Topics. Emo3onal States by dura3on. Paul Glue March Bipolar Disorder Clinical characteris3cs and pharmacotherapy

Transcription

1 Bipolar Disorder Clinical characteris3cs and pharmacotherapy Paul Glue March 2017 Topics Dimensions of mood Bipolar Disorder Concepts/History Epidemiology Pathophysiology Treatments for Bipolar depression Mania Prophyllaxis Emo3onal States by dura3on Affect Brief modula3on of emo3onal state in response to circumstances External; reason for emo3onal change is self-evident moment-to-moment expression of feelings Mood: Sustained (hours-days) emo3onal state. Internal and subjec3ve, but can be inferred e.g. from posture, behaviour. consistent, sustained feeling state Temperament/personality traits: Very long-las3ng emo3onal quali3es associated with a person s characteris3c behavioural tendencies Some personality traits (e.g. op3mism, neuro3cism) may predispose to certain types of moods. 1

2 Dimensional vs categorical characteriza3on Dimensional: mainly psychologists tes3ng college students (e.g.) Thayer (1980 s) 2 dimensions: energy (energe3c 3red) and tension (tense calm). Watson and Tellegen 1985: Posi3ve and Nega3ve Affect dimensions Schoberg 1979: Pleasantness and level of ac3va3on Categorical: mainly psychiatrists working with clinical popula3ons Neuro3c vs psycho3c Endogenous vs reac3ve Unipolar vs bipolar Etc etc Spectrum of Mood Bipolar Disorder Mood Behavior Thoughts Mania Expansive, euphoric, elevated, irritable energy, sleep, extravagant Racing; grandiose; unable to concentrate Euthymia Normal Normal Normal Depression Low, empty, depressed hopeless appe3te, energy, early AM waking Loss of interest/ pleasure; suicidal thoughts A brief history (lumpers and splicers) Arateus (C1) iden3fied mania and melancholia pa3ents who laugh, play, dance night and day, and some3mes go openly to the market crowned, as if victors in some contest of skill only to be torpid, dull, and sorrowful at other 3mes Falret C19: folie circulaire Baillarger C19: folie a double forme Kraepelin 1899: manic depressive insanity (vs demen3a praecox) 2

3 More history Carl Jung 1903 BP with/without psycho3c mania Forerunner of BP-I vs BP-II Karl Leonhard 1957 bipolar vs unipolar dis3nc3on Yet more history Karl Leonhard those subgroups in full. Clinical Pictures of Phasic Psychoses (without Cycloid Psychoses) Manic Depressive Illness Pure Melancholia and Pure Mania Pure Melancholia Pure Mania Pure Depressions and Pure Euphorias Pure Depressions Agitated Depression Hypochondriacal Depression Self-Tortured Depression Suspicious Depression Apathe3c Depression Pure Euphorias Unproduc3ve Euphoria Hypochondriacal Euphoria Exalted Euphoria Confabulatory Euphoria Indifferent Euphoria Enough history already! RDC (1978) and DSM-III (1980) unipolar depression (MDE) vs bipolar disorder (BP-I/BP-II) Taylor and Fink 2006 back to Kraepelin unipolar depression = nonmelancholic depression - bipolar depression = melancholic depression 3

4 A more elaborate version. Two-dimensional mood/affective spectrum (does not include schizoaffective disorder, as a transition to the schizophrenic spectrum). Jules Angst BJP 2007;190: Now for the tough diagnoses: Mixed affec9ve states Symptoms of mania and depression appear simultaneously or in rapid succession e.g. racing thoughts in a depressive episode Tearfulness during mania DSM must meet criteria for MDE and a manic episode daily for 1 week Other concepts: Dysphoric mania (mania with prominent depressive symptoms) Agitated depression (depression with hypomanic symptoms) Bipolar spectrum disorder Popular if unproven diagnosis Pa3ents present with depression but no mania/hypomania Soo symptoms main one is reduced responsiveness to ADs vs unipolar depression; may need MS/APs 4

5 Main mood disorder spectrum phenotypes in DSM-5 2: Mood lowering component 1: Mood eleva3on component - m M - - hypomania pure mania d dysthymia cyclothymia BP-I D major depression BP-II BP-I 3:Cycle frequency BIPOLAR I DISORDER Diagnosed aoer at least one episode of mania. Pure unipolar mania is rare; almost all pa3ents also may experience major depressive episodes in the course of their lives. DIAGNOSTIC CRITERIA FOR MANIC EPISODES THREE TO FOUR* OF THE FOLLOWING CRITERIA ARE REQUIRED DURING THE ELEVATED MOOD PERIOD Highly inflated or grandiose self-esteem Decreased need for sleep, or rested aoer only a few hours of sleep Pressured speech Racing thoughts and flight of ideas Easy distrac9bility, failure to keep acen3on Increased goal-directed ac9vity High excess involvement in pleasurable ac9vi9es (sex, travel, spending money) General criteria for a manic episode require a period of elevated, expansive, or irritable mood that lasts 1 week or requires hospitalization. A general medical condition and substance abuse must be ruled out before these symptoms are considered mania. *4 if mood is only irritable 5

