1. IS THERE SUCH A THING AS A CURE FOR MENTAL ILLNESS? TOM SENSKY Assurance Medical and Underwriting Society March 2011

3. CURE versus REMISSION CURE The complete eradication of the illness REMISSION State of absence of disease activity (usually in someone with a chronic disease)

4. WHAT SORTS OF ILLNESSES CAN BE CURED? Those which have.... Clear-cut pathology Simple aetiology (as opposed to multifactorial) Illnesses which have multifactorial causes or maintaining factors are likely to be chronic – cure here is unlikely

5. OVERVIEW – DIFFERENT TYPES OF CONDITIONS CONDITION TYPE EXAMPLESMANAGEMENT STRATEGY AcuteCommon cold Fractured humerus Remove pathology Cure Potentially Relapsing Cerebro- vascular accident Self-management Reduce risks where possible Contingency plan to manage relapse ChronicDiabetes Rheumatoid arthritis Continue treatment indefinitely Shared decision-making Self-management

6. OVERVIEW – DIFFERENT TYPES OF MENTAL HEALTH CONDITIONS CONDITION TYPE EXAMPLESMANAGEMENT STRATEGY AcuteSpecific phobias Remove pathology Cure Potentially Relapsing Depression Anxiety Self-management Reduce risks where possible Contingency plan to manage relapse ChronicSome cases of schizophrenia and bipolar disorder Continue treatment indefinitely Shared decision-making Self-management

7. OVERVIEW Focus on depression and anxiety, as common mental disorders Review of selective factors contributing to depression being best regarded as a chronic condition For anxiety, focus on some primitive psychological factors associated with the persistence of symptoms

8. DEPRESSION Depression is often referred to as the common cold of psychiatry. But this analogy is wrong: although common, most depressive disorders are not mild and self limiting. It is time that we treated depression as the chronic disease that it is. Jan Scott: Br Med J (editorial) (2006)

9. EPIDEMIOLOGY OF MENTAL DISORDERS (Health of the Nation) Of adults aged 16–64 years living in private households,1 in 6 had suffered from some type of neurotic disorder in the week before the survey interview Half of these experienced anxiety and/or depression Jenkins R et al: Br J Psychiatry (1998)

10. EPIDEMIOLOGY OF MENTAL DISORDERS (Health of the Nation) Rates of common mental disorders higher among women those who were separated, divorced and widowed individuals of both genders, and among cohabiting women the unemployed those with longstanding physical complaints Jenkins R et al: Br J Psychiatry (1998)

11. PREVALENCE OF COMMON MENTAL DISORDERS (AGES 18-32 years) 1972-3 Dunedin birth cohort, followed up prospectively to age 32 years (95% follow-up) Moffit TE et al: Psychological Medicine (2010) Higher prevalence than previously reported attributed to prospective follow-up (likely to be more accurate)

12. DEPRESSION IN WOMEN : AETIOLOGICAL MODEL DEPRESSION PROVOKING AGENTS Life events Chronic difficulties VULNERABILITY FACTORS Maternal derivation Parental separation Social supports Social circumstances BACKGROUND Personality Genetics After Brown GW & Harris T (1978)

13. COMMON MENTAL DISORDERS : AETIOLOGY RATE OF LIFE EVENTS IMPACT OF LIFE EVENTS ONSET OF DISORDER Good parenting Good marital relationship Psychological factors PROTECTIVE FACTORS VULNERABILITY FACTORS FAMILY Parental loss Lack of care Child abuse SOCIAL Marital discord Poor social support SOCIAL ADVERSITY Poor housing Unemployment PHYSIOLOGICAL Genetic Emotional reactivity PERSONALITY Neuroticism Low self esteem Low emotional strength

14. AETIOLOGICAL FACTORS RELEVANT TO DEPRESSION Sample of 10,045 primary care patients, from 7 countries, followed up at 6 and 12 months Bottomley C et al: Br J Psychiatry (2010)

