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  • DISCUSSION NOTES: Twelve new-generation antidepressants were evaluated in this meta-analysis, including: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline and venlafaxine. In this meta-analysis, efficacy was measured using the traditional concept of response rates, and “acceptability” was measured by the number of study drop-outs for any reason. In clinical reality, the concept of patient acceptability combines medication tolerability, dosing simplicity, and acquisition costs. Key message: Differences in efficacy and patient acceptability of 12 new-generation antidepressants were evaluated in this large meta-analysis, which was free of industry funding.
  • DISCUSSION NOTES: As we can see, two of these treatments appear in both groups of superior efficacy and superior acceptability: escitalopram and sertraline. These results also suggest that two of the most efficacious treatments (mirtazapine and venlafaxine) might not be the best for overall acceptability. In terms of response rates, mirtazapine, escitalopram, venlafaxine, and sertraline were more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine, and reboxetine. In terms of acceptability, escitalopram, sertraline, citalopram, and bupropion were better tolerated than other new-generation antidepressants. Key message: Effective treatment of depression can hasten a working patient’s return to work.
  • Key Point A discussion of the pathophysiology of depression should include consideration of neuroanatomy in addition to neurotransmitters Background Over the past several decades, it has become increasingly clear that depression is a macroscopic disease with specific areas of the brain that are known to be affected (e.g., the amygdala, cingulate cortex, and hippocampus are part of neural circuits involved in emotion) Recent evidence suggests that the effects of antidepressants extend beyond the level of the synapse. Antidepressants not only enhance neurotransmission in normal monoamine neurons but may also restore functioning to brain areas modulated by them Thus, research investigating the neurobiology of depression seeks to evaluate not just monoamine systems, but the areas of the brain modulated by these systems Reference Delgado PL, Moreno FA. J Clin Psychiatry . 2000;61(suppl 1):5-12.
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  • Lecture Notes

    1. 1. Mood Disorders Prof Allan Young University of British Columbia [email_address]
    2. 2. Lecture Outline <ul><li>Types of mood disorders </li></ul><ul><li>Epidemiology, impact </li></ul><ul><li>Risk factors </li></ul><ul><li>Presentation and symptoms </li></ul><ul><li>Treatment </li></ul><ul><li>Neurobiology </li></ul><ul><li>Unipolar then Bipolar </li></ul>
    3. 3. <ul><li>Unipolar </li></ul><ul><li>Bipolar </li></ul>
    4. 4. “ NORMAL” DEPRESSION <ul><ul><li>e.g., Grief </li></ul></ul><ul><ul><ul><li>Death of a loved one, separation/divorce, financial loss, retirement, leaving home, loss of a pet </li></ul></ul></ul><ul><ul><ul><li>Gradually lose capacity to evoke pain, but have fantasies of the loss </li></ul></ul></ul><ul><ul><ul><li>Typical functioning should return within 1 year, usually a few weeks or months </li></ul></ul></ul><ul><ul><ul><li>“ Normal” depression is usually overdiagnosed </li></ul></ul></ul>
    5. 5. Important Aspects of Typology <ul><li>Polarity: Unipolar vs Bipolar </li></ul><ul><li>Severity: hypomania vs mania </li></ul><ul><li>major vs minor depression </li></ul><ul><li>Subtyping: Melancholia; Psychotic </li></ul><ul><li>Course: Chronicity (2 years); </li></ul><ul><li>Rapid Cycling </li></ul><ul><li>Comorbidity: Schizoaffective; mixed anxiety depression </li></ul><ul><li>n.b., generally do not now type by antecedent events except for Post-natal depression; adjustment disorder </li></ul>
    6. 6. Diagnosis in Psychiatry <ul><li>There are no diagnostic tests for mood disorders only diagnostic interviews </li></ul><ul><li>Diagnosis is based on identification of “symptoms” which cluster into “syndromes” </li></ul><ul><li>2 main classification systems : </li></ul><ul><li>USA DSM (IV): WHO ICD </li></ul>
    7. 7. Classification of Mood Disorders Bipolar I Bipolar II Cyclothymia Unipolar single episode Unipolar- Hyperthymic Dysthymia Unipolar recurrent Unipolar Bipolar
