monoamine oxidase inhibitors (RIMAs) 272 Selective serotonin reuptake inhibitors (SSRIs) 27 6 Other antidepressants 1 278 Other antidepressants 2 280 ECT 1: background 282 ECT 2: indi cations, contraindications, and considerations 284 ECT 3: work-up and administration 286 EC T 4: notes on treatment 290 ECT 5: further notes on treatment 292 ECT 6: side-effects and o ther speci \201 c problems 294 Neurosurgery for mental disorder (NMD) 296 Other physical t reatments 298 07_Semple_Chap07.indd 231 12/10/2012 6:36:06 PM CHAPTER 7 Depressive illness 232 Introduction Depressive disorders are common, with a prevalence of 5 \200\22310% in primary care settings. They rank fourth as causes of disability worldwide, and it has been project ed that they may rank second by the year 2020. The preva- lence of depressive symptoms may be as high as 30% in the general popula- tion with women being twice as likely to be affect ed as men. Although effective treatments are available, depression often goes undi- agnosed and undert reated. Symptoms often are regarded by both patients and physicians as understandable given current social circumstances and/ or background. Although in many cases this may be true, people should not be denied interventions that may help relieve some of the disabling sympt oms of the disorder, allowing them to cope better with any current social problems. It should be borne in mind that depressive disorder has signi \201 cant potential morbidit y and mortality. Suicide is the second leading cause of death in persons aged 20 \200\22335 yrs and depressive disorder is a major factor in around 50% of these deaths. Depressive dis order also contributes to higher morbidity and mortality when associated with other physica l disor- ders (e.g. myocardial infarction [MI]) and its successful diagnosis and treat- men t has been shown to improve both medical and surgical outcomes. It is also associated with high rates of comorbid alcohol and substance misuse, and has a considerable social impact o n relationships, families, and productivity (through time off work). The majority of patients will present to primary care, often with prob- lems other than low mood (see b p. 240). Physicians ought to remain alert to this possibility as early interve ntions may be critical in the preven- tion of major morbidity and comorbidity. There remains an innate reluctance to consider pharmacological inter- ventions for emotiona l problems, despite overwhelming evidence of ef \201 - cacy. There is also a widespread co ncern that drugs which improve mood must be addictive, despite evidence to the contrary. Wh ile medication is not the only possible treatment for mild to moderate depression, when ant idepressants are prescribed the onus is on the physician to give a thera- peutic dose for a n adequate length of time. Treatment failure is often due to patient non-compliance, partic ularly when the patient feels that their problems have not been taken seriously and they ha ve been \200\230fobbed off \200\231. In a group of patients who generally have feelings of low self-worth or guilt, it is critical that they understand the rationale behind any trea tment, and that their progress is regularly reviewed, at least in the early stages. Depression amongst the famous As depression is common it is not surprising that many famous people have had a depressive illness (see Box 7.1). However, there still remains a stigma attached to psychiatric illness and it is only recently that peo- ple have become more will ing to discuss their illnesses publicly. A recent study examined the lives of almost 300 wo rld-famous men and found that over 40% had experienced some type of depression during their lives.1 Highest rates (72%) were found in writers, but the incidence was also high in arti sts (42%), politicians (41%), intellectuals (36%), composers (35%), and scientists (33%). 07_Semple_Chap07.indd 232 12/10/2012 6:36:06 PM INTRODUCTION 233 Box 7.1 Famous people who have publicly stated they have had a depressive illness include: Alanis Morissette, musician, composer Anthony Hopkins, actor Barbara Bush, former First Lad y (US) Billy Joel, musician, composer Courtney Love, musician, actor Donny Osmond, musician Ellen DeGeneres, comedienne, actor Elton John, musician, composer Germaine Greer, writer H alle Berry, actress Harrison Ford, actor Janet Jackson, musician Jessica Lange, actress Jim Carrey, actor, comedian Joan Rivers, comedienne, TV host John Cleese, comedian, actor, wri ter Leonard Cohen, musician, writer Lou Reed, musician Marie Osmond, musician Marlon Brando, ac tor Monica Seles, athlete (tennis) Ozzy Osbourne, musician Paul Gascoigne, professional foo tballer Paul Merton, comedian Paul Simon, composer, musician Roseanne Barr, actress, writer , comedienne Sheryl Crow, musician Sinead O \200\231Connor, musician S.P. Morrissey, musici an Stephen Hawking, scientist, writer Winona Ryder, actress Other famous people (deceased) known to have had a depressive illness: Samuel Beckett, Mena chem Begin, Kurt Cobain, Michel Foucault, Judy Garland, Ernest Hemingway, Audrey Hepburn, W illiam James, Franz Kafka, Claude Monet, Richard M. Nixon, Laurence Olivier, Wilfred Owen, George S. Patton, Sylvia Plath, Jackson Pollock, Cole Porter, Mark Rothko, Dmitri Shostakov ich, Tennessee Williams, Yves Saint Laurent. 