15. AFFECTIVE DISORDERS : GENETICS Genetic loading : bipolar (BP)>unipolar (UP) Concordance (MZ twins) : BP=70%, UP=40% Risk of mood disorder in 1st degree relatives : BP=30%, UP=15% Close relative with BP disorder = increased lifetime risk of both BP and UP disorder Close relative with UP disorder = increased risk of UP disorder only

16. EFFECT OF 5HT TRANSPORTER POLYMORPHISM ON SUSCEPTIBILITY TO LIFE EVENTS Individuals homozygous for the short allele of the 5HT Transporter gene [s/s] were significantly more likely to develop a major depressive episode in response to stressful life events than those homozygous for the long allele [l/l] Caspi A et al: Science (2003)

17. AUTOBIOGRAPHICAL MEMORY AUTOBIOGRAPHICAL MEMORY IN DEPRESSION CONSEQUENCES Depressed people recall fewer autobiographical memories (40% cf 70% for non-depressed people) Impairment most noticeable for positive events Autobiographical memory for negative events less impaired Depressed people have difficulty remembering events or activities that give pleasure or satisfaction Remember details of unhappy events Poor autobiographical memory leads to impaired problem-solving The ability to recall specific memories in response to cues

18. ATTRIBUTIONS: AN EXAMPLE Being criticised for a piece of work STABLE Shes right – I dont think Im up to this work UNSTABLE She must have got out of bed the wrong side today GLOBAL Nothing I do is ever good enough SPECIFIC I didnt put as much effort into this piece of work as I usually do INTERNAL Its all my fault EXTERNAL If she hadnt overloaded me with other assignments, I could have spent more time on this one

19. REFORMULATION OF THE LEARNED HELPLESSNESS MODEL: ATTRIBUTION TYPES Abramson LY, Seligman K, Teasdale J: J Abnormal Psychology (1978) UNSTABLESTABLE INTERNAL EXTERNAL GLOBAL SPECIFIC Attributions by depressed people for NEGATIVE events Attributions by depressed people for POSITIVE events

20. ASSOCIATION OF STRESS AT WORK WITH DEPRESSION: SYSTEMATIC REVIEW Demand- control model High psychological demands Low degree of control over ones tasks Combination of factors that prevents the experience of autonomy 8 studies 44,114 respondents Depression associated with high demands plus low control Effort reward imbalance model Usually expect reciprocity of contractual exchange at work – efforts compensated by adequate rewards (money, career opportunity, job security and esteem Imbalance occurs if rewards are not commensurate with efforts 4 studies 81,582 respondents Depression assoiciated with effort-reward imbalance Sigrist J: Eur Arch Psychiatry Clin Neurosci (2009)

21. ASSOCIATION OF STRESS AT WORK WITH DEPRESSION: SYSTEMATIC REVIEW Demand- control model High psychological demands Low degree of control over ones tasks Combination of factors that prevents the experience of autonomy 8 studies 44,114 respondents Depression associated with high demands plus low control Effort reward imbalance model Usually expect reciprocity of contractual exchange at work – efforts compensated by adequate rewards (money, career opportunity, job security and esteem Imbalance occurs if rewards are not commensurate with efforts 4 studies 81,582 respondents Depression associated with effort-reward imbalance Sigrist J: Eur Arch Psychiatry Clin Neurosci (2009)

22. WORK-RELATED FACTORS CONTRIBUTING TO DEPRESSION ONSET Longitudinal study examining onset of depression in 7 countries (6 European) Examined influence of 39 potential risk factors Sample: 7558 people not depressed at baseline Factor Adjusted HR 95% CI of HR Discrimination1.941.46-2.58 Distress at work without respect2.021.56-2.63 Difficulties at work without support2.011.49-2.72 Lack of control at work2.091.44-3.02 Bottomley C et al. British Journal of Psychiatry 196 (1):13-17, 2010

