Genetical heterogenity of mood disorders PowerPoint Presentation

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MOOD DISORDERSProf. Zoltán Rihmer, MD, PhD, DScDepartment of Psychiatry and Psychotherapy, Semmelweis Medical UniversityBudapest, Hungary 2013

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Heterogeneity of mood disorders Clinical Polarity* Severity Periodicity Sex distribution Age of onset Comorbidity Biological Genetics Biochemistry Brain morphology Electrophysiology Treatment response Psychosocial Early negative life events Acute stressors Social support *Unipolar versus bipolar ____________________________________________

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Mood disorders - Polarity Unipolar(Non-bipolar) major minor - subthresh. Bipolar Bipolar I Mixed episodes (depr.>mania) Bipolar II Subthreshold forms (incl. cyclothymia)

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Clinical manifestations of mood (affective) disorders MAJOR Minor ------------------------------------------------------------ UNIPOLAR Unipol. maj. depr. Minor depr. Recurrent brief depr Dysthymia Subs. sympt. depr. BIPOLAR Bipolar I Min. bipol. disord. Bipolar II Cyclothymia

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Genetical heterogenity of mood disorders --------------------------------------------------------------- Noon-familial (sporadic) cases (40-50%) Familial cases (50-60%) chromosomes: - X,18, 21, 5, 9, (TPH, 5-HT,NA, DA transporter etc) ---------------------------------------------------------------

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Gene-phenotype relationships

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Clinical heterogeneity of mood disorders -------------------------------------------------------- Primary vs Secondary Unipolar vs Bipolar Major vs Minor Episodic vs Chronic --------------------------------------------------------

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Different level of severity in major depression-------------------------------------------------------- Major depressive episode - nonmenalncholic - melancholic-nonpsychotic - melancholic-psychotic mood-congurent features mood-incongurent features - catatonic --------------------------------------------------------

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Biochemical heterogeneity of mood disorders --------------------------------------------------------------- Serotonin (5-HT) Noradrenaline (NA) Dopamine (DA) Acethylcholine (?) MAO, COMT, TPH, 5-HT transporter (genetical polymorphism) Receptor function ---------------------------------------------------------------

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Psycho-social heterogeneity of mood disorders --------------------------------------------------------------- Early (childhood) negative life events (predisposition) Adulthood negative life events (provocation) Social support (present, absent) ---------------------------------------------------------------

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DSM-IV criteria of major depression - 1 x Five (or more) of the following symptoms for at least two weeks: 1, DEPRESSED MOOD 2, LOSS OF INTEREST/PLEASURE 3, Significant weight change 4, Insomnia or hypersomnia 5, Psychomotor agitation or retardation 6, Fatigue, loss of energy 7, Worthlessness, guilt, self-blaming 8, Diminished ability to think or concentrate 9, Thoughts of death, suicidality

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DSM-IV criteria of major depression - 2 Minimum duration: 2 weeks Possible organic casuses (brain tumor, toxic agents etc.) are excluded No grief-reaction

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DSM-IV criteria of Dysthymic Disorder/Minor Depression x Depressed mood for at least 2 yrs/wks+ x Two (or more) of the following: 1, Poor appetite or overeating 2, Insomnia or hypersomnia 3, Low energy of fatigue 4, Low self-esteem 5, Poor concentration/making dicisions 6, Feelings of hopelessness Organic causes, grief-reaction is excluded, time criterof for DD: 2 years

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DSM-IV criteria of Mania x Abnormally elevated/expansive/irritable mood for at least 1 week and: x Three (or more) of the following: 1, Grandiosity 2, Decreased need for sleep 3, Talkative, pressured speach 4, Flight of ideas, racing thoughts 5, Distractibility 6, Psychomotor agitation 7, Excessive pleasurable activities x Markedly impaired functions/hospitalization Organic causes excluded, time criterion: 1 week (or hospitalization)

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DSM-IV criteria of Hypomania x Persistently elevated/expansive/irritable mood, for at least 4 days and x Three (or more) of the following: 1, Grandiosity 2, Decreased need for sleep 3, More talkative, pressured speach 4, Flight of ideas, racing thoughts 5, Distractibility 6, Psychomotor agitation 7, Excessive pleasurable activities x No markedly impaired functions/hospitalization

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Most frequent clinical manifestations of major mood disorders-------------------------------------------------------- Unipolar major depression - single episode - recurrent Bipolar I disorder - major depression + mania - minor depression + mania Bipolar II disorder - major depression + hypomania ---------------------------------------------------------------

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Bipolar type I Mania Depression Bipolar type II Hypomania Depression Bipolar type II1/2 Bipolar type III Pharmacological Hypomania Depression Antidepressants Cyclothymia Bipolar spectrum

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Evolution of bipolar disorder >2 years Hantouche, 2004

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Unipolar – Bipolar conversion 12.5 – 46 % of „unipolar” major depressives become Bipolar I or II during the 5 -15 year follow-up Predictors: early onset, severe depr., psychotic features, retardation, bipolar FH, cyclothymia/mood-energy lability Akiskal et al, Arch Gen Psychiat, 1995, 52: 114-125. Goldberg et al, Amer J Psychiat, 2001, 158. 1265-1270.