1 Post F (1994) Creativity and psychopathology. A study of 291 world-famous men. Br J Psych iat 165: 22 \200\22334. 07_Semple_Chap07.indd 233 12/10/2012 6:36:06 PM CHAPTER 7 Depressive illness 234 Historical perspective The changing face of depression1 Current ideas of what constitutes d epression date from the mid-18th cen- tury. Earlier, the illness was understood in terms of \200\230melancholia \200\231, from classical humoural theories (melancholia derived from the Greek melaina kole \200\224black bile), re \202 ecting \200\230intensity of idea \200 \231 (Haslam 1809), i.e. the pres- ence of few, rather than many, delusions. Sadness or low mood were not primary symptoms. The \200\230melancholic \200\231 symptoms we now regard a s part of depressive disorder would have been called \200\230vapors \200\231, \200\230hyp ochondria \200\231, or \200\230neuroses \200\231. \200\230Depression \200\231, a term use d to mean \200\230reduced functioning \200\231 in other medical disciplines, came to be as sociated with \200\230mental depression \200\231, adopted because it implied a physiologic al change, de \201 ned as \200\230a condition characterized by a sinking of the spirits, lack of courage or initiative, and a tendency to gloomy thoughts \200\231 (Jastrow 1901). The concept was enlarged and legitimized by Kraepelin (1921) who used the term \200\230dep ressive states \200\231 in his description of the unitary concept of \200\230manic-depress ive illness \200\231, encompassing melancholia simplex and gravis, stupor, fantastical mela ncholia, delirious melancholia, and involutional melancholia. A number of assumptions surro unded the affective disor- ders; they involved the primary pathology of affect, and had sta ble psycho- pathology and brain pathology, were periodic in nature, had a genetic basis, oc curred in persons with certain personality traits, and were \200\230endogenous \200\231 (u nrelated to precipitants). In 1917 Freud published Mourning and melancholia, in \202 uencing more than a generation o f practitioners in emphasizing cognitive and psychic fac- tors in the etiology of depressio n, and shifting clinical descriptions from objective behavioral signs to subjective symptom s. Over the intervening years there has been much debate as to whether a \200\230biological \200\231 type of depression exists separate from a \200\230neurotic \200\231 type. Termino logy has \202 uctuated around endogenous, vital, autonomous, endomorphic, and melancholic depression, characterized by distinctive symptoms and signs, a genetic basis, and running an independent course unrelated to psychosocial factors. In contrast, \200\230neurotic \200\231 or \200\230reactive \200\231 depression could manifest in multiple forms, showed clear responsiveness to the environment, and ran a more variable course. Both ICD-10 and DS M-IV fudge the issue somewhat by using severity speci \201 ers (i.e. mild, moderate, sever e), as well as symptom speci \201 ers (i.e. somatic symptoms, psychotic symptoms). The advent of antidepressant drugs in the 1950s introduced a fur- ther complication into th e mix. Although ECT was widely accepted as a treatment for \200\230vital \200\231 depressi on, the idea of a drug treatment for \200\230reac- tive \200\231 depressive disorders ran counter to the received wisdom of the psychological basis to these conditions and the need for psychological treatment. The antidepressants and beyond The antidepressant effects of isoniazid were \201 rst obse rved in 1952 by Lurie and Salzer in patients being treated for TB. Similar effects were not ed for 07_Semple_Chap07.indd 234 12/10/2012 6:36:06 PM HISTORICAL PERSPECTIVE 235 reserpine by Shepherd and Davies, who conducted the \201 rst RCT in psy- chiatry, clearly demonstrating ef \201 cacy in anxious depression in 1955. The psychiatric community was i nitially reluctant to accept the idea of chemical \200\230cures \200\231 for mental disord ers. It was not until iproniazid was promoted by Kline in 1957 as a \200\230psychic energi zer \200\231, capable of treating \200\230nervous \200\231 condi- tions, that the tide beg an to turn. In 1956, Kuhn demonstrated the antidepressant effects of imipramine, the tricyclic antidepr essant (TCA), marketed worldwide