    8. 8. Depression is Common <ul><li>Major Depression (lifetime)-10% of men; 20% of women </li></ul><ul><li>Most common mental disorder in primary care </li></ul><ul><li>Three times more primary care visits </li></ul><ul><li>Higher rates of depressed patients in primary care offices </li></ul>
    9. 9. One-Month Prevalence Rates for Affective Disorders Ustun & Sartorius, 1993 USA 5.2% London 7% Edinburgh 5.9% Athens 7.4% Canberra 4.8% WPA/PTD Educational Program on Depressive Disorders
    10. 10. Depression is Significant <ul><li>Impact on quality of life greater than most chronic medical diseases </li></ul><ul><li>Increases morbidity/mortality from co-existing medical conditions </li></ul><ul><li>Decreased work productivity </li></ul><ul><li>Suicide-7th leading cause of death in US; 70% have mood disorder </li></ul><ul><li>Costs over $44 billion yearly (1990) </li></ul>
    11. 11. Digestive disorder (6%) Musculoskeletal disorders (4%) Endocrine (4%) Neuropsychiatric disorders (28%) Cancer (11%) Cardiovascular disease (22%) Sense organ impairment (10%) Other non-communicable diseases (7%) Respiratory disease (8%) Schizophrenia Bipolar disorder Dementia Substance-use and alcohol-use disorders Other mental disorders Epilepsy Other neurological disorders Other neuropsychiatric disorders Depression 2% 10% 2% 2% 4% 3% 1% 2% 3% Prince et al 2007 Psychiatric Disorders: Underestimated and Disabling Conditions Contribution (%) by different non-communicable diseases to disability-adjusted life-years worldwide in 2005 October 2009, CZ002663-SERO
    12. 12. Recognition and Treatment Problems <ul><li>Up to 70% of depression is not recognized or treated </li></ul><ul><li>50% of treated patients stop medication within first 3 months </li></ul><ul><li>Medication often not used at dosage sufficient to give full remission </li></ul>
    13. 13. Pathway to Psychiatric Care (Goldberg & Huxley, 1980) 230 140 17 Conspicuous Morbidity Level 3 Filter 2 Psychiatric Patients Level 4 Filter 3 Morbidity in the Community Morbidity in Primary Care Level 1 Level 2 Filter 1 250 (per 1000 per year) Psychiatric In-patients Level 5 Filter 4 6
    14. 14. Barriers to Recognition <ul><li>Somatization-present with physical symptoms </li></ul><ul><li>Competing demands </li></ul><ul><li>Comorbidity-multiple problems </li></ul><ul><li>Stigma </li></ul><ul><li>Insurance </li></ul><ul><li>Reimbursement </li></ul>
    15. 15. Risk Factors For Mood Disorders <ul><li>First degree relatives with mood disorders (at least 3 times higher) </li></ul><ul><li>Women twice as likely as men </li></ul><ul><li>Care taking responsibilities </li></ul><ul><li>Current or history of abuse, trauma </li></ul><ul><li>Stressful events, loss </li></ul>
    16. 16. DSM-IV Criteria For Major Depression <ul><li>Four hallmarks, nine symptoms: </li></ul><ul><ul><li>depressed mood </li></ul></ul><ul><ul><li>anhedonia (loss of interest/pleasure) </li></ul></ul><ul><ul><li>four physical symptoms </li></ul></ul><ul><ul><li>three psychological symptoms </li></ul></ul><ul><li>For diagnosis-depressed mood or anhedonia & at least 5 of the 9 symptoms </li></ul><ul><li>Symptoms most of time for 2 weeks </li></ul>
    17. 17. <ul><li>SYMPTOMS OF DEPRESSION </li></ul><ul><ul><li>Depressed mood most of the day, nearly every day </li></ul></ul><ul><ul><li>Markedly diminished interest/pleasure in all/almost all activities </li></ul></ul><ul><ul><li>Significant weight loss/gain when not dieting, or decrease/increase in appetite </li></ul></ul><ul><ul><li>Insomnia/hypersomnia </li></ul></ul><ul><ul><li>Psychomotor agitation/retardation </li></ul></ul><ul><ul><li>Fatigue/loss of energy </li></ul></ul><ul><ul><li>Feel worthless or excessive/inappropriate guilt </li></ul></ul><ul><ul><li>Diminished ability to think/concentrate or indecisiveness </li></ul></ul><ul><ul><li>Recurrent thoughts of death </li></ul></ul>
    18. 18. Depressed Mood <ul><li>Neither necessary nor sufficient for the diagnosis </li></ul><ul><li>Can be misleading </li></ul><ul><li>Don’t hang everything on the question “Are you depressed?” </li></ul>
    19. 19. Anhedonia <ul><li>Loss of interest or pleasure in things that you normally enjoy </li></ul><ul><li>May be the most important and useful hallmark </li></ul>
    20. 20. Physical Symptoms <ul><li>Sleep disturbance </li></ul><ul><li>Appetite or weight change </li></ul><ul><li>Low energy or fatigue </li></ul><ul><li>Psychomotor retardation or agitation </li></ul>