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Adapted from A. Koukopoulos

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Depression and mania are only successive conditions (false) m M D D D UPMD Bp II Bp I Rihmer, 2004

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Depression and mania are both successive and simultaneous conditions (true) m m M D D D D D UPMD UPMD Bp II Bp II Bp I (DMX) (DMX) m m Agitated depression Rihmer, 2004

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Mood generator + - Traditional concept: mania is an active and depression is a passive condition Rihmer, 2005 overactivity underactivity (Sleep as an example) Clinical level Biology

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Current concept: Both mania and depression are active processes that can occur both successively and simultaneously Rihmer, 2005 Generators ofmood + + Clinical level Biology

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The three clinical phenotypes of overlapping affective episodes Rihmer, 2005

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Pure vs comorbid mood disorders-------------------------------------------------------- Pure mood disorder (i.e. mood disorders without comorbid Axis I disorders) is relatively rare ( 30-40 %) The most frequent Axis I comorbid disorders in mood disorders are: - Anxiety disorders (30-60 %) - Substance use disorders (25-70 %) --------------------------------------------------------

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Depression and suicide-------------------------------------------------------- 60-75 % of suicide victims have (mostly untreated) major depression (UP or BP) 15-19 % of patients with major mood disorders subsequently suicide 35-65 % of patients with major mood disorders have prior suicide attempt(s) Succesfull acute/long-term treatment of mood disorders significantly reduces the suicide mortality --------------------------------------------------------------- Rihmer et al, Curr Opin Psychiat, 2002, 15: 83-87

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Hospitalized mood disorder patients Suicide attempters Suicide victims 4 -19 % subsequently suicide 7-13 % suicide within 5 -10 years 45-87 % of suicides have current major mood disorder (mostly untreated) 19-42 % of suicides have prior suicide attempt Major mood disorder, suicide attempt and suicide Avery and Winokur, Arch Gen Psychiat 1978; 35: 749-753 Bostwick and Pankratz, Amer J Psychiat 2000, 157: 1925-1932 Rihmer and Kiss, Bipol Disord 2002, 4:(Suppl.1), 21-25. Suokas et al, Acta Psychiat Scand 2001,104: 117-121

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When do major mood disorder patients commit or attempt suicide?------------------------------------------------------------------ Isometsä et al., AJP, 1994; 151: 1020–1024 Tondo et al., JCP, 1998; 59: 405–414 Rouillon et al. JCP, 1991, 52: 423-431 Valtonen et al, JCP, 2005, 66: 1456-1462. 0-7% 11-20% 79–89% Major depression (pure or mixed) Dysphoric (mixed) mania

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Suicide risk factors Primary suicide risk factors Psychiatric disorder: major depression, schizophrenia, substance-use disorders Secondary suicide risk factors Early negative life events, acute psycho-social stressors, unemployment Tertiary suicide risk factors Male gender, old age, spring, morning

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Pharmacological treatment and medical contact of depressed suicides The rate of appropriate antidepressant pharmacotherapy among currently depressed suicide vistims is between 10 and 20 % Up to 60 % of suicide victims contact their GPs or psychiatrists 1-3 months before the suicide Luoma et al, Amer J Psychiat, 2002; 159: 909-916. Rihmer, Curr Opin Psychiat, 2007; 20: 17-22.

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Suicidal behaviour in treated vs untreated mood disorder patients The yearly risk of completed suicide General population 0.011 % (USA, UK, Australia) Untreated depressives 0.298 % Patients on antidepressants 0.090 % (USA, UK, Australia) Untreated depressives vs gen. population: 27 X Untreated depressives vs patients on ADs: 3 X Patients on ADs vs gen. population: 8 X Simon et al, Amer J Psychiat, 2006, 163, 41-47. (Risk reduction: 71 %)

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3-month risk of suicide among AD-treated persons (USA, UK, Australia) ‘ Harris and Barraclough, 1997, ‘’ Jick et al, 2004, Didham et al, 2005, Simon et al, 2006,

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Estimated yearly suicide rates (per 100.000) of depressives with and without AD treatment in Sweden (1990-1991) Isacsson et al, J Aff Dis 1996, 41, 1-8