in 1958, closely followed by amitriptyline in 1960. At the same time new anxiolytics were also emerging, with meprobamate in 1955, and the \201 rst benzodiazepine \200\224 chlordiazepoxide \200\224in 1960. The search for greater dissociat ion of anxio- lytic and sedative properties led to the introduction of diazepam in 1963. Th e downside of this new psychopharmacology was the over-prescrip- tion in the 1960s and \200\23170s of these drugs to help with \200\230the problems of living \200\231 and eviden ce of dependence, particularly in the case of the benzo- diazepines. As a result, non-pharm acological treatments \202 ourished, in the form of \200\230re-branded \200\231 psychoth erapies. Behind the scenes, biological psychiatrists and psychopharmacologists developed the monoami ne theories of depression, based upon the discov- ery of the neuropharmacological action of the antidepressants. This led to the development of more selective antidepressants \200 \224in the \201 rst instance, the SSRIs, with zimelidine patented in 1971, and indalpine marketed in 1978. The emphasis on safety and side-effect issues when comparing the SSRIs with TCAs, and the d ecline of the benzodiazepines, opened the \202 oodgates in the 1980s and \200\23190s for the promotion of SSRIs (e.g. \202 uoxetine [1989]) not only in the treatment of depressi on, but also for anxiety disorders. Advances in monoamine theories also allowed the develop ment of \200\230dual- action \200\231 agents (e.g. SNRIs \200\224venlafaxine [1995]; NaSSA s \200\224nefazodone [1995]/mirtazapine [1997]; DNRIs \200\224bupropion [2000]) and other s elective agents (e.g. NARIs \200\224reboxetine [1997]). Current theories of depression attempt to integrate biological mod- els of stress (involvin g the hypothalamic \200\223pituitary \200\223adrenal [HPA] axis) with evidence from biologi cal psychology, genetics, neuropharmacology, and functional neuropathology. A multifactoria l biopsychosocial model (see b p. 245) emerged, which helped to unite the divergent ideas o f depression. Clinical symptoms and signs are seen as the \201 nal common pathway in a complex interact ion between genes and the environment in determining predisposition or biological vulnerabi lity, which may subsequently lead to biological variations in functioning necessary for beh avioral and emotional change. This may be due to further psychosocial stressors or genetica lly predetermined factors, which give rise to alterations in brain functioning. Research in to these interdependent factors may well lead to greater understanding of the etiology of d epressive disorder, as well as allowing the development of diagnostic tests and individuali zed treatments. 1 For an exhaustive critique of conceptual ideas see: Jackson SW (1987) Melancholia and dep ression: from Hippocratic times to modern times. New Haven: Yale University Press. 07_Semple_Chap07.indd 235 12/10/2012 6:36:06 PM CHAPTER 7 Depressive illness 236 Diagnosis 1: symptoms Although the terminology is slightly different between ICD-10 and DSM -IV (see Table 7.1), the core symptoms are almost identical and, for a positive diagnosis, should ful \201 l the following criteria: \200 \200 Present for at least 2 wks and represent a change from normal. Are not secondary to the eff ects of drug/alcohol misuse, medication, a medical disorder, or bereavement (see b p. 393). May cause signi \201 cant distress and/or impairment of social, occupational, or general functioning. Core symptoms \200 Depressed variation, and often lack of responsiveness to changes in circumstances. There ma y be diurnal variation in mood with mood being worse in the morning and improving as the da y goes on. Anhedonia: markedly diminished interest or pleasure in all, or almost all, activ ities most of the day, nearly every day (as indicated by either subjective account or obser vation made by others). Weight change: loss of weight when not dieting or weight gain (e.g. a change of more than 5% of body weight in a month), associated with decreased or increase d appetite. Disturbed than usual) or hypersomnia (especially in atypical depression, see b p. 462). Psychomotor subjective feelings of restlessness or being slowed down. Fatigue or l oss of energy. Reduced libido. Feelings of worthlessness or excessive or inappropriate guil t (which may be delusional): not just self-reproach or guilt about being ill. Diminished ab ility to think or concentrate or indecisiveness. Recurrent thoughts of death may not have b een acted upon. mood: present most of the day, nearly every day, with little sleep: insomnia (with early morning wakening 2 \200\2233 hr sooner agitation or retardation: observable by others, not just \200 \200 \200 or suicide (not \200\230fear of dying \200\231), which may or Somatic