    21. 21. Psychological Symptoms <ul><li>low self-esteem or guilt </li></ul><ul><li>Poor concentration </li></ul><ul><li>Suicidal ideation or persistent thoughts of death </li></ul>
    22. 22. Dysthymia <ul><li>Long term problem with moderate symptoms </li></ul><ul><li>Depressed mood most of time for 2 years </li></ul><ul><li>Plus 2 other symptoms of depression </li></ul><ul><li>High level of chronic impairment </li></ul><ul><li>Increased risk for major depression </li></ul>
    23. 23. Bipolar Disorder <ul><li>Episodes of mania or hypomania along with depressive episodes </li></ul><ul><li>Hypomania may be overlooked; patient may hide symptoms or not see as problem </li></ul><ul><li>Often misdiagnosed and managed as unipolar depression </li></ul>
    24. 24. Misdiagnosis of Bipolar Patients <ul><li>Potential risks from antidepressants </li></ul><ul><ul><li>May induce mania or hypomania </li></ul></ul><ul><ul><li>Can cause rapid cycling </li></ul></ul><ul><li>Requires mood stabilizer (e.g. lithium or valproic acid) before brief use of antidepressant </li></ul><ul><li>Generally need psychiatry consultation or referral </li></ul>
    25. 25. Depression Treatment <ul><li>Psychotherapy </li></ul><ul><ul><li>Alone or as adjunctive therapy </li></ul></ul><ul><li>Pharmacotherapy </li></ul><ul><ul><li>Effective for major depression and dysthymia </li></ul></ul><ul><ul><li>Questionable effectiveness in minor depression </li></ul></ul><ul><li>Primary care supportive counseling </li></ul><ul><ul><li>Important part of treatment </li></ul></ul>
    26. 26. Evolution of Antidepressants <ul><li>MAOIs 1950s </li></ul><ul><li>TCAs 1950s </li></ul><ul><li>Selective Drugs (SSRIs, NARIs, NDRIs) 1970s </li></ul><ul><li>SNRIs 1980s </li></ul><ul><li>Melatonin Agonists/5-HT Antagonists 2000s </li></ul>
    27. 27. Antidepressants <ul><li>Tricyclics </li></ul><ul><li>MAO Inhibitors-rarely used now except by specialists </li></ul><ul><li>SSRIs: citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft) </li></ul>
    28. 28. Antidepressants <ul><li>Other new agents (multiple actions) </li></ul><ul><ul><li>bupropion (Wellbutrin) </li></ul></ul><ul><ul><li>mirtazapine (Remeron) </li></ul></ul><ul><ul><li>venlafaxine (Effexor) </li></ul></ul><ul><li>Dual action agents: SNRIs </li></ul><ul><li>More coming </li></ul>
    29. 29. 1.524 TCA Tofranil Imipramine 3.105 TCA Pamelor Nortriptyline 5.129 TeCA Remeron Mirtazapine 12.551 SNRI Cymbalta Duloxetine 13.462 TCA Elavil Amitriptyline 15.473 SRI Desyrel Trazodone 16.246 SSRI Celexa Citalopram 17.200 SNRI Effexor Venlafaxine 18.141 SSRI Paxil Paroxetine 20.184 NDRI Wellbutrin Bupropion 22.266 SSRI Prozac Fluoxetine 27.023 SSRI Lexapro Escitalopram 29.652 SSRI Zoloft Sertraline USA, 2007 Prescriptions (in millions)     Class     Brand     Drug    
    30. 30. STAR*D Project Results Warden D, et al. Curr Psychiatry Rep. 2007;9:449–459. QIDS-SR = Quick inventory of depressive symptomatology – self report. Level n Remission (%) QIDS-SR ≤ 5 Cumulative Remission (%) 1 3,671 2 1,439 3 390 4 123 37% 31% 14% 13% 37% 56% 62% 67%
    31. 31. First-line Antidepressants with Evidence for Superior Efficacy Against Comparators Lam RW, et al. J Affect Disord 2009; 117 Suppl 1:S26-S43 . Antidepressant Comparator(s) Level of evidence Duloxetine Paroxetine; pooled SSRIs 2 Escitalopram Citalopram; duloxetine; paroxetine; pooled SSRIs 1 Mirtazapine Trazodone 2 Sertraline Fluoxetine; pooled SSRIs 1 Venlafaxine Duloxetine; fluoxetine; pooled SSRIs 1
    32. 32. Efficacy and Acceptability of Antidepressants: A Multiple-Treatments Meta-analysis <ul><li>Trials published between 1991 and 2007 (117 trials), including 25,928 patients </li></ul><ul><li>Direct and indirect comparisons of 12 second generation antidepressants </li></ul><ul><li>Main outcomes: </li></ul><ul><li>Meta-analysis was not funded by industry </li></ul>Cipriani et al. Lancet. 2009; 373(9665):746-58. Efficacy (response rates) Acceptability (early termination for any reason)
    33. 33. Multiple-Treatments Meta-analysis of 12 Second-Generation Antidepressants FLUOXETINE Bupropion Citalopram Sertraline Escitalopram Mirtazapine Venlafaxine Paroxetine Duloxetine l 0.8 l 0.9 l 1.0 l 1.1 l 1.2 l 1.3 l 1.4 0.80 – 0.85 – 0.90 – 0.95 – 1.00 – 1.05 – 1.10 – 1.15 – 1.20 – 1.25 – Efficacy (OR) Acceptability (OR) Fluvoxamine Adapted from Cipriani et al. Lancet. 2009; 373(9665):746-58.