6 DIFFERENTIAL DIAGNOSIS OF MANIA May be induced by: An3depressant medica3ons Psychos3mulants Electroconvulsive therapy If the above occurs, the pa3ent is diagnosed with (substance-) induced mood disorder BIPOLAR II DISORDER Bipolar II disorder is similar to bipolar I disorder except that mania is absent in bipolar II disorder. Hypomania is the essen3al diagnos3c finding. CLINICAL MANIFESTATIONS OF BIPOLAR II DISORDER Characterized by the occurrence of hypomania and episodes of major depression in an individual who has never met criteria for mania or a mixed state. Hypomania is determined by the same symptom complex as mania, but the symptoms are less severe, cause less impairment, and usually do not require hospitaliza9on. Bipolar II is cyclic Suicide occurs in 10% to 15% of pa3ents (same as bipolar I) 6

7 Mania vs hypomania how to decide? Based on severity, dura3on, and degree of func3onal impairment. Mania Hypomania Dura3on 1 week OR 4 days Severity Requires hospitaliza3on - Func3oning Marked impairment < marked impairment Psycho3c* features +/- No *Most common are grandiose delusions however any manifesta3on is possible CYCLOTHYMIC DISORDER Cyclothymic disorder is a recurrent, chronic, mild form of bipolar disorder in which mood typically oscillates between hypomania and dysthymia. If a manic episode or depressive episode is experienced, cyclothymic disorder is not diagnosed. DSM-5 Diagnosis Diagnos3c Classifica3on Cyclothymia For at least 2 years (1 in children and adolescents), numerous periods with hypomanic symptoms that do not meet the criteria for hypomania Present at least ½ the 3me and not without for longer than 2 months Criteria for major depressive, manic, or hypomanic episode have never been met 7

8 CLINICAL PRESENTATION OF CYCLOTHYMIC DISORDER Cyclothymic disorder is a milder form of bipolar disorder consis3ng of recurrent mood disturbances between hypomania and dysthymic mood. A single episode of hypomania is sufficient enough to diagnose cyclothymic disorder, although most individuals also have dysthymic periods. Cyclothymic disorder is never diagnosed when there is a history of mania, major depressive episode, or mixed episode. Epidemiology Bipolar Disorder Onset: 15-24y (peak) Life3me prevalence: 1% Gender ra3o: M=F Likelihood of recurrence aoer a single manic episode: 90% Likelihood of >10 episodes: 10% Rapid cycling (4+ cycles/yr): 10-15% Major depression Onset: 20-29y Life3me prevalence: ~15% Gender ra3o: F (2x) >M Likelihood of recurrence: ~80% Recurrence of Bipolar Disorder Pre-lithium: ~4 recurrences/10 yrs Interval between episodes tends to decrease as pa3ent ages (cycle accelera3on) Lifelong recurrence study (Eur Arch Psych Clin Neurosci 2003, 253:236) BP recurrence ~2X higher than for UP depression Cumulative intensity ( risk) BP MDD Diagnosis BP-I BP-II MDD n Follow up duration (yr) Number of episodes Number of episodes/yr time from 1 st episode (y) 8

9 Ae3ology Gene3cs 1. Family Studies 2. Twin Studies concordance: q MZ =.67; DZ = ve Adop3on Studies 4. Gene3c Epidemiology q Early onset BD = confers greater risk to rela3ves 5. Molecular gene3c CACNA1C, ANK3, ITIH3-ITIH4, ZNF804A and NCAN Lower associajon with CNVs (Green 2015, Mol Psychiatry) Aggregates among family members Appears highly heritable Environment = a minority of disease risk Aetiology Neuroanatomical differences White macer hyperintensi3es. Small abnormal areas in the white macer of the brain (especially in the frontal lobe). Smaller amygdala Decreased hipocampal volume 26 Hajek et al. (2005); Pavuluri et al. (2005) Aetiology Neuroanatomical differences Reduced gray macer volume in the dorsolateral prefrontal cortex (DLPFC) Bilaterally larger basal ganglia Specifically larger putamen DLPFC Basal Ganglia 27 Hajek et al. (2005); Pavuluri et al. (2005) 9