symptoms Also called biological, melancholic (DSM-IV), or vital. Include: \200 \200 \200 \200 \200 \200 \200 Loss of emotional reactivity. Diurnal mood variation. Anhedonia. Early morning wakening. Ps ychomotor agitation or retardation. Loss of appetite and weight. Loss of libido. Psychotic symptoms/features \200 Delusions: \200 poverty; \200 personal inadequacy; \200 guilt over presumed misdeeds; e.g. 07_Semple_Chap07.indd 236 12/10/2012 6:36:07 PM DIAGNOSIS 1: SYMPTOMS 237 \200 \200 Hallucinations: auditory \200 screaming; olfactory \202 esh; visual or to rture. responsibility for world events \200\224accidents, natural disasters, war; deserving of pun ishment; other nihilistic delusions. e.g. \200\224defamatory or accusatory voices, cries for help or \200\224bad smells, such as rotting food, feces, decomposing \200\224tormentors, demons, the Devil, dead bodies, scenes of death Note: These examples are mood-congruent. However, other mood-incon- gruent psychotic sympto ms are also possible (i.e. persecutory delusions, thought insertion/withdrawal, delusions o f control \200\224not of a clearly depressive nature). Catatonic symptoms or stupor). marked psychomotor retardation (depressive Table 7.1 ICD-10 and DSM-IV terminology ICD-10 DSM-IV Depressive episode Depressive disorders Mild depressive episode: major depressive disorder, single episode; major depressive disorder, recurrent without somatic symptoms; with somatic symptoms Severity speci \201 ers Moderate depressive episode: mild, moderate, severe (with/without psychotic features), partial/full remission Special sy ndrome speci \201 ers without somatic symptoms; with somatic symptoms Severe depressive episode: with catatonic, melancholic, or atypical features; with post-partum onset without psychotic symptoms; with psychotic symptoms Other depressive episode Depressive episode unspeci \201 ed Recurrent depressive episode Longitudinal course speci \201 ers with/without full inter-episode recovery; with seasonal pattern; with rapid cycling Depressive disorder, not otherwise stated premenstrual dysphoric disorder; minor depressive disorder; recurrent brief depressive diso rder; post-psychotic depressive disorder of schizophrenia; major depressive disorder; super imposed on delusional disorder; psychotic disorder NOS; active phase of schizophrenia; unce rtain etiology Dysthymic disorder 07_Semple_Chap07.indd 237 12/10/2012 6:36:07 PM CHAPTER 7 Depressive illness 238 Diagnosis 2: caseness and subtypes Clinically signi \201 cant depressive episode (minimum criteria) \200 ICD-10 speci \201 es the presence of at least 2 mood, anhedonia, or fatigue), plus at leas t 2 others from the core symptoms list. DSM-IV requires the presence of 5 or more symptoms from the core symptoms list (at least one of which must be depressed mood or anhedonia). typical symptoms (depressed Severity criteria \200 Both ICD-10 and DSM-IV distinguish episodes on the basis of symptomatology (see Table 7.2). mild, moderate, and severe Subtypes \200 Non-melancholic (DSM-IV) or without somatic symptoms (ICD-10): essentially, de \201 ned as absence of psychotic or marked somatic symptoms, this subtype captures the clinical pictur e historically described by \200\230neurotic depression \200\231 (in those with certain pr emorbid personality traits and/or high levels of anxiety) and \200\230reactive depression \200\231 (due to a severely stressful life event \200\224see b p. 384). Counter-intuitively , there is little need to subdivide on the basis of there being a clear precipitant. Life e vents appear to be provoking factors, but only in those with a predisposition to depression , and treatment should focus on the underlying disorder, as well as coming to terms with an y signi \201 cant provoking factors. Recent research1 also supports the long-held clinical impression of two different presentations: \200 Irritable/hostile depression history of \200\230acting out \200\231 behaviors in response to stress (e.g. yelling, smashing things up, recklessness, impulsiveness, deliberate self-h arm [DSH]). Poor response to antidepressants. \200\230Anxious \200\231 depression worrier \200\231), usually early onset depression, with a recurrent, persistent course, increased l ikelihood of drug/alcohol dependency, and frequent DSH/attempted suicide. Better response t o antidepressants (e.g. SSRIs). \200\224younger, anxiety expressed as irritability, \200\224shy and withdrawn, highly anxious ( \200\230always a Melancholic (DSM-IV) or with somatic symptoms (ICD-10): of \200\230somatic symptoms \200 \231 (see b p. 236) de \201 nes what is regarded as a more \200\230biological \200\231 or \200\230endogenous \200\231 depressive episode, which is more severe (and more amenable t o antidepressant treatment). DSM-IV also includes \200\230excessive or inappropriate guilt \200\231, although this may often be dif \201 cult to distinguish from delusional guilt. In clinical studies, the best distinguishing factor from \200\230non-melancholic \200\231 disorders is actually the presence of psychomotor disturbance (an objective sign manifest b y motor retardation, periodic agitation, and reduced/slowed cognitive functioning). With ps ychotic symptoms (ICD-10) or features (DSM-IV): pervasive depressed mood (no reactivity) an d marked psychomotor the presence usually there is 07_Semple_Chap07.indd 238 12/10/2012 6:36:07 PM DIAGNOSIS 2: CASENESS AND SUBTYPES 239 disturbance (sometimes to the point of depressive stupor/catatonia) accompanying delusions (commonly) and hallucinations (10 \200\22320%). Constipation is often a feature ( 30%), unr elated to medication, and may have a delusional interpretation (e.g. presence of cancer, bo wels having been sewn up). Table 7.2 Severity criteria ICD-10 DSM-IV Mild 2 typical symptoms + 2 other core symptoms 5 core symptoms + minor social/ occupational impairment Moderate 2 typical symptoms + 3+ other core symptoms 5+ core symptoms + variable degree of social/occupational impairment Severe 3 typical symptoms + 4+ other core symptoms 5+ core symptoms + signi \201 cant social/occupational impairment 1 Parker G, Hadzi-Pavlovic D, Roussos J, et al. (1998) Non-melancholic depression: the cont ribu- tion of personality, anxiety and life events to subclassi \201 cation. Psychol Med 2 8: 1209 \200\22319. 07_Semple_Chap07.indd 239 12/10/2012 6:36:07 PM CHAPTER 7 Depressive illness 240 Diagnosis 3: other clinical presentations There may be marked individual variation in the c linical presentation. Sometimes anxiety may also be prominent (mixed anxiety and depressive disorder \200\224ICD-10). Patients with a depressive disorder may not present complaining of low mood, but may consult with other primary problems. The possibility of a depressive d isorder should be borne in mind, particu- larly in the primary care setting, where many of these patients \201 rst seek treatment. Indirect presentations may include: \200 Insomnia, fatigue, or other somatic complaints (e.g. headache, GI upset, change in weight). On further questioning patients may describe irritability or anhedonia, but attribute this as secondary to what they regard as the primary problem (see b p. 428, b p. 816, b p. 806) . Elderly persons presenting with agitation, confusion, or a decline in normal functioning (pseudodementia) \200\224see b p. 524. Children presenting with symptoms such as irritabili ty, decline in school performance, or social withdrawal \200\224see b p. 656. Persons from a different cultural background presenting with culture- speci \201 c symptoms \200\224see b p. 914. Other symptoms that may hinder diagnosis \200 s symptoms (e.g. anorexia, Presence of a physical disorder whose fatigue, insomnia) may mask symptoms of depression. H istrionic behavior (making assessment of severity dif \201 cult). Exacerbation of other un derlying disorders (phobias, OCD \200\224especially when there are depressive ruminations). Hypochondriacal ideas (which may have been long-standing). The presence of self-harming be haviors (e.g. cutting, frequent overdose) which may represent underlying borderline traits (usually individuals will say they have never felt happy, or describe chronic feelings of \200\230emptiness \200\231). Cognitive impairment or LD (which may mask depressive symptoms , or appear more severe because of depression and hence improve with antidepressants). Alco hol and drug misuse (primary or secondary). \200 \200 Other subtypes of depressive disorder These are formally recognized in DSM-IV, but are subs umed under the rubric \200\230other depressive episodes \200\231 in ICD-10. They include: b p. 262) \200 b p. 474) \200 \200 \200 As a description of the experience of the s ymptoms of depression, the following has never been bettered: Atypical depression ( Postnatal depression ( Seasonal affective disorder ( Premenstrual dys phoric disorder ( b p. 263) b p. 470) 07_Semple_Chap07.indd 240 12/10/2012 6:36:07 PM DIAGNOSIS 3: OTHER CLINICAL PRESENTATIONS 241 I have of late but wherefore I know not lost all my mirth, forgone all custom of exercises; and indeed it goes so heavily with my disposition that this goodly frame, the earth, seems to me a sterile promontory, this most excellent canopy, the air, look you, this brave o \200\231erhanging \201 rma- ment, this majestical roof fretted with golden \201 re, why , it appears no other thing to me than a foul and pestilent congregation of vapors. What a piece of work is a man! how noble in reason! how in \201 nite in faculty! in form and movi ng how express and admirable! in action how like an angel! in apprehension how like