23. OFFSPRING OF SEVERELY DEPRESSED PARENTS Prospective 20-year follow-up of offspring of severely depressed patients Matched comparison group – offspring of parents without psychiatric morbidity Mean age of offspring at follow-up was 35 years Weissman MMet al: Am J Psychiatry (2006) DIAGNOSIS Cumulative Rate (%) Relative Rate DepressedControl Any mood disorder80503.3 Major depressive disorder65273.3 Any anxiety disorder67342.9 Any substance abuse21181.1 Any physical illness78602.5 Overweight51700.4

24. OFFSPRING OF SEVERELY DEPRESSED PARENTS Prospective 20-year follow-up of offspring of severely depressed patients Matched comparison group – offspring of parents without psychiatric morbidity Mean age of offspring at follow-up was 35 years Weissman MMet al: Am J Psychiatry (2006) DIAGNOSIS Cumulative Rate (%) Relative Rate DepressedControl Any mood disorder80503.3 Major depressive disorder65273.3 Any anxiety disorder67342.9 Any substance abuse21181.1 Any physical illness78602.5 Overweight51700.4

25. ADVERSE EVENTS IN CHILDHOOD AND ADULT DEPRESSED MOOD Survey of 9508 adults registered with a health maintenance organisation Assessed a variety of adverse childhood events, including abuse, violence against mother, parent in prison, etc Assessed the odds of having at least 2 weeks of depressed mood in the past 12 months Felitti VJ et al: Am J Prev Med (1998)

26. ETHNIC DENSITY AND COMMON MENTAL DISORDERS Random community sample (N=4281) After adjusting for confounders, as own-group ethnic density rose, the prevalence of common mental disorders decreased in (a) the whole ethnic minority sample; (b) the Irish group; (c) the Bangladeshi group This was despite areas of high minority ethnic density being socially deprived These results were not explained by discrimination, social support or social networks Das-Munshi J et al : Br Med J (2010)

27. WILL THE INCIDENCE OF DEPRESSION RISE IN MEN? All research to date indicates higher incidence of depression in women Women tend to derive their self-esteem from reflected appraisals, while men focus on social comparisons, particularly regarding traditional male roles Women are increasingly the primary household earners (4% in 1970, 22% in 2007) Male jobs are arguable more sensitive to the effects of recession than female jobs Dunlop BW & Mietzko T: Br J Psychiatry (2011)

28. DEPRESSION RELAPSE RATES – ANTIDEPRESSANTS vs PLACEBO S Reid & C Barbui. Long term treatment of depression with selective serotonin reuptake inhibitors and newer antidepressants. BMJ 340 (mar26_1):c1468, 2010. 4.5*5.0* 3.1* 2.4* 4.2* * Number Needed to Treat

29. EFFICACY OF ANTIDEPRESSANT TREATMENT FOR DEPRESSION IN PRIMARY CARE Arroll B et al. Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev (3):CD007954, 2009

30. UK PRESCRIPTION OF ANTIDEPRESSANT MEDICATIONS From www.tuesday1st.blogspot.com/ (dated 28 January 2010)www.tuesday1st.blogspot.com/

31. VARIATIONS IN ANTIDEPRESSANT PRESCRIBING IN ENGLAND http://www.guardian.co.uk/news /datablog/2011/mar/05/data- store-pharmaceuticals- industry?intcmp=239# Northern doctors prescribe more antidepressants, study reveals Patients in areas such as Blackpool are prescribed up to three times as many antidepressants as those in parts of London James BallJames Ball and Sarah BoseleySarah Boseley guardian.co.ukguardian.co.uk, Friday 4 March 2011 21.30 GMT

32. GP DIAGNOSIS OF DEPRESSION Meta-analysis of 41 studies involving 50,371 patients Weighed sensitivity = 50% Weighed specificity = 81% GPs tend to rule out non-cases more effectively than recognising cases, but the modest prevalence of depression means that there are more false positives than missed cases For every 100 unselected cases seen, 10 true cases of depression are identified, 10 cases missed, and 15 people diagnosed as false positives Mitchell AJ et al. Lancet 374 (9690):609-619, 2009.

