeratogenicity - in 1st trimester,increased incidence of neural tubedefects (1-4%), reduced risk withfolate supplementation
  85. 85. Lamotrigine (Lamictal)Indications: Bipolar depression Maintenance Tx of bipolar d/o Refractory partial Sz Pain d/oMechanism: Inhibition of glutamate release Inhibition of voltage-gated sodium channels
  86. 86. Lamotrigine - PharmacologyModerate protein bindingInitial daily dose: 25mg /day Increase weekly to maintenance dose of 75-250mg / dayValproate inhibits metabolism oflamotrigine Requires slower dose titration
  87. 87. Lamotrigine – Adverse EventsRash in 10% of patientsRequires discontinuation because ofrisk of progression to Stevens-Johnson syndromeUsually occurs in first 8 weeks of TxAseptic meningitis
  88. 88. Atypical Antipsychotics Olanzapine 5-20mg daily Risperidone 1-6mg range daily Quetiapine dose range 300-600mg daily Risk of tardive dyskinesia less than typical antipsychotics but still present Have antidepressant effect*
  89. 89. Medication approved for bipolardepression MonotherapyLithiumOlanzapine/fluxetineQuetiapineLamotrigine
  90. 90. Drug Specificity: Comparative Receptor Binding Profiles Quetiapine Clozapine Olanzapine D1 D2 M D1 D2 5HT2A H1 5HT1A 5HT2A H1 A1 A2 5HT1A A2 A1 Aripiprazole* Ziprasidone Risperidone Haloperidol 5H12C A1 D2 D1 5HT1A D3 H1 A1 A2 D2 5HT1A 5HT2A 5HT2AAdapted from Gareri P, et al. Clin Drug Invest. 2003;23(5):287-322.* BMS Data on file.
  91. 91. Rationale-based Pharmacotherapy Important Principles Effects of Receptor Receptor Binding Affinities Receptors Blockade Drug H1 D2 5-HT2C 5-HT2A α1 M1 Sedation, weight gain, H1 postural dizziness Haloperidol 440 0.7 > 10,000 45 6 > 1,500 EPS, prolactin elevation, D2 antipsychotic Aripiprazole 61 0.34 15 3.4 57 > 10,000 5-HT2C Satiety Blockade Olanzapine 7 11 23 4 19 1.9 5-HT2A Anti-EPS? α1- Hypotension Quetiapine 11 160 1,500 295 7 120 adrenergic Deficits in memory and Risperidone 20 4 25 0.5 0.7 > 10,000 cognition, dry mouth, M1 constipation, tachycardia, Ziprasidone 50 5 1 0.4 11 > 1,000 blurred visionValues represent Ki (nM); values in blue reflect the highest binding affinity for agiven drug; values in green reflect the lowest affinityAdapted from Weiden P, et al. J Clin Psychiatry. 2007;68(7):5-46.
  92. 92. Binding Affinities for Atypical Antipsychotics and Tricyclic Antidepressants for Norepinephrine Transporter (NET) Compound / drug NET Ki (nM) Quetiapine > 10000 Norquetiapine 35 Clozapine 3168 Olanzapine > 10000 Risperidone > 10000 Paliperidone > 10000 Aripiprazole 2093 Ziprasidone 44* Nortriptyline 2 Amitriptyline 13.3-35 Imipramine 52 Desipramine 0.55Data from NIMH Psychoactive Drug Screening ProgramGoldstein J, et al. Eur Psychopharmacol. 2007;17(S4):S401.*Using ex vivo methodology there was no inhibition of norepinephrine reuptake with ziprasidoneat serum concentrations typically observed during treatment (Owens and Nemeroff, personal communication).
  93. 93. Drugs are not enoughProdrome Detection: Perry and colleaguesPsycho education: Colom and colleagues3. Cognitive Therapy: Lam and colleagues,Interpersonal and Social Rhythm Therapy(IPSRT) : Frank and colleaguesFamily-Focused Therapy (FFT) and IntegratedFFT/IPSRT: Miklowitz and colleagues
  94. 94. AntidepressantsAppropriate use and effectiveness iscontroversialAntidepressant-induced mania in 20-40% withall antidepressant classes (TCAs > others)¹‚²Increased risk of switching³: Previous antidepressant-induced mania Bipolar family history Exposure to multiple antidepressant trials
  95. 95. AntidepressantsConflicting evidence for efficacy againstdepressive relapse: Protective?: Altshuler L, et al¹ (retrospective, 39 pts, 1 year): 35% relapse rate with antidepressant continuation 68% relapse rate with antidepressant discontinuation Altshuler L, et al² (prospective, 84 pts, 1 year): 36% relapse rate with antidepressant continuation 70% relapse rate with antidepressant discontinuation
  96. 96. AntidepressantsNo benefit?: Frankle WG, et al¹ (retrospective, 50 pts, 30 weeks): No difference in length of depressive episode regardless of antidepressant status Ghaemi S, et al² (open, randomized 33 pts, 1 year): Relapse rate 50% within 20 weeks regardless of antidepressant status
  97. 97. Initiation of sustained ultradian cycling during unopposed antidepressant treatment in a bipolar II female. 30–year delay in onset of appropriate treatment Severe Two brief bursts of ultradian cycling Mania Moderate Mid * * Depression Mid Moderate 1942 1956 1958 1960 1962 1964 1966 1968 1970 1972 Hypomanias and major depressive recurrences Severe Fluoxetine Carbamazepine depressions Trazodone Lithium Nimodipine age 13 Aprozalam Antidepressant treatment in absence of a mood stabiliser continued 1974 1976 1980 1982 1984 1986 1988 1990 1992 Conversion to continuous ultradian cycling following fluoxetinePost RM, Altshuler LL. In: Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment ofBipolar Disorders. 2009.
  98. 98. FUTURE DIRECTIONS
  99. 99. Brain Affection
  100. 100. Brain Affection
  101. 101. Brain affection
  102. 102. Structural Changes With BPD Progression: Episodes Are Associated With Brain Tissue LossPrefrontal Cortex↓ Left inferior prefrontal gray volumes with ↑ illness duration↓ Gray matter volume with ↑ ageStriatumNo difference in putamen between first- and multi-episode patientsCerebellum↓ Cerebellar vermis volume in multi- vs first-episode patientsAmygdala↑ Amygdala volume with ↑ age in young patientsVentricles↑ Ventricular volume in multi- vs first-episode patients↑ Ventricular volume with ↑ number of manic episodes↑ Ventricular volume with ↑ number of affective episodes
  103. 103. HPA Axis Dysregulation in Bipolar Disorder  HPA axis hyperactivity prominent in BPD  Significant hypersecretion of cortisol; state dependent abnormalities  Dexamethasone non-suppression  Abnormal response to physical and psychological stressors  Chronic elevation of glucocorticoidsGoodwin F, Jamison K. Manic Depressive Illness. Oxford University Press; New York, NY: 2007.
  104. 104. Anterior Limbic NetworksThalamus (MD) Cerebellar vermisVentral pallidum Amygdala Hypothalamus Ventral striatum Anterior cingulate OFC/VLPFC DLPFC subgenual dorsal Expression of emotions
  105. 105. Future treatmentBifeprunoxPramipexolelicarbazepineGLYT1 (glycine transporter) inhibitorGlycine site specific NMDA modulatorNK-3 antagonistGlucocorticoid receptor type II (GRII) antagonist,progesterone receptor antagonist
  106. 106. THANK YOU

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