a god! the beauty of the world! the paragon of animals! And yet, to me, what is this quintessence of dust? man delights not me: no, nor woman neither. Shakespeare: Hamlet, Act II Scene 2 07_Semple_Chap07.indd 241 12/10/2012 6:36:07 PM CHAPTER 7 Depressive illness 242 Epidemiology Prevalence 6-mth prevalence range: 2.2% (ECA) \200\2245.3% (NCS) \200\2246.7% (NCS-R; note 2% prevalence of severe episodes) in the general population. Lifetime rates Wide range: 4.4% (ECA) \200\22416.5% (NCS-R) \200\22430% (Virginia Twin Stud y); most authorities agree the true rate in the general popula- tion is probably 10 \200 \22320%. There is also evidence that rates are increasing among younger adults. Sex ratio 4 :5 = 1:2. Risk factors (see also b p. 244) \200 Genetic (mean 37%) and families also have high rates of anxiety disorders and neuroticism s uggesting a shared genetic basis. Childhood experiences: loss of a parent (inconsistent acr oss studies), lack of parental care, parental alcoholism/antisocial traits, childhood sexua l abuse. Note: cumulative childhood disadvantage confers a greater risk than any single var iable. High intelligence and one good adult relationship are protective and increase resili ence. Personality traits: neuroticism scores). Social circumstances: Marital status \200 \224men, low rates associated with marriage, high rates \200 with separation or divorce; women, probably similar, but less clear- cut). Brown and Harris 1 found that, for women, ha ving 3 or more children under the age of 11, lack of paid employment, and lack of a con \201 ding relationship were associated with increased risk of depression (recent studies su pport the lack of a con \201 ding relationship, but not the other factors). Adverse life e vents after event) in vulnerable individuals. (see Box 7.2): heritability estimates range from 17 to 75% anxiety, impulsivity, obsessionality (i.e. high \200\224particularly \200\230loss \200\231 events (increased risk 2 \200\2233mths Physical illness: especially if chronic, severe, or painful. Neurological disorders (e.g. P arkinson \200\231s disease, MS, stroke, epilepsy) have higher risk (perhaps due to \200 \230shared \200\231 pathology). Higher rates also noted in post-MI, diabetic, and cancer pa tients, although family or personal histories of depression are important determinants of o ccurrence. Comorbidity About two-thirds of patients will also meet criteria for another psychiatric di sorder (e.g. anxiety disorders, substance misuse, alcohol dependency, personality disorders ). 07_Semple_Chap07.indd 242 12/10/2012 6:36:07 PM EPIDEMIOLOGY 243 Box 7.2 Genetic factors While the existence of genetic vulnerability to depression is well-es- tablished in family and twin studies, progress in the identi \201 cation of its molecular basis has been slow. Functional candidate gene studies have identi \201 ed few replicable associations, and ge nome-wide linkage studies have yielded suggestive rather than conclusive results. Genome-wi de asso- ciation studies (GWAS) have detected suggestive evidence for a role of genetic var iants in the piccolo (PCLO) gene (which encodes a presynaptic cytomatrix protein that in \202 uences monoamine neurotransmitter release and regulation of the HPA axis) and neurolig in-1 (NLGN1, which has a role in formation and remodeling of CNS synapses). However, the ge n- eral \201 ndings of these studies indicate that the genetic liability to depres- sion is likely to involve multiple genetic variants of weak effects.1 Similarly, GWAS of antidepressant treatment outcome which hope ultimately to help match med ications with patients have been disap- pointing. Three independent samples \200\224The Seq uenced Treatment Alternatives to Relieve Depression sample (STAR*D) (n = 1953), the Munich Antidepressant Response Signature (MARS) sample (n = 339) and the Genome-based Therapeutic Drugs for Depression (GENDEP) sample (n = 706) \200\224fail to report any results that achi eved genome-wide signi \201 cance, suggesting that larger samples and better outcome meas- ures will be needed.2 1 Lewis CM, Ng MY, Butler AW, et al. (2010) Genome-wide association study of major recurren t depression in the U.K. population. Am J Psychiat 167: 949 \200\22357. 2 Laje G, McMahon F J (2011) Genome-wide association studies of antidepressant outcome: a brief review. Progr N euro-Psychopharmacol Biolog Psychiat 35: 1553 \200\2237. 1 Brown GW, Harris TO (1978) Social origins of depression: a study of psychiatric disorders in women. London: Tavistock Publications. 