The “bible” with which the diagnosis of BPD is currently made is the APA’s DSM, currently in it’s fourth edition with a text revision update. Diagnosis of BPD according to the DSM is complex: Four subtypes: 1. Bipolar Disorder I 2. Bipolar Disorder II 3. Cyclothymia 4. Bipolar Disorder Not Otherwise Specified Five types of episodes: 1. Manic 2. Hypomanic 3. Mixed 4. Depressed 5. Unspecified Four severity levels: 1. Mild 2. Moderate 3. Severe without psychosis 4. Severe with psychosis Three course specifiers 1. With or without inter-episode recovery 2. Seasonal pattern 3. Rapid cycling
This study of patients with bipolar disorder who were members of the US National Depressive and Manic Depressive Association found that 60% reported significant problems related to symptoms of bipolar disorder before the age of 20 years. References Hirschfeld RM, et al. J Clin Psychiatry 2003;64:161-174.
Patients with bipolar disorder have high rates of psychiatric comorbidity. The most common psychiatric comorbidities are anxiety disorders, substance abuse and dependence, and conduct disorders. The presence of psychiatric comorbidity complicates the diagnosis and treatment of bipolar disorder and is often associated with poor prognosis. References Kessler RC, et al. Psychol Med 1997;27:1079-1089.
An analysis of the impact of bipolar I or II disorder compared with unipolar depression in the workplace reveals that the impact of bipolar disorder is substantially worse than that of unipolar disorder (US study). Approximately 50 days of work are lost annually per worker with bipolar disorder compared with 32 days per worker with major depression. References Kessler RC, et al. Arch Gen Psychiatry 2005;62:590-592: National Comorbidity Survey Replication (NCS-R).
Bipolar disease state slide kit _ 10 January 2008 [FINAL VERSION] Impact of bipolar disorder on patients’ lives It is estimated that an adult who has developed bipolar disorder loses 12 years of a healthy life, 14 years of working life and that their life expectancy is reduced by 9 years. Bipolar disorder also has an effect on employment and marriage as shown in a study by Coryell et al, who examined the impact bipolar disorder had on patients’ lives. Patients with bipolar disorder (n=148) were assessed when they first sought treatment and then again after 5 years follow-up. Results showed that employment problems and divorce/separation were twice as common in patients with bipolar disorder. References Coryell W et al. The enduring psychosocial consequences of mania and depression. Am J Psychiatry 1993; 150: 720-727. Scott J. Psychotherapy for bipolar disorder. Br J Psychiatry 1995; 167: 581-588.
This slides summarises standardised mortality ratios (observed deaths/expected deaths) among untreated and treated hospitalised patients with bipolar disorder followed prospectively in Switzerland by Angst. Not only was suicide more common in bipolar disorder, but many general medical causes of death were also elevated. Being on any form of treatment consistently reduced the mortality rates. Overall mortality was significantly lower in treated than in untreated patients. Mortality was also significantly lower among treated patients for cancer, vascular diseases, suicide and other causes except accident or intoxication. In particular, treatment was associated with marked reductions in rates of suicide. This highlights the importance of accurate diagnosis of bipolar disorder so that patients receive appropriate drug therapy. References Angst F, et al. J Affect Disord 2002;68:167-181.
The Mood Disorder Questionnaire (MDQ), a validated screening instrument for bipolar I and II disorders, was sent to a sample of 127,800 people selected to represent the US adult population by demographic variables. 85,358 subjects (66.8% response rate) that were 18 years of age or above returned the survey and had usable data. Of the non-respondents, 3404 subjects matched demographically to the 2000 US Census data completed a telephone interview to estimate non-response bias. Among persons who elected to complete the MDQ, only 20% with scores indicative of bipolar disorder had ever received any diagnosis for bipolar disorder. References Hirschfeld RM, et al. J Clin Psychiatry 2003;64:53-59.
As you can see from the 2000 National Depressive and Manic Depressive Association’s Bipolar Survey, correct diagnosis has been a tough challenge, historically. Just three years ago, 69 percent of patients in the survey had been misdiagnosed as having unipolar depression, when in fact they were suffering with bipolar disorder. And 35 percent of them waited at least 10 years for the correct diagnosis to be made.
This study of patients with bipolar disorder who were members of the US National Depressive and Manic Depressive Association found that for the patients who had ever received any other psychiatric diagnosis, the diagnoses were widely varying, but with depression and anxiety clearly at the top. References Hirschfeld RM, et al. J Clin Psychiatry 2003;64:161-174.
The diagnosis of bipolar depression may be particularly difficult to make in the absence of spontaneous mania or hypomania. A series of empirical studies have suggested the existence of several predictors of bipolarity in such cases. The latter are related to personal and family history, temperament, characteristics of the depressive episode and response to antidepressants. The main identifying features of bipolar depression suggested by these studies are presented on this slide as well as on the following one. References Nassir Ghaemi S et al. Can J Psychiatry 2002;47:125–134. Kaye NS. J Am Board Fam Pract 2005;18:271–281.