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Estimated SRs (per 100.000 persons) of AD-treated and AD-untreated major depressives in Hungary (2003) 27.7 232 279 169 N=1625 N=1117 N=508 Suicide rate per 100.000 Whole Hungary,10 Millions All depressivesN=700.000 Depressives, no ADsN=400.000 Depressives taking ADsN=300.000 -39% 8x 10x 1.7x N=2801 Rihmer, 2007

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Figure 5. Rates of Suicide Attempts During the 4 Weeks Before and 4 Weeks After Initial Antidepressant Prescriptiona aBars indicate 95% confidence intervals. Simon et al., Amer J Psychiat 2006, 163:41-47

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Biological basis of mental disorders Genetical predisposition Life events (early and current) Neurotransmitter vulnerability Mood diasorders: serotonin, noradre- nalin, dopamine Schizophrenia: dopamine, glutamate Anxiety disorders: GABA, serotonin Alzheimer disease: acethylcoline

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Reuptake inhibition, receptor (ant)agonismand antidepressive/antimanic action serotoninergic system Noradrenergic/dopaminergic system Julius Axelrod (1912-2004)

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Martinowich et al, J Clin Invest, 2009; 119: 726-736.

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Neurotransmission in the CNS MAO Autoreceptor Release Re-uptake Catabolism COMT Syntethizing enzimes Post- synaptic cell Neurotransmitter Amino acids

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Serotonin transporter gene (5HTTLPR ) SERT gene (SLC6A4): 17q11.1-q12 Functional polymorphism in promoter s and l alleles Lesch KP. J Affect Disord, 2001; 62: 57-76.

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5HTTLPR Associated with Affective disorders (major depression, bipolar disorders, subthreshold depr, DE, CT, IRR, ANX temperament) Suicidal behaviour Por response to SSRIs, AD-induced switches Psychological traits related to neuroticism and responsivity to stress Anxiety disrders, migraine Neurodevelopment

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Lesch & Mössner R.(1998) Biological Psychiatry, 44: 179-192.

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Biological/neuroendocrine changes in depression-------------------------------------------------------- Abnormal DST Shortened REM-latency Blunted TSH response to TRH Reduced cortisol response to DMI Decreased cellular immune function 5-HT and DA/NA depletion Brain imaging techniques (MRI,SPECT etc.) ---------------------------------------------------------------

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5-HT and DA/NA depletion in depression-------------------------------------------------------- SSRI responders: - 5-HT depletion: relapse - DA/NA depletion: no change NRI responders: - 5-HT depletion: no change - DA/NA dedpletion: relapse --------------------------------------------------------

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Lifetime Prevalences of Bipolar I, Bipolar II, and Unipolar Major Depression (%) in the Adult Population Source Diagnosis BP-I BP-II UPMD %BP -------------------------------------------------------------------------- Weissman DIS- 0,8 0,5 4,4 23 et al.1988 DSM-III Kessler et CIDI- 1,6 0,2 15,8 10 et al. 1994 DSM-IIIR Szádóczky DIS- 3,0 2,0 15, 1 25 et al. 1998 DSM-IIIR Ten Have CIDI- 1,3 0,6 15,4 11 et al. 2002 DSM-IIIR Faravelli MINI/FPI- 0,8 9,5 8 et al. 2004 DSM-IV --------------------------------------------------------------------------

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Prevalences of DSM-III-R Major Mood Disorders (%) in the Adult Population of Hungary (N=2953, 18-64 yrs) Diagnosis Lifetime 1-year 1-month -------------------------------------------------------------------------- Major Depr. Dis. 15,1 7,1 2,6 Bipolar Dis. 5,0 2,7 1,3 Bipolar I 3,0 1,1 0,5 Bipolar II 2,0 1,6 0,8 %,bipolars 25 28 33 -------------------------------------------------------------------------- Szádóczky et al. J.Aff.Dis. 1998,50:153-162 Szádóczky et al. Orv.Hetil. 2000,141:17-22

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Prevalence of Bipolar (I+II) Disorders in Primary Care Source, country Diagnosis Point prev. (%) ------------------------------------------------------------------------- Spitzer et al. PRIME-MD 1,0 1994, USA DSM-III n=1000, Szádóczky DIS 1,3 et al.1998,Hungary DSM-III-R n=301 Ansseau et PRIME-MD 1,9 al. 2004, Belgium DSM-IV n=2316 -------------------------------------------------------------------------

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Complications of untreated major mood disorders-------------------------------------------------------- Suicidal behaviour Secondary alcohol/drog abuse (depen- dence) Loss of productivity, disability, loss of job Family breakdown, interpersonal conflicts Increased somatic morbidity/mortality Increased health-care costs ---------------------------------------------------------------

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Depression and cardiac mortality (RR)-------------------------------------------------------- Cardiac Depression Cardiac- IHD- disease death death no no 1,0 1,0 no minor 1,6 1,4 no major 3,8 5,1 yes no 3,4 4,5 yes minor 5,1 8,5 yes major 10,5 17,7 --------------------------------------------------------------- Penninx et al, Arch Gen Psychiat 2001,58:221-.

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Successful acute and long-term treatment of mood disorders-------------------------------------------------------- Significantly reduces the suicide morta- lity and morbidity Reduces the development of secondary substance-use disorders Reduces the cardiovascular morbidity and mortality Reduces the cost of health care -------------------------------------------------------- Rihmer, Curr Opin Psychiat, 2007; 20: 17-22.

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Tereatment of mood disorders Biological treatments - pharmacotherapy - sleep-deprivation - light therapy (winter depression) - ECT - TMS, DBS, VNS (?) Non-biological treamtnets - psychoeducation - supportive psychotherapy - specific psychotherapies - CBT Combination of biological/nonbiological treatments

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Pharmacotherapy of mood disorders Pharmacoterapy of depression momotherapy with ADs combination of ADs and ANXLs, APs, mood stabilizers Pharmacotherapy of mania APs Mood stabilizers (Li, VPA, CBZ, LTG) Long-term treatment of mood disorders (mood stabilizers)

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Classification of antidepressants First-generation reuptake-inhibitors - tri/tetracyclic ADS (impir., amitript., clompir., maprot. etc) SSRIs (flox., fluvox., sertr., citalpor., paroxetin, escitalopram.) Dual action ADs - 5-HT+NA (venlafaxine, mirtazapine, duloxetine) - NA+DA (bupropion) MAO inhibitors/RIMA (phenelzine, tranylcipro- mine/moclobemide)

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Mirtazapine – Mechanism of action 2-heteroreceptor mirtazapine vesticle 2-autoreceptor 1-adrenoreceptor

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Selection of antidepressants Personal and family history of drug- treated depression (same response) Clinical picture - agitated/suicidal/winter depression: mainly SSRIs - retarded, anhedonic depression: mainly NA-DAergic antidepressants - depressive mixed state: MS/AP+AD - psychotic depression: ADs + APs Niculescu and Akiskal, Molec Psychiat 2001, 6: 263-266. Ferguson et al, Int Clin Psychopharmacol, 2002, 17: 45-51.

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Recommendations for AD pharmacotherapy (1) Appropriate dose Appropriate duration (min. 2-3-4 weeks) Inncrease the dose in non/patrial responders Augmentation of the effect in non/partial responders (Li, VPA, CBZ, APs, folic acid, L-thyroxin) Change the medication after 4-5 weeks in nonresponders – long term treatment in respodenrs if needed (2 or more episodes)

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Recommendations for AD pharmacotherapy (2) Mood stabilizers (+ ADs) in all bipolar depressives Atypical antipsychotics (+ ADs) in psychotic depression Anxiolytics (+ADs) in depression with comorbid anxiety/anxiety disorders

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Antidepressant monotherapy in bipolar depression: The major source of treatment resistance/destabilization Akiskal and Mallya, Psychopharmacol Bull, 1987; 23: 68-73. Sharma, J Affect Disord, 2001; 64: 99-106. Shi et al, J Affect Disord, 2004; 82: 373-383 Sharma et al, J Affect Disord, 2005; 84: 251-257. El-Mallakh et al, J Affect Disord, 2005; 84: 267-272. Inoue et al, J Affect Disord, 2006; 95: 61-67. Woo et al, Int J Psychiat Clin Pract, 2008; 12: 142-146. O’Donovan et al, J Affect Disord, 2008; 107: 293-298.

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Antidepressant monotherapy in pre-bipolar and unipolar depression Pre-bipolar Unipolar n=17 n=17 Response to ADs full response 41% 82% partial response 18% 18% nonresponse 41% 0% Treatment emerg. symptoms sleep loss 47% 0% rage 24% 0% agitation 65% 0% mood lability 47% 12% suicidality 18% 0% psychomotor activation 47% 0% mixed symptoms 47% 6% FH of suicide 65% 6% O’Donovan et al, J Affect Disord. 2008; 107: 293-298.

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Most frequent cause of antidepressant resistance in major depression Unrecognized bipolar disorder Inoue et al, J Affect Disord, 2006; 95: 61-67. Woo et al, Int J Psychiat Clin Pract, 2008, 12: 142-146.

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Pharmacotherapy of hypomania/mania Mood stabilizers (Li, VPA, CBZ) Antipsychotics (atypicals) Anxiolytics (clonazepam, alprazolam)

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Treatment phases of unipolar major depression Normalicy Phase of treatment Mainten. Prohylactic Treatm. Responder REMISSION Relapse Recurrence (new episode) Recovery Kupfer, 1991 után módosítva Acute