10 Network abnormali3es Baker, JAMA Psychiatry 2014, 71: Pa3ents with psycho3c BP disorder had disrupted brain networks, specifically reduc3ons in func3onal connec3vity within the frontoparietal control network (parts of dorsolateral prefrontal cortex, posteromedial prefrontal cortex, lateral parietal cortex, and posterior temporal cortex) Also seen in psycho3c pts with SCZ Cor3cal informa3on processing is disrupted in psychosis Disrup3ons within the frontoparietal control network may be a shared feature across both schizophrenia and affec3ve psychosis. Treatments for Bipolar Depression 10

11 Psychosocial An3depressive effects of Mood Stabilizers 80% of BP depressed pa3ents show a par3al or good response to Li (J Clin Psychopharm 1993; 13: ) onset of ac3vity may not be seen for 6-8 weeks Efficacy of Li + an3depressant > AD + placebo (Psychopharm 1995, 118: ; Arch Gen Psych 1984, 41: ) Much less data for CBZ and VPA in BP depression posi3ve studies although mostly small, open-label Pa3ents Showing an An3depressant Response to Lamotrigine Treatment at Endpoint Response a (%) b b c b Placebo Lamotrigine 50 mg/day 30 Lamotrigine 200 mg/day Item HAM-D MADRS CGI-I a Response defined as 50% reduction on the HAM-D or MADRS scales or a rating of very much improved or much improved on the CGI-I scale; b p<0.05 vs. placebo; c p<0.01 vs. placebo; Calabrese JR et al. J Clin Psychiatry. 1999;60:

12 An3depressants in BP depression (1) TCAs, SSRIs, MAOIs, buproprion alone are probably effec3ve in BP depression Few data from RCTs Risk of an3depressants inducing mania: may be up to 10% risk factors: BP-I>BP-II; F>M; recent manic episode ~4% for SSRIs, pbo, 11% for TCAs (Br J Psychiat 1994, 164: ) rates may be lowest for buproprion An3depressants in BP depression (2) An3depressant induced rapid cycling poor prognosis (may be irreversible) risk factors: F>M; BP-II; history of AD-induced mania; young age of onset of BP disorder assess by life chart of episode frequency manage by stopping an3depressant; con3nue on mood stabilizer con3nued depression may require ECT; an3depressant use unclear (?buproprion, mirtazapine) slowly up-3trated in combina3on with a mood stabilizer Other agents ECT is highly effec3ve T3 or T4 supplementa3on, esp if baseline TFTs low doses may range from normal replacement doses to hypermetabolic doses published response rates highly variable Newer non-approved drugs: ketamine, pramipexole, amatadine, N-acetylcysteine 12

13 STEP-BD: Adjunc3ve An3depressants in BP Depression - NEJM 2007, 356:1711 Acute depression is the most frequent cause for disability in BP disorder Issues: Limited evidence to date that ADs work in BP depression Evidence to suggest that ADs can precipitate mania or accelerate cycle frequency is also uncertain Objec3ve: Evaluate efficacy of ADs vs placebo when added to mood stabilizers in BP depression Treatments: ADs: paroxe3ne or buproprion for up to 26w Mood Stabilizers: Li, VPA, CBZ, atypical an3psycho3cs Methods (contd) Mood stabilizers 3trated to therapeu3c levels/dose ranges Dosing: Paroxe3ne 10-40mg/d Buproprion SR mg/d Review aoer 6 weeks: Responders remain on drug for up to 20 addi3onal weeks Nonresponders offered dose increases in blinded meds or open label dose increases, with review every 2 weeks Hypomania/mania or severe intolerability- AD/placebo stopped Effec3veness Outcomes 13

14 Patient Disposition Results Overall recovery rate (~25%) disappoin3ng Mood stabilizer + AD gave no addi3onal benefits compared with mood stabilizer + pbo Risk of treatment emergent mania also not different between groups 14

15 Discussion (1) Is the lack of AD ac3vity a true finding? Very low recruitment rate (366/2689 or 14% randomized) Goes against previous literature (review AJP 2004, 161:1357) Remission Response Discussion (2) Is the lack of effect of ADs on inducing mania correct? Findings are consistent with literature reviews Risk of inducing mania Study does not support safety of other AD classes (esp TCAs) Study does not resolve issue of whether AD (in absence of mood stabilizer) could increase risk of induc3on of mania TCAs have 3x higher switch rate than other classes 15

16 CANMAT 2013 Treatments for acute mania Monotherapy Two recent network MA s in acute mania Cipriani 2011 Lancet WinBUGS analysis of individual drugs using both monotherapy and combina3on studies Yildiz 2014 Psychol Med WinBUGS analysis of individual drugs using only monotherapy studies 16

17 Cipriani 2011: Network for efficacy comparisons Network MA; Note: combina3on Rx not evaluated 2015 Local Network MA Data Set 62 separate studies selected 141 study arms par3cipants 46/62 studies had a treatment dura3on of 3wks; the remaining 16 studies ranging from 2-6 weeks. 50 arms: an3psycho3c monotherapy 44 arms mood stabilizer monotherapy 16 arms combina3on AP/MS treatment 31 arms placebo 17