References Nassir Ghaemi S et al. Can J Psychiatry 2002;47:125–134. Kaye NS. J Am Board Fam Pract 2005;18:271–281.
In the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (NIMH STEP BD), among 1,360 US patients who entered experiencing a depressive episode, 69% had at least one manic symptom. The most frequent manic symptoms did not include elation or grandiosity. Rather, distractibility, racing thoughts, rapid speech, increased activity were the most prevalent, with the latter four associated with at least four manic symptoms in the majority of patients. References Goldberg JF et al. Am J Psychiatry 2009; 166:173–181.
The MDQ can be used to identify patients most likely to have bipolar disorder. The MDQ is a screening instrument and not a diagnostic tool. It has been validated in a psychiatric outpatient setting and in the general population. It contains 13 questions, concerning mood, self–confidence, energy, sociability, interest in sex, and other behaviours, plus two items assessing symptom co–occurrence and the severity of functional impairment caused. References Hirschfeld RM et al. Am J Psychiatry 2000;157:1873–1875. Available at http://www.dbsalliance.org/pdfs/MDQ.pdf
The HCL-32 is a 32-item questionnaire that may help identify the hypomanic component of depressive episodes and increase the detection rate of both bipolar disorder type II and minor bipolar disorders (bipolar spectrum disorders). Using this brief questionnaire helps to identify patients most in need of more detailed psychiatric diagnosis. The HCL–32 is currently validated in several countries. References Angst J et al. J Affect Disord 2005;88:217–233.
The BSDS was originally designed to detect the milder portions of the bipolar spectrum in outpatients. It is composed of two parts: The first part is a paragraph containing 19 positively valenced sentences describing many of the symptoms of bipolar disorder. Each sentence is followed by an underlined space for subjects to place a checkmark if they feel that it applies to them. Each checkmark is worth one point The second part of the BSDS is one simple, multiple–choice question, asking subjects to rate how well the story describes them overall: This story fits me very well, or almost perfectly (6 points) This story fits me fairly well (4 points) This story fits me to some degree, but not in most respects (2 points) This story doesn't really describe me at all (0 point) The total score on the BSDS can range from 0 to 25 References Nassir Ghaemi S et al. J Affect Disord 2005;84:273–277. Available at http://www.psycheducation.org/depression/BSDS.htm
References Sachs GS. Acta Psychiatr Scand 2004;110(suppl 422):7–17. Post RM, Altshuler LL. In: Kaplan & Sadock ’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment of Bipolar Disorders. 2009.
This slide presents a schema for graphing the prospective course of mood disorders. Hard copies of the National Institute of Mental Health Life Chart Method (NIMH–LCM) are available from www.bipolarnews.org References Post RM, Altshuler LL. In: Kaplan & Sadock ’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment of Bipolar Disorders. 2009.
Bipolar disease state slide kit _ 10 January 2008 [FINAL VERSION] Treatment aims in bipolar disorder Patients with bipolar disorder require a comprehensive and long-term programme of medical care to help them overcome their symptoms and functional impairment associated with this highly recurrent disorder. The main goal of treatment is to ensure mood stabilisation in patients with bipolar disorder. This can be achieved by controlling the acute symptoms of bipolar disorder and in the long term preventing relapse. It is also important to ensure that patients adhere to treatment and that any comorbid conditions are managed effectively. Reference Vieta E. The package of care for patients with bipolar depression. J Clin Psychiatry 2005; 66 (Suppl 5): 34-39.
Electroconvulsive therapy (ECT) is considered a mood-stabilizing treatment. It tends to be used for patients who are suicidal or severely ill and cannot wait for medications to work, or have a history of nonresponse to treatments. Lithium has been the main treatment for acute mania for over 40 years. Lithium appears to be effective for individuals with euphoric mania, but is less effective in mixed manic episodes and in rapid-cycling bipolar disorder. First-generation antipsychotic treatments have been prescribed to combat the psychotic symptoms sometimes associated with manic episodes of bipolar I disorder. Antipsychotics are also used to treat symptoms of anxiety, insomnia, and agitation often associated with manic episodes, even when no psychosis occurs. Antipsychotics are used both as monotherapy and as adjuncts to mood stabilizers for the initial treatment of acute mania. However, intolerable side effects associated with conventional antipsychotics, such as EPS and tardive dyskinesia (TD), can increase patient health burden and have a negative impact on compliance. Valproic acid and its salts (divalproex sodium and sodium valproate), originally developed as an anticonvulsant to treat seizures, have been used to treat bipolar disorder for a number of years. While data support its efficacy in treating euphoric and mixed manic episodes, the data to support efficacy in prophylaxis are considerably weaker. Preliminary research suggests that several other anticonvulsants (eg, lamotrigine, gabapentin, and topiramate) may also possess mood- stabilizing properties. Second-generation antipsychotics have a greatly improved side-effect profile over conventional antipsychotics in terms of EPS and TD liability. Currently, olanzapine is the only atypical agent approved for use in acute mania. Although atypical agents show improvements over conventional agents, concerns remain regarding the emergence of drug-specific side effects such as excessive weight gain, diabetes, lipid abnormalities, QTc prolongation, and somnolence. Aripiprazole is a novel antipsychotic with a unique mechanism of action. This new agent shows promise as a treatment with efficacy against acute mania and an improved safety and tolerability profile. 1. Nemeroff CB. An ever-increasing pharmacopoeia for the management of patients with bipolar disorder. J Clin Psychiatry . 2000;61(suppl 13):19-25. 2. McElroy SL, Keck PE Jr. Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry . 2000;48:539-557. This slide provides a historic overview of current therapies used to treat acute mania and potential treatments that may help to improve treatment outcomes.