    34. 34. Rates of Adequate Dose and Duration 32.9% 6.0% 29.0% 1.0% 0% 5% 10% 15% 20% 25% 30% 35% TCAs SSRIs UK-DINLINK* MacDonald** Adequate Dose and Duration: At least 90-120 days at recommended doses within first six months *Dunn et. al. J Psychopharmacology , 1999. **MacDonald et. al. Primary Care Psychiatry, 1997;3(1 Suppl):S7-S10
    35. 35. Possible Increased Risk of Suicide <ul><li>FDA Public Health Advisory March, 2004: possible risk of worsening depression and suicidality in patients taking antidepressants </li></ul><ul><li>Done in reaction to reports of suicidal ideation and attempts in treatment of major depression in pediatric patients. </li></ul><ul><li>Black box warning for children / adolescents September, 2004 </li></ul><ul><li>Simon et al, 2006 changed our view of things </li></ul>
    36. 36. Suicide risk during antidepressant treatment. Simon et al AMJPsych, 2006 Jan;163(1):41-7. <ul><li>Population-based data to evaluate the risk of suicide death and serious suicide attempt in relation to initiation of antidepressant treatment. </li></ul><ul><li>METHOD: 65,103 patients with 82,285 episodes of antidepressant treatment between Jan. 1, 1992, and June 30, 2003. </li></ul><ul><li>RESULTS: 31 suicide deaths (40 per 100,000 treatment episodes) and 76 serious suicide attempts (93 per 100,000) were identified in the study group. </li></ul><ul><li>The risk of suicide attempt was 314 per 100,000 in children and adolescents, compared to 78 per 100,000 in adults. The risk of death by suicide was not significantly higher in the month after starting medication than in subsequent months. </li></ul><ul><li>The risk of suicide attempt was highest in the month before starting antidepressant treatment and declined progressively after starting medication. </li></ul><ul><li>An increase in risk after starting treatment was seen only for the older drugs. </li></ul><ul><li>CONCLUSIONS: The risk of suicide during acute-phase antidepressant treatment is approximately one in 3,000 treatment episodes, and risk of serious suicide attempt is approximately one in 1,000. </li></ul><ul><li>Available data do not indicate a significant increase in risk of suicide or serious suicide attempt after starting treatment with newer antidepressant drugs. </li></ul>
    37. 41. Summary of Main Points <ul><li>Mood disorders very common, have major impact </li></ul><ul><li>Important to be able to distinguish specific mood disorder-affects treatment, prognosis, course </li></ul><ul><li>Many patients not diagnosed or, if diagnosed, not treated at adequate dosage or long enough </li></ul>
    38. 42. ECT <ul><li>Kellner et al, British Journal of Psychiatry (2010) 196: 226-234. </li></ul><ul><li>RCT of 230 individuals treated with ECT for depression </li></ul><ul><li>Overall remission rate with ECT in the intention-to-treat analysis was 60%. </li></ul><ul><li>When ECT is used to treat unipolar major depression that has already failed to remit with vigorous antidepressant treatment, then the remission rate is still about 50%. </li></ul><ul><li>The patients in the present study had already been ill for an average of 2.4 years. </li></ul>
    39. 43. Copyright © 2010 The Royal College of Psychiatrists Kellner, C. H. et al. The British Journal of Psychiatry 2010;196:226-234 Fig. 2 Observed Hamilton Rating Scale for Depression-24 (HRSD-24) total score means.
    40. 44. Copyright © 2010 The Royal College of Psychiatrists Kellner, C. H. et al. The British Journal of Psychiatry 2010;196:226-234 Fig. 4 95% CI estimates of remission proportions for bitemporal (BT), bifrontal (BF) and right unilateral (RUL) electrode placements.
    41. 46. The Spectrum of Bipolar Disorders Mania Hypomania Depression Normal Mood Variation Normal Goodwin FK, Jamison KR. Manic-Depressive Illness ; 1990. Cyclothymic Personality Cyclothymic Disorder Bipolar II Disorder Unipolar Mania Bipolar I Disorder Severe Depression
    42. 47. Classification of Mood Disorders Bipolar I Bipolar II Cyclothymia Unipolar single episode Unipolar- Hyperthymic Dysthymia Unipolar recurrent Unipolar Bipolar
    43. 48. Bipolar Disorder: Clinical Features <ul><li>At least 1 episode of mania or hypomania or a mixed episode </li></ul><ul><li>Usually associated with episodes of major depression </li></ul><ul><li>Cyclic change between mood states </li></ul><ul><li>In severe episodes of mania and depression, psychotic symptoms may also be present </li></ul>
    44. 49. Bipolar Disorder Manic Depressive Illness <ul><li>Mania </li></ul><ul><ul><li>Elevated or irritable mood </li></ul></ul><ul><ul><li>Grandiosity </li></ul></ul><ul><ul><li>Decreased need for sleep </li></ul></ul><ul><ul><li>Increased or pressured speech </li></ul></ul><ul><ul><li>Flight of ideas or racing thoughts </li></ul></ul><ul><ul><li>Increased goal directed activity </li></ul></ul><ul><ul><li>Risk taking </li></ul></ul><ul><ul><li>Functional impairment </li></ul></ul><ul><li>Depression </li></ul><ul><ul><li>Low mood </li></ul></ul><ul><ul><li>Loss of interest or pleasure </li></ul></ul><ul><ul><li>Change in appetite or weight </li></ul></ul><ul><ul><li>Insomnia or hypersomnia </li></ul></ul><ul><ul><li>Fatigue </li></ul></ul><ul><ul><li>Feelings of worthlessness </li></ul></ul><ul><ul><li>Impaired memory or concentration </li></ul></ul><ul><ul><li>Suicidality </li></ul></ul><ul><ul><li>Clinically significant distress or impairment </li></ul></ul>
    45. 50. <ul><li>SYMPTOMS OF MANIA (3+) </li></ul><ul><ul><li>Symptoms last at least 1 week </li></ul></ul><ul><ul><li>Abnormally & persistently elevated/expansive/ irritable mood </li></ul></ul><ul><ul><li>Inflated self-esteem, grandiosity </li></ul></ul><ul><ul><li>Decreased need for sleep </li></ul></ul><ul><ul><li>More talkative than usual </li></ul></ul><ul><ul><li>Flight of ideas </li></ul></ul><ul><ul><li>Distractibility </li></ul></ul><ul><ul><li>Increase in goal-directed activity, or psychomotor agitation </li></ul></ul><ul><ul><li>Excessive involvement in pleasurable activities that have high risk of painful consequences </li></ul></ul><ul><ul><li>Accelerated & pressured speech/disjointed </li></ul></ul>
    46. 51. <ul><li>SYMPTOMS OF HYPOMANIA (3+) </li></ul><ul><ul><li>Sustained, elevated, expansive, or irritable mood, lasting 4 days </li></ul></ul><ul><ul><li>Same symptoms as mania, but less severe </li></ul></ul>
    47. 52. Summary of Prevalence Rates Diagnoses Number of Studies Range of Rates Bipolar I 21 0.0-2.4 Bipolar II 11 0.3-3.0 Cyclothymia 5 0.5-2.8 Spectrum 11 2.6-7.8-(10.8) Hypomania 2 2.2-5.7
    48. 53. Relationship Between Cycle Length and Number of Episodes of Bipolar Disorder Episode Cycle Length (Months)
    49. 54. Rate of relapse leading to hospitalisation: Bipolar disorder <ul><li>Rate of relapse leading to hospitalisation (after being discharged for at least 3 days) following first, second, third, fourth and fifth discharges </li></ul>Kessing et al. Br J Psych 2004 0.0 0.2 0.4 0.6 0.8 1.0 Cumulative survival 0 1 2 3 4 5 6 7 Time to relapse (years) 0.0 0.2 0.4 0.6 0.8 1.0 Cumulative survival 0 1 2 3 4 5 6 7 Time to relapse (years) Men Women Time 1 Time 2 Time 5 Time 3 Time 4 Time 1 Time 2 Time 3 Time 4 Time 5
    50. 55. Early Prospective Findings > 2000 patient-years <ul><li>Among those who achieve recovery </li></ul><ul><ul><li> 5% relapse each month. </li></ul></ul><ul><ul><li>80% of relapses = Depression </li></ul></ul><ul><li>Psychiatric hospitalization = 14.2 /100 pt-yrs </li></ul><ul><li>Mortality = 0.11/100 pt-yrs (9 deaths including 2 suicides ) </li></ul>S T E P B D
    51. 56. Patients are symptomatic for almost half of the time they are ill BP II, Judd et al 2003, n=86, m=13.4 years No symptoms Depressive Manic / hypomanic Mixed / rapid cycling BP I, Judd et al 2002, n=146, m=12.8 years BP I, Kupka et al 2004, n=392, m=1 year BP II, Kupka et al 2004, n=98, m=1 year 53% 32% 9% 6%
    52. 57. Natural History of Bipolar <ul><li>Early onset </li></ul><ul><li>Lifelong high risk of recurrence </li></ul><ul><li>High rates of Depression </li></ul><ul><li>Frequent biphasic symptomatology </li></ul><ul><li>Low rates of fully sustained recovery </li></ul><ul><li>High rates of incomplete remission </li></ul><ul><li>Considerable chronicity </li></ul><ul><li>Considerable suicide risk </li></ul>
    53. 58. Natural History <ul><li>The recurrence risk of bipolar I and bipolar II disorders is constant over decades </li></ul><ul><li>The suicide risk is 15 – 20-fold higher than in the general population </li></ul><ul><li>The suicide risk persists over decades </li></ul>
    54. 59. Dual Diagnosis: High Prevalence of Comorbid Psychiatric Disorders *p<.05. Kessler RC. In: Tohen M, ed. Comorbidity in Affective Disorders ; 1999:1-26. Cookson: SADAD2001
    55. 60. Long term outcome <ul><li>In the Zurich study, long-term medication reduced suicides by about 2/3 in both bipolar and unipolar disorders </li></ul><ul><li>Unipolar and bipolar patients showed elevated cardiovascular mortality; this mortality was also significantly reduced among treated patients </li></ul>
    56. 61. Bipolar Disorder: Untreated vs Treated Standardized Mortality Ratios Neoplasm Cardio- vascular Cerebro- vascular Accidents Suicide Other All Causes Untreated Treated 29.2* 6.4 1.4* 0.6 2.2* 1.7 1.6† 1.3 1.6 2.0 2.0* 1.3 2.2* 1.3 * p< 0.001 † p< 0.05 Zurich Cohort, n=406 1959-1997 Adapted from Angst, 2000
    57. 62. Phases of treating Bipolar Disorder <ul><li>Acute episodes continue until symptomatic remission </li></ul><ul><li>Acute phase of recovery lasts for a further two months </li></ul><ul><li>Continuation phase lasts to month six following recovery </li></ul><ul><li>Maintenance phase follows this </li></ul>Ghaemi, 2004
    58. 63. Treatment A. Long-term effective antimanic drugs Acute Phase Maintenance Phase C. Psychoeducation B. Long-term effective antidepressant drugs
    59. 64. A vast array of treatment options exist for bipolar disorder Traditional treatments Lithium Divalproex Carbamazepine Quetiapine Olanzapine Risperidone Ziprasidone Aripiprazole Clozapine Haloperidol Antipsychotics Cital o pram Fluoxetine Fluvoxamine Paroxetine Sertraline Bupropi o n Venlafaxine Nefadozone Antidepressants New anticonvulsants Lamotrigine
    60. 65. Meta-analysis of lithium maintenance- RCTs of prevention of any relapse <ul><li>Lithium was more effective than placebo in preventing any new episodes of mood disturbance. The average risk of relapse in the placebo group was 60% compared with 40% for lithium. This means that one patient would avoid relapse for every five patients who were treated for a year or 2 with lithium. </li></ul>Geddes et al, 2004
    61. 66. .010061 1 99.398 Risk ratio (95% CI) No. of events Control Treat. 0.43 (0.02, 10.21) Bowden 2003 1 / 59 0 / 46 0.19 (0.01, 3.48) Coppen 1971 3 / 37 0 / 28 0.31 (0.01, 7.44) Dorus 1989 1 / 82 0 / 89 0.44 (0.04, 4.69) Glen 1984 2 / 50 1 / 57 0.34 (0.01, 8.14) Greil 1996 1 / 41 0 / 40 0.17 (0.02, 1.37) Greil 1997a 6 / 88 1 / 87 0.22 (0.03, 1.85) Greil 1997b 5 / 58 1 / 52 3.00 (0.15, 61.74) Hardy 1997 0 / 6 1 / 6 0.33 (0.01, 8.10) Lamictal Study 605a 1 / 121 0 / 121 0.47 (0.02, 11.44) Lamictal Study 605aa 1 / 171 0 / 121 0.42 (0.04, 4.48) Prien 1973a 2 / 38 1 / 45 0.43 (0.04, 4.60) Prien 1973aa 2 / 39 1 / 45 0.51 (0.05, 5.59) Prien 1973b 2 / 104 1 / 101 0.35 (0.18, 0.71) Overall (95% CI) Relative risk – fixed effect DEATHS + DSH Composite outcome Cipriani A et al,AmJ Psychiatry. 2005 Oct;162(10):1805-19; Baldessarini Rj et al, Bipolar Disord. 2006 Oct;8(5 Pt 2):625-39. RCT
    62. 67. Suicide risk in bipolar disorder during treatment with lithium and divalproex Frederick K. Goodwin Among patients treated for bipolar disorder, risk of suicide attempt and suicide death is lower during treatment with lithium than during treatment with divalproex