07_Semple_Chap07.indd 243 12/10/2012 6:36:07 PM CHAPTER 7 Depressive illness 244 Etiology 1 The etiology of depression has yet to be fully understood, however it is likely to be due to the interplay of biological, psychological, and social fac- tors in the lifesp an of an individual. Psychosocial stressors may play a role both as precipitants and perpet uating factors, increasing the risk of chronic- ity and recurrence; while individuals with established depression are at higher risk of further stressors of many kinds. One attempt t o integrate these factors is the biopsychosocial model (see Fig. 7.1). Early adverse experience Developmental or social effects have previously been viewed as not being biological in nature. The modern view is that the fetal environment and later enviro nmental stressors do have neurobiological consequences mediated through the HPA axis. These changes in stress regulation may contribute to the expression of psychiatric disorder. Mor e research is needed in this area as data from human studies is limited. Personality/temperament factors These are enduring traits with a biological basis, in \202 uenced over the lifespan by inherited factors, experience, and maturation. They mediate th e level and nature of response to sensory experience, regulated by context, and manifest as subjective emotions and objective behaviors. Certain temperaments (e.g. neuroticism or hig h \200\230N \200\231) may increase vulner- ability to depression, perhaps due to the prese nce of autonomic hyper- arousal (heightened responses to emotional stimuli), lability (unpr edictable responses to emotional stimuli), or negative biases in attention, processing and memory for emotional material. Psychological factors Disruption of normal social, marital, parental, or familial relations hips is correlated with high rates of depression, and is a risk factor for recurrence. An a etiological role has yet to be demonstrated, but adverse childhood experiences/chronic stre ssors may in \202 uence the sensitivity of individuals to later stressful events. Low self -esteem (negative view of self, the past, current events, and the future) is proposed as a vulnerability factor \200\224it remains debatable whether this is a causal factor or merely a symptom of depression. Gender Although the increased prevalence of depression in women is a robust \201 nding, e xplanations of why this may be so are various. These include: restricting social and occupa tional roles, being over- or under-occupied, ruminative response styles, and endocrine fact ors (suggested by increased risk of depression in the premenstrual and post-partum periods) . There is little supportive evidence for these theories. One popular hypothesis is that wo men are more likely to admit to depressive symptoms, whereas men are not and tend to expres s their symptoms differently (e.g. through alcohol abuse and antisocial behavior). 07_Semple_Chap07.indd 244 12/10/2012 6:36:08 PM etiology 1 245 Social factors In explaining why people of low socio-economic status (i.e. low levels of in come, employment, and education) are at demonstrably higher risk of depression, two main ar guments exist: social causation \200\224stress associated with such problems leads to depre ssion (i.e. an environmental argument); and social selection \200\224predisposed individual s drift down to lower social positions, or fail to rise from them (i.e. a genetic argument) . Note: There is stronger evidence for the social causation argument, as social isolation has been shown to be a key risk factor. Genetic predisposition Early adverse life experiences Biological vulnerability Personality / temperament Traumatic or adverse life events Social circumstances Alcohol/substance misuse Physical ill ness Biological alterations in brain functioning Symptoms of depressive illness Fig. 7.1 The biopsychosocial model of depression. 07_Semple_Chap07.indd 245 12/10/2012 6:36:08 PM CHAPTER 7 Depressive illness 246 Etiology 2 Brain pathology Structural brain changes Severe depression is associated with ve ntricular enlargement and sulcal prominence. Increased rate of white matter lesions in olde r patients (perhaps related to vascular disease). Refractory cases associated with reduced gray matter in left hippocampus (correlating with verbal memory), basal ganglia and thalamu s. Other studies \201 nd reduced cortical volumes in the left parietal and frontal associ ation areas. Post-mortem \201 ndings Reduced GABA function, abnormal synaptic den- sity or neuronal pl asticity in the hippocampus; glial cell abnormalities; reduced expression of SERT mRNA in d orsal raphe nucleus.1 Functional imaging (see Box 7.3) Studies report hypoperfusion in frontal, temporal, and par ietal areas (esp. older patients) and increased perfusion in frontal and cingulate cortex ( in younger patients, associated with good treatment response). Activation, lesioning, and b rain stimulation studies in humans2 all point to 2 functionally segregated areas of the pre frontal cortex as being critical neural