Drug Response Dependent on 3 Variables As noted above. Reference Preskorn S. The slippery slide. J Pract Psychiatry Behav Health . 1999;5:50-55.
Bipolar disease state slide kit _ 10 January 2008 [FINAL VERSION] FDA-approved treatments [Please note that this chart does not imply comparable efficacy or safety profiles] Reference Physicians’ Desk Research. PDR: Guide to drug interactions, side effects and indications. Thompson Healthcare; 62 nd Annual Edition, 2007.
1 4 Drug Specificity: Comparative Receptor Binding Profiles As noted above. Reference Gareri P, et al. Conventional and atypical antipsychotics in the elderly: a review. Clin Drug Invest. 2003;23(5):287-322.
Rationale-based Pharmacotherapy Important Principles This slide shows the receptor binding affinities of common antipsychotic medications, with lower inhibition constant (Ki) indicating very high affinity for the receptor. It also indicates the major physiological effects of blockade of each receptor type. Reference Weiden P, et al. Translating the psychopharmacology of antipsychotics to individualized treatment of severe mental illness: a roadmap. J Clin Psychiatry . 2007;68(7):5-46.
Binding Affinities for Atypical Antipsychotics and Tricyclic Antidepressants for Norepinephrine Transporter (NET) As noted above. Reference Goldstein J, et al. Quetiapine’s antidepressant properties: direct and indirect pharmacologic actions on norepinephrine and serotonin receptors. Eur Neuropsychopharmacol . 2007;1 7(S4):S401.
This slide shows the initiation of sustained ultradian cycling during unopposed antidepressant treatment in a bipolar II female with a 30 year delay in onset of appropriate treatment (in 1988). References Post RM, Altshuler LL. In: Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment of Bipolar Disorders. 2009.
Bipolar Disorder: Challenges & Horizons Prof. Hisham Ramy Professor of Psychiatry (ASU) Consultant Psychiatrist (UK) Secretary GeneralNational Mental Health Commission
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
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.
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
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
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
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)
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
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
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"
Personal Tragedies: Hemingwayborn on July 21,1899Several suicideattempts1961 shot himself.
Personal Tragedies: Vivian LeihBorn in 1913Throughout herpossession by thatuncannily evilmonster, manicdepression, with itsdeadly ever-tightening spirals.Died in 1967
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
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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
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
TypesAncient Treatments exorcism, caged like animals, beaten, burned, castrated, mutilated, blood replaced with animal’s blood
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.
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
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
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
IdeallyThe ideal treatment for bipolardisorder would achieve moodstabilisation by effectivelytreating mania and depressionand preventing relapse amongpatients with bipolar I and IIdisorder and rapid cyclers
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
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
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
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
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
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
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
Lithium - Pharmacology Dosed to a serum therapeutic range of0.6 – 1.2 mEq/L Usual dosage: 900 – 1200 mg / day Excreted unchanged by kidneys
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
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)
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
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
Valproate - PharmacologyMetabolized by liver90% plasma protein boundAnticonvulsant serum level: 50 -100 mcg/mLBlood levels for Tx of mania notestablished but usually the same
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
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,
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
Carbamazepine - Pharmacology Inhibits voltage-dependent sodium channels 70-80% protein bound Induces its own metabolism (autoinduction), requiring increase in dose after 2-3 weeks
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
Carbamazepine – Adverse EventsTeratogenicity - in 1st trimester,increased incidence of neural tubedefects (1-4%), reduced risk withfolate supplementation
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
Lamotrigine - PharmacologyModerate protein bindingInitial daily dose: 25mg /day Increase weekly to maintenance dose of 75-250mg / dayValproate inhibits metabolism oflamotrigine Requires slower dose titration
Lamotrigine – Adverse EventsRash in 10% of patientsRequires discontinuation because ofrisk of progression to Stevens-Johnson syndromeUsually occurs in first 8 weeks of TxAseptic meningitis
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*
Medication approved for bipolardepression MonotherapyLithiumOlanzapine/fluxetineQuetiapineLamotrigine
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.
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.
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).
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
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
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
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
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.
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
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.
Future treatmentBifeprunoxPramipexolelicarbazepineGLYT1 (glycine transporter) inhibitorGlycine site specific NMDA modulatorNK-3 antagonistGlucocorticoid receptor type II (GRII) antagonist,progesterone receptor antagonist