33. ARE ANTIDEPRESSANTS EFFECTIVE IN TREATING DEPRESSION? Meta-analysis of all clinical trials submitted to the US (FDA for licensing of the four new-generation antidepressants for which full datasets were available 35 clinical trials involving 5,133 patients (3,292 randomised to antidepressants, 1,841 to placebo) Kirsch I et al: Plos Medicine (2008)

34. COMPARATIVE EFFICACY OF ANTIDEPRESSANT MEDICATIONS Data from Cipriani et al (2009) – table from Bandolier (http://www.medicine.ox.ac.uk/bandolier)

35. META-ANALYSIS OF COMPUTER CBT FOR DEPRESSION AND ANXIETY DIAGNOSISSTUDIES EFFECT SIZE (g) NNT Major depression60.782.39 Social phobia80.922.07 Panic disorder60.832.26 Generalised anxiety21.121.75 All combined220.882.15 Andrews Get al : PLoS ONE (2010)

36. DEPRESSION TREATMENT: SHORT- TERM EFFECTS OF ANTIDEPRESSANT MEDICATION OR COGNITIVE THERAPY DeRubeis R et al: Nature Reviews Neuroscience (2008) Severely depressed patients (n=240) were randomized to ADM (n = 120), CT (n = 60) or a (pill) placebo control (n = 60) treatment. ADM involved paroxetine, augmented with lithium or desipramine as needed. Treatment phase lasted 16 weeks. The clinicians providing either ADM or CT were experienced practitioners who received feedback and supervision throughout the period of the study.

37. CBT vs ANTIDEPRESSANTS: CHANGE IN COGNITIONS I Simons AD et al (1984) Arch Gen Psych 41:45-51

38. CBT vs ANTIDEPRESSANTS: CHANGE IN COGNITIONS II Simons AD et al (1984) Arch Gen Psych 41:45-51

39. PROGNOSIS OF PEOPLE DIAGNOSED WITH DEPRESSION % FOLLOW-UP MONTHS Episodes of depression30% Symptoms of depression52% Antidepressant prescription59% Prospective cohort study of people diagnosed with depression 8-11 year follow-up (N=61) Kennedy N et al: Br J Psychiatry (2005) 18% of the cohort never achieved asymptomatic status

40. DEPRESSION TREATMENT: DIFFERENCES WITH/WITHOUT ANXIETY PRESENT Data from STAR*D trial – 2,876 adults with major depressive disorder, started initially on treatment with citalopram Fava M et al: Am J Psychiatry (2008)

41. EFFECTS OF PAST HISTORY AND SUBTHRESHOLD DEPRESSIVE SYMPTOMS ON LATER DEPRESSION INCIDENCE Prospective cohort study from the Netherlands N=1167 Community sample 2-year follow-up Those who had depression within 6 months of baseline assessment were excluded Karsten J et al: Br J Psychiatry (2011)

42. FACTORS PREDICTING LESS FAVOURABLE PROGNOSIS IN PEOPLE DIAGNOSED WITH DEPRESSION FACTOR Adjusted Odds Ratio Female gender5.45 Severe index episode5.70 Index anxiety3.64 Depression prior to index episode3.50 Kennedy N et al: Br J Psychiatry (2005)

43. DEPRESSION: RELAPSE FOLLOWING ANTIDEPRESSANT MEDICATION OR COGNITIVE THERAPY DeRubeis R et al: Nature Reviews Neuroscience (2008) After 16 week treatment phase, patients on ADM were randomised to continuation with ADM or placebo Patients who had CBT were allowed no more than 3 booster sessions after acute treatment