substrates for depression: the ventromedial prefron tal cortex (vmPFC) \200\224associated with negative affect, physiological symptoms, self-aw areness/insight; and the dorsolateral prefrontal cortex (dlPFC) \200\224associated with cog nitive/executive functioning, (re)-appraisal of affect states, suppression of emotional res ponses. Neurotransmitter abnormalities The discovery that all antidepressants increase monoamine (i .e. 5-HT, NE, DA) release and/or reduce their reuptake in the synaptic cleft, led to develo pment of the monoamine theory of depression, which suggests that reduced monoamine function may cause depression. Blunted neuroendo- crine responses and symptom induction by tryptoph an depletion (5-HT precursor) suggest an important role for 5-HT. Neuroendocrine challenge tests Blunted prolactin and growth hormone (GH) responses to trypt ophan/ citalopram (5-HT system), blunted GH responses to clonidine (NE sys- tem) and apomor phine (DA system), increased GH response to phys- ostigmine (ACh system) suggest reduced mo noamine functioning and increased cholinergic functioning in depression. Increased cortisol seen in 50% of patients (particularly \200\230endogenous \200\231 subtype), associated w ith adrenal hypertrophy, and dexamethasone non-suppression of cortisol (also in other psych iatric conditions, hence not a sensitive test, despite apparent speci \201 city of 96%). Thyroid abnormalities Abnormalities in the thyrotropin (TSH) response to TRH have been foun d \200\224both blunting and enhancement \200\224despite normal thyroid hor- mone levels, su ggesting further research necessary esp. when T3 shown to have utility in treatment resista nt cases (see b p. 260). 07_Semple_Chap07.indd 246 12/10/2012 6:36:08 PM etiology 2 247 Changes in sleep pattern Early morning wakening is most typical in endogenous or melancholi c depression; initial insomnia, frequent waking, and unsatisfactory sleep are also commonly seen in depression. Causal relationship of sleep to depres- sion currently unknown. In sev ere depression there is reduced total SWS and shortened REM latency (secondary to increased cholinergic [REM-on], and/or reduced serotonergic/noradrenergic [REM-off] drive.) Sleep ch anges resolve with recovery from depression and sleep disturbance may be an early predictor of impending relapse. Box 7.3 Endophenotypes, imaging, and genetic correlates in the etiology of depression Imaging studies identify traits or \200\230endophenotypes \200\231 that are heritable, int ermediate phenotypes associated with depression. These presumably have a simpler genetic ba sis than the full syndrome (or even individual symptoms), making them more amenable to gene tic analysis, and enabling the generation of testable hypotheses. Examples include: \200 Mood-congruent phenomenon of increased activity of the amygdala in response to negative sti muli, which is likely moderated by the 5-HT transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR). Hippocampal volume loss esp. in elderly or chronically ill samples related to val66met brain-derived neurotrophic factor (BDNF) gene variant and 5-HTTLPR SLC6A4 polymorp hism. White matter pathology in elderly and more severely ill samples (allowing for complic ations of cerebrovascular disease). Increased blood \202 ow or metabolism of the subgenua l anterior cingulate cortex (sgACC) and associated gray matter loss. Attenuation of the usu al pattern of fronto-limbic connectivity, particularly a decreased temporal correlation in amygdala \200\223anterior cingulate cortex (ACC) activity. Decreased 5-HT1A binding in the raphe, medial temporal lobe, and medial prefrontal cortex (mPFC), and a functional polymorp hism in the promoter region of the 5-HT1A gene. Alterations in the binding potential of the 5-HT transporter. Hopefully, it will not be long before we begin to see further advances in these areas as ep igenetic, copy-number variant, gene \200\223gene interaction, and GWAs (see p. 243) approac hes are brought to bear on imaging data. See review: Savitz JB and Drevets WC (2009) Imagin g phenotypes of major depressive disorder: genetic correlates. Neuroscience 164: 300 \200 \22330. 1 Arango V, Underwood MD, Boldrini M, et al. (2001) Serotonin 1A receptors, serotonin trans - porter binding and serotonin transporter mRNA expression in the brainstem of depressed su icide victims. Neuropsychopharmacol 25: 892 \200\223903. Note: If replicated, this has prof ound implications for those who have taken MDMA and other methamfetamines. 2 Steele JD and Lawrie SM (2004) Segregation of cognitive and emotional function in the prefrontal cortex: a stereotactic meta-analysis. Neuroimage 21: 868 \200\22375. 07_Semple_Chap07.indd 247 12/10/2012 6:36:08 PM CHAPTER 7 Depressive illness 248 Differential diagnosis \200 