    63. 68. Neurobiology of Depression Hippocampus Amygdala Cingulate cortex
    64. 69. Neurobiology of long term treatment Moorel et al Lancet 2000
    65. 70. <ul><ul><ul><li>Causal factors in Bipolar Disorder </li></ul></ul></ul><ul><ul><ul><ul><li>Genes </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>8-9% of 1 st -degree relatives can be expected to have Bipolar Disorder </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>MZ = 72-80% DZ = 14% </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Probably multiple genes of small effect </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Biochemical </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Neurotransmitter levels (norephinephrine, serotonin, dopamine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Psychosocial </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Stressful life events might trigger an episode of either depression or mania </li></ul></ul></ul></ul></ul>
    66. 71. Genes Summary <ul><li>Genes explain about 60% of the cause of mood disorders </li></ul><ul><li>Family members are about 7 times more likely to also have bipolar disorder </li></ul><ul><li>Many genes are involved </li></ul>
    67. 72. Common Genes for Bipolar Disorder and Schizophrenia Bipolar Schizophrenia
    68. 73. Genes and environment Gene subset C Pathophysiology C Gene subset A Pathophysiology A Gene subset B Pathophysiology B Environment Final Common pathway Disease
    69. 74. Serotonin pathways Raphe Nucleus Sleep Appetite Sexual activity Stress response Anxiety ? Mood
    70. 75. Noradrenaline Pathways Locus Coeruleus Sleep Attention and concentration Energy Stress response ? Mood
    71. 76. 5-HT/NA Interactions brake accelerator Raphe and LC
    72. 77. Role of 5-HT in mood regulation <ul><li>Acute tryptophan depletion (ATD) </li></ul><ul><ul><li>Little or no effect on mood in healthy subjects ( Abbott et al . 1992; Oldman et al . 1994; McAllister-Williams et al . 2003) </li></ul></ul><ul><ul><li>Leads to depression in vulnerable groups </li></ul></ul><ul><ul><ul><li>Subjects with strong family history ( Benkelfat et al . 1994; Klassen et al. 1999) </li></ul></ul></ul><ul><ul><ul><li>Euthymic subjects with a history of recurrent depression (Smith et al . 1997; Moreno et al. 1999) </li></ul></ul></ul>
    73. 78. Evidence for a role of 5-HT/NA in depression <ul><li>Noradrenergic systems </li></ul><ul><ul><li>Few consistent findings </li></ul></ul><ul><ul><ul><li>Density and affinity of α 2 -adrenoceptors increased in depressed patients at PM (Meana et al. 1992; Callado et al. 1998) </li></ul></ul></ul><ul><li>Serotonergic system </li></ul><ul><ul><li>Most consistent findings concern </li></ul></ul><ul><ul><li>5-HT 1A receptors </li></ul></ul>
    74. 79. Postsynaptic 5-HT 1A receptors and depression <ul><li>Function: </li></ul><ul><ul><li>Prolactin and growth hormone responses to intravenous l-tryptophan </li></ul></ul><ul><ul><ul><li>Blunted responses in depressed subjects in 5 studies (Power and Cowen, 1992) </li></ul></ul></ul><ul><ul><ul><li>State dependent finding (Upadyaya et al . 1991) </li></ul></ul></ul><ul><li>Number of receptors: </li></ul><ul><ul><li>PET scanning of WAY-100635 binding </li></ul></ul><ul><ul><ul><li>10-30% decrease binding sites ( Sargent et al. 2000; Drevets et al. 2000) </li></ul></ul></ul><ul><ul><ul><li>? Trait marker </li></ul></ul></ul>
    75. 80. Somatodendritic 5-HT 1A autoreceptors and depression <ul><li>Reduced numbers of receptors (Sargent et al. 2000, Drevets et al. 2000) </li></ul><ul><li>5-HT 1A receptor polymorphism (Albert et al. 2004) </li></ul><ul><li>Increased number of receptors in antidepressant naïve patients (Parsey et al. 2005) </li></ul><ul><li>? Changes in function </li></ul>
    76. 81. Somatodendritic 5-HT 1A receptor function in depression (McAllister-Williams et al. 2004)
    77. 82. 5-HT Neuronal control points Decreased Postsynaptic 5-HT 1A number and function in depression ? Increased Somatodendritic 5-HT 1A and α 2 -adrenoceptor number or function in depression 1A Somatodendritic autoreceptor (5-HT 1A ) 1D Terminal autoreceptor (5-HT 1D ) 5-HT raphe cell post- synaptic cell 1A 2A Postsynaptic 5-HT receptors (e.g. 5-HT 1A or 5-HT 2A )   Terminal heteroceptor (  2 ) Postsynaptic NA receptors (  1 )  1
    78. 83. Pathogenesis Foetus Child Adult Older person Illness Genes Social Environment Stress Psychological Social Somatic
    79. 84. HPA Axis GR PVN GR Pituitary Adrenals CRH AVP ACTH CORT GRs MRs GR/MR Hippocampus -ve -ve -ve GR/MR mediated -ve feedback Circadian Stress
    80. 85. Cortisol in Depression
    81. 86. Cortisol response on dex / CRH test Watson et al, 2002, 2004. Dexamethasone pretreatment 0 10 20 30 40 50 60 70 80 Cortisol response controls chronic depressed euthymic bipolars Bipolar depressed CRH
    82. 87. HPA axis and depression <ul><li>HPA axis involved with stress response </li></ul><ul><li>50% + of depressives hypercortisolaemic ; 90% have evidence of HPA hyperactivity </li></ul><ul><li>Depressed patients also have: </li></ul><ul><ul><li>raised CRH levels in CSF </li></ul></ul><ul><ul><li>enlarged pituitary glands </li></ul></ul><ul><ul><li>enlarged adrenal glands </li></ul></ul><ul><li>? Abnormality in depression is impaired feedback </li></ul><ul><li>Foetal/infant stress in animals produces long lasting effects on HPA axis responsivity </li></ul><ul><ul><li>? Mechanism for social adversity predisposing to depression </li></ul></ul>
    83. 88. What is wrong with the HPA in depression? <ul><li>Hypercortisolaemia resulting from </li></ul><ul><li>CRH hypersecretion (possible AVP involvement) </li></ul><ul><li>which may result from corticosteroid receptor down-regulation and thus impaired negative feedback (see Sapolsky et al, 1986) </li></ul><ul><li>Is the core abnormality at the corticosteroid receptor level? </li></ul>
    84. 89. The Glucocorticoid Receptor in Mood Disorders <ul><li>The GR receptor is reduced in frontal and hippocampal regions in unipolar and bipolar brains </li></ul><ul><li>Antidepressants, Lithium and ECS increase brain GR receptor number in experimental animals </li></ul><ul><li>This effect occurs in vitro and may be independent of effects on monoamines </li></ul>
    85. 90. DEPRESSION Serotonin System Hypothalo- Pituitary Adrenal Axis Corticosterone 5-HT 1A receptors
    86. 91. 0 10 20 -60 0 60 120 180 240 Time (min) 5-HT (fmol/sample) sham/fluoxetine cort/fluoxetine Cort treatment attenuates ability of SSRI to elevate of forebrain 5-HT Gartside, Leitch and Young, Neuropsychopharmacology, 2003. Local fluoxetine Systemic fluoxetine
    87. 92. HAMD-21 scores for the metyrapone group (solid circles) and the placebo group (open circles) for days 0, 3, 7, 14, 21, 28, and 35 on the intention-to-treat sample. Data are presented as mean±SEM. Jahn, H. et al (2004) Metyrapone as Additive Treatment in Major Depression: A Double-blind and Placebo-Controlled Trial. Archives of General Psychiatry , 61 , 1235-1244. Cortisol Synthesis Inhibition boosts Antidepressant Effects
    88. 93. CORT effects on 5-HT 1A receptors CORT Somatodendritic 5-HT 1A receptors Postsynaptic 5-HT 1A receptors 5-HT 1A receptor binding 5-HT 1A receptor mRNA 5-HT 1A electrophysiology 5-HT 1A behavioural models ? ? ? ?
    89. 94. Conclusions <ul><li>Types of mood disorders: a group of illnesses </li></ul><ul><li>Mood Disorders are a leading cause of ill-health world wide </li></ul><ul><li>Effective Treatments, both psychological and physical exist </li></ul><ul><li>Neurobiology is unknown, however the following are important: </li></ul><ul><li>- Genes; probably multiple genes of small effect </li></ul><ul><li>- Neurotransmitters; important for MOA of drugs </li></ul><ul><li>- HPA axis; potentially provides an integrated of pathophysiology and new treatment options </li></ul>

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