44. ANXIETY - AETIOLOGY PSYCHOLOGICAL FACTORS Classical conditioning Operant conditioning Social learning GENETIC FACTORS Modest genetic contribution overall Sensitivity of CO 2 inhalation ?related to polymorphism of lactate dehydrogenase gene Panic attacks more common in people who have joint hypermotility NEURO- TRANSMITTERS Serotonin and GABA receptors important Serotonin depletion increases susceptibility to panic Treated with benzodiazepines/SSRIs BRAIN CHANGES Anxiety associated with changes in amygdala, cingulate gyrus and prefrontal/anterior temporal cortex

45. THE EXPERIENCE OF ANXIETY Many people who experience anxiety recognise their fears as unwarranted Such people know (intellectually) that they have no need to be anxious, yet the anxiety persists Very simple psychological factors contribute to this persistence Conditioning (classical and operant) Social learning

46. CLASSICAL CONDITIONING (PAVLOVS DOG)

47. Context eg playground CLASSICAL CONDITIONING Bullying Anxiety Context eg playground Anxiety Unconditioned stimulus Unconditioned response Conditioned stimulus Conditioned response

48. Waterway CLASSICAL CONDITIONING Accident in boat in water Anxiety Waterway Anxiety Unconditioned stimulus Unconditioned response Conditioned stimulus Conditioned response

49. PROBLEMS WITH REGARDING SPECIFIC PHOBIAS AS CLASSICALLY CONDITIONED There isnt always a past history of a traumatic event If there is a past history of trauma, it does always lead to development of a phobia Mineka S & Zinbarg R: American Psychologist (2006)

50. VICARIOUS CONDITIONING In normal classical conditioning, the individual is exposed directly to the fearful stimulus Laboratory-reared rhesus monkeys (not afraid of snakes) became afraid of snake by seeing wild-reared monkeys reacting fearfully to snakes Humans can develop fears by watching videotapes of other people reacting fearfully

51. INDIVIDUAL DIFFERENCES IN VULNERABILITY TO ACQUIRE SPECIFIC PHOBIAS Modest genetic vulnerability for phobias (?mediated by genetic contribution to fear conditioning) Phobias more likely with certain personality variables High trait anxiety Behavioural inhibition (shyness, timidity) Differences in life experience (before, during and after the conditioning event(s))

52. EXPERIENCES PRIOR TO CONDITIONING EVENT(S) Exposure to the conditioned stimulus (2) before this is paired with the unconditioned stimulus (3) reduces the extent to subsequent conditioning Example: children visiting the dentist Unlike experimental animals, humans are seldom naïve to any conditioning stimulus

53. EXPERIENCES DURING CONDITIONING Fear is less likely to be conditioned when the aversive event is seen as escapable controllable

54. EXPERIENCES AFTER CONDITIONING Mild fear (previously conditioned) Exposure to a more intense but unrelated traumatic experience Increased fear to the original conditioned stimulus INFLATION EFFECT EXAMPLE Mild driving phobia after car accident Subsequent personal assault Driving phobia then becomes much worse

55. CONDITIONING OF PHOBIAS – OTHER FACTORS In monkeys, easier to condition fears for snakes or crocodiles than for flowers or toy rabbits Similar findings in humans – fears are selectively conditioned (people fear spiders more frequently than guns) Such prepared fears are probably similar now to the experience of prehistoric man Prepared fears more easily acquired, and more difficult to get rid of

56. EXAMPLES OF SOCIAL LEARNING IN SOCIAL PHOBIA VICARIOUS LEARNING Observing someone else being humiliated or ridiculed may be sufficient to generate social phobia SOCIAL REINFORCEMENT Parents of anxious children are more likely than other parents to support their childrens wishes to avoid social situations CULTURAL NORMS In Western cultures, social phobia commonly involves a fear of being scrutinised, while in Japan, it commonly involves a fear of causing offence by staring inappropriately, blushing, etc

57. OPERANT CONDITIONING The individual learns by operating appropriately on the environment Example Mouse learns that pressing lever in response to red light results in getting a food pellet, while pressing lever in response to green light leads to electric shock

58. OPERANT CONDITIONING – EXAMPLE OF A CHILD HAVING A TANTRUM Mother gives child immediate attention POSITIVE REINFORCEMENT Tantrums repeated Mother withdraws NEGATIVE REINFORCEMENT Tantrum ends Mother gives attention when tantrum ended POSITIVE REINFORCEMENT Tantrums reduce

59. OPERANT CONDITIONING IN ANXIETY: EXAMPLES Avoidance of phobic stimuli or of vicarious conditioning Child avoids dogs because mother is afraid of them Persistent safety behaviours Always going out accompanied Taking alcohol before going out

60. SAFETY BEHAVIOURS INHIBIT IMPROVEMENT IN PATIENTS WITH SOCIAL PHOBIA Wells A et al: Behavior Therapy (1995) Case series (N=8) Within-subjects crossover design One therapy session with safety behaviours, one session without Monitored in- session anxiety and thoughts

61. CONCLUSIONS Chronic conditions can seldom be cured Disorders like schizophrenia and bipolar disorder are often considered chronic However, even common mental disorders (depression and anxiety) are best understood and managed as chronic conditions

62. CONTACT DETAILS t.sensky@imperial.ac.uk

64. PTSD and subsyndromal PTSD, and change of diagnoses over three years (N=90) 5 19 66 62 4 13 4 2 2 3 2 weeks post accident 1 4 9 77 73 4 4 4 2 1 78 10 2 1 1 3 year follow-up 1 year follow-up Subsyndromal PTSD no PTSD 1 Time criterion for PTSD not fulfilled

65. Psychiatric comorbidity at one-year follow-up (N=106) Schnyder et al. (2001) Am J Resp Crit Care Med 164: 653-656 PTSD full or subsyndromal Anxiety (HADS) Depression (HADS) 3 + 3* 8 4 4 2 1 2

66. PERSONALITY DISORDER versus NEUROSIS PERSONALITY DISORDER NEUROSIS ONSET Childhood/ adolescence May be in adulthood ENVIRONMENTAL PRECIPITANTS ??Present DISCRETE SYMPTOMS No (except transiently) Yes SYMPTOMS CHANGE OVER TIME NoUsually DURATION Always chronic May be brief

67. Affective disorders : prognosis UNIPOLAR DEPRESSIVE DISORDER First episode lasts 4-6 months 25% recurrence after 1 year 75% recurrence within 10 years, 93% within 20 years Average gap is 65 months Typically 4-6 episodes over 20 years 10% will eventually have hypomanic / manic episode (diagnosis then = Bipolar Disorder) BIPOLAR DISORDER Recurrence common (depression or mania) Average gap is 48 months Remission periods become shorter Average 6.5 episodes in lifetime Suicide rate in severe affective disorder = 10 - 15%

68. DEPRESSION : AETIOLOGY

69. PROGNOSIS OF PEOPLE DIAGNOSED WITH DEPRESSION Prospective cohort study of people diagnosed with bipolar affective disorder, symptomatic at baseline (N=1469) 24-month follow-up Perlis RH et al: Arch Gen Psychiatry (2006) 58% achieved recovery 48% had a recurrence (depression 34%, other 13%) FACTORS INDEPENDENTLY ASSOCIATED WITH TIME TO RECURRENCE RELAPSE TYPEFACTOR HAZARD RATIO Depression Residual manic symptoms1.22 % days depression (past yr)1.02 % days anxiety (past yr)1.01 Mania/Mixed Episodes depression (past yr)1.07 % days depression (past yr)0.99 % days elevated mood (past yr)1.02

70. SELECTIVE PUBLICATION OF ANTIDEPRESSANT TRIALS Turner EH et al. N Engl J Med 358 (3):252-260, 2008 Obtained reviews from FDA for studies of 12 antidepressants (12,564 patients) Identified relevant published papers Examined papers to determine whether their conclusions agreed with FDA decision, or conflicted with it

71. ETHNIC DENSITY, PHYSICAL ILLNESS AND ANTIDEPRESSANT PRESCRIBING Data from 8515 GP practices in England Performance data from Quality and Outcomes Framework (QOF) (2004-5) Sociodemographic data from 2001 census Prescribing from Prescribing Analysis and CosT (PACT) data Multiple regression analysis Walters P et al: Br J Psychiatry (2008) ANTIDEPRESSANT PRESCRIBING – UNIVARIATE ASSOCIATIONS VARIABLE VARIANCE EXPLAINED UNADJUSTED BETA Chronic respiratory disease25%574 Coronary heart disease22%329 % Black ethnic patients12%-52 % Chinese ethnic patients9%-179 % S Asian ethic patients7%-19 % White ethnic patients15%20 Index of multiple deprivation4%12 Group practice4%465 List size3%-0.2

72. ETHNIC DENSITY, PHYSICAL ILLNESS AND ANTIDEPRESSANT PRESCRIBING Data from 8515 GP practices in England Performance data from Quality and Outcomes Framework (QOF) (2004-5) Sociodemographic data from 2001 census Prescribing from Prescribing Analysis and CosT (PACT) data Multiple regression analysis Walters P et al: Br J Psychiatry (2008) ANTIDEPRESSANT PRESCRIBING – UNIVARIATE ASSOCIATIONS VARIABLE VARIANCE EXPLAINED UNADJUSTED BETA Chronic respiratory disease25%574 Coronary heart disease22%329 % Black ethnic patients12%-52 % Chinese ethnic patients9%-179 % S Asian ethic patients7%-19 % White ethnic patients15%20 Index of multiple deprivation4%12 Group practice4%465 List size3%-0.2

73. EPIDEMIOLOGY OF MENTAL DISORDERS (Health of the Nation) Disorder Point Prevalence Lifetime Risk Schizophrenia0.2-0.5%0.7-0.9% Bipolar affective disorder0.1-0.5%1% Depressive disorder3-6%20% Dementia at age >65 years5% Dementia at age >80 years20% Jenkins R et al: Br J Psychiatry (1998)

74. PANIC DISORDER: REDUCTION IN GABA RECEPTOR BINDING GABA A receptor binding measured by positron emission tomography (PET) imaging with 11 C-flumazenil (benzodiazepine antagonist) Malizia AL et al: Arch Gen Psychiatry (1998 ) Marked reduction noted in GABA A receptor binding throughout the brain, with greatest decrease in orbitofrontal and temporal cortex (?involved in the experience of anxiety)

75. THE BURDEN OF DEPRESSION Depression is the third most common presentation among GP referrals 20% of those with depression will not recover fully from the index episode 70-80% of those achieving remission will have at least 1 recurrence 15% will eventually commit suicide Scott J: Br Med J (2006)

76. WORLDWIDE DISABILITY BY DISEASE Source: WHO Collaborative Project on Psychological Problems in General Health Care

77. DEPRESSION : AETIOLOGY

78. DEPRESSION AND THE RESPONSE OF OTHERS Female undergraduates (N=45) randomised to 3 groups to have phone conversations with: Depressed people (N=15) People with a history of depression (N=15) Controls with no history of depression (N=15) Coyne JC: J Abnormal Psychology (1976)

79. DEPRESSION AND THE RESPONSE OF OTHERS Those subjects talking to depressed patients reported: more depression, anxiety and hostility increased reluctance to re-engage The speech of the depressed patients contained more self-references, particularly of negative personal and private events Coyne JC: J Abnormal Psychology (1976) Depression is not a social skills deficit but depressed patients tend to alienate others, leading to less positive reinforcement