18 Network Diagram for the 4 endpoints Comparison of effect of drug categories on All ac9ve drug categories efficacy beat and PBO acceptability endpoints. APs > MS Sta9s9cally Comb actual/trend > significant APs differences are bolded. Placebo vs AP MS Comb MS/AP Comb >MS An9psycho9cs vs SMD (95% CI) (-0.55 to -0.40) (-0.42 to -0.23) (-0.76 to -0.47) Efficacy Change in YMRS (95% CI) -5.3 (-6.3 to -4.3) -3.8 (-5.2 to -2.5) -6.5 (-8.4 to -4.7) Response rate OR (95% CI) 2.18 (1.88 to 2.53) 2.09 (1.66 to 2.62) 3.34 (2.44 to 4.58) Acceptability Dropout rate OR (95% CI) 0.63 (0.54 to 0.73) 0.82 (0.67 to 1.00) 0.73 (0.54 to 0.98) MS Comb MS/AP 0.15 (0.05 to 0.25) (-0.29 to 0.02) 1.7 (0.2 to 2.8) -1.2 (-3.0 to 0.6) 0.96 (0.76 to 1.20) 1.53 (1.12 to 2.09) 0.76 (0.62 to 0.95) 0.87 (0.64 to 1.18) Mood Stabilizers vs Comb MS/AP (-0.40 to -0.17) -2.7 (-3.9 to -1.4) 1.60 (1.28 to 2.01) 1.14 (0.90 to 1.43) Probability of being the best treatment Outcome Placebo An9psycho9c Mood Stabilizer Combined AP/ MS Mania score YMRS Responder Dropout

19 Other Agents in Acute Mania ECT is effec3ve in mania (66% response) Am J Psych 1994, 151: Benzodiazepines effec3ve in acute management of mania doses/agents as for acute schizophrenia co-administer with mood stabilizer acutely then down-3trate Tamoxifen (PKC inhibitor) Maintenance Treatment Pa3ents: prophylaxis needed if >2 episodes in 5 years Lithium is first choice acute response predic3on factors also predict lowest likelihood of relapse despite efficacy, relapse occurs (~20% over 1 yr; 76% over 5 yrs) maintain adequate blood levels (relapse is higher with lower concs) check weight, TFTs, renal func3on poor tolerability may reduce compliance VPA/CBZ/newer agents no obvious efficacy advantages over lithium much less controlled data than for lithium Data to support long term neurolep3cs are weak Most studies used SGA-responsive enriched popula3ons Lithium maintenance Effec9veness of Lithium for the Preven9on of Any Relapse in Bipolar Disorder Pa9ents Am J Psych 2004, 161:217 Manic Relapse Effec9veness of Lithium for the Preven9on of Depressive Relapse 19

20 Lamotrigine vs Li Maintenance J Clin Psych 2004, 65:432 BALANCE Study (Li vs VPA vs combina3on) Lancet 2010, 375:385 BP-I pa3ents randomized to Li, VPA or combina3on Primary Endpoint: new treatment emergent mood episode Hazard ra9os (95% CI) VPA Combina3on 0.59 ( ) 0.82 ( ) Li 0.71 ( ) Li Time to first admission/new Rx for emerging mood episode Combined VPA/Li and Li monotherapy are becer for BP-I maintenance than VPA monotherapy CANMAT Guideline 2013 Overenthusias3c interpreta3on of VPA and SGA literature 20

21 Lithium and Suicide (Arch Gen Psych 2005, 62:860) Danish observa3onal cohort study linking Li Rxs (n=13,186) and reported suicides over 5 years # Li scripts None 1 >2 Total N Suicides (n) Suicide RR Suicide rela3ve risk (95% CIs) ( ) 2.1 ( ) F Total M Con3nued Li use is associated with decreased suicide risk, regardless of gender and age >10 No. Of Li Rxs Discon3nua3on of Lithium Percent Remaining in Remission Bipolar-1 Patients Off Lithium Gradual Gradual* (N=15) Rapid First year Rapid (N=108) Time After Stopping Lithium (months) Ref: Suppes, Harv Rev Psych 1993, 1:131. *Gradual = reduction over period of 1 month Clozapine in Bipolar Disorder 15 open trials of clozapine in treatment-refractory pa3ents suggest mood-stabilizing as well as an3psycho3c effects 1 Pooled response rate: 70% 1 1 controlled open trial found significant improvement in refractory pa3ents over 1 year with clozapine vs. standard treatment 2 1 Zarate CA Jr et al. J Clin Psychiatry. 1995;56: ; 2 Suppes T et al. Am J Psychiatry. 1999;156: