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 Other psychiatric disorders: dysthymia, stress-related disorders (adjustment disorders/bere avement, PTSD), bipolar disorder, anxiety disorders (OCD, panic disorder, phobias), eating disorders, schizoaffective disorders, schizophrenia (negative symptoms), personality disord ers (esp. borderline personality disorder [BPD]). Neurological disorders: dementia, Parkins on \200\231s disease, Huntington \200\231s disease, MS, stroke, epilepsy, tumors, head inju ry. Endocrine disorders: hypothyroidism, perimenstrual syndromes, menopausal symptoms, prol actinoma, hyperparathyroidism, hypopituitarism. Metabolic disorders: Hematological disorder s: In \202 ammatory conditions: Infections: Sleep disorders: Medication-related: methyldop a, and calcium channel blockers); steroids; H2 blockers (e.g., ranitidine, cimetidine); sed atives; muscle relaxants; chemotherapy agents (e.g. vincristine, procarbazine, L-asparagina se, interferon, amphotericin B, vinblastine); medications that affect sex hormones (estroge n, progesterone, testosterone, gonadotrophin-releasing hormone [GnRH] antagonists); cholest erol-lowering agents; and psychiatric medication (esp. antipsychotics) Substance misuse: am fetamines, and derivatives. Addison \200\231s disease, Cushing \200\231s disease, hyper/ \200 \200 \200 \200 \200 hypoglycaemia, hypercalcaemia, porphyria. anemia. SLE. syphilis, Lyme disease, and HIV encephalopathy. esp. sleep apnoea. antihypertensives (beta-blockers, reserpine, alcohol, BDZs, opiates, marijuana, cocaine, 07_Semple_Chap07.indd 248 12/10/2012 6:36:08 PM DIAGNOSIS AND INVESTIGATIONS 249 Diagnosis and investigations Diagnosis \200 The diagnosis of depression is primarily based on a good psychiatric history and physical e xamination (see Why don \200\231t psychiatrists look at the brain? b p. 10). In addition to focused questioning on mood (see b p. 236), it is useful to administer a standardized rati ng scale such as the Hamilton Depression Rating Scale (HAM-D), the Beck Depression Inventor y (BDI) or the Zung Self-Rating Depression Scale1 as a baseline measure prior to any change to management plans. Given the signi \201 cant comorbidity with anxiety, some clinicians will also rate anxiety symptoms separately, e.g. the Hamilton Anxiety Rating Scale (HAM-A), the Beck Anxiety Inventory (BAI), or the Zung Self- Rating Anxiety Scale.2 Patients with d epression often complain of poor memory or concentration. In these cases it is also worth a dministering the MMSE (see b p. 70). If cognitive impairment is signi \201 cant, further m ore detailed neuropsychological testing may be indicated (e.g. ACE-R). b pp. 49 \200\22351; Investigations There are no speci \201 c tests for depression. Investigations focus on the exclusion of treatable causes (see Differential diagnosis b p. 248), or other secondary pr oblems (e.g. loss of appetite, alcohol misuse). \200 \200 FBC, ESR, B12/folate, U&Es, LFTs, TFTs, glucose, Ca2+. Standard tests: Focused investigations: \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 only if indicated by history and/or physical signs: urine or blood toxicology; breath or blood alcohol; arterial blood gas (ABG); thyroid antib odies; antinuclear antibody; syphilis serology; additional electrolytes \200\224e.g. phosph ate, magnesium, zinc; dexamethasone suppression test (Cushing \200\231s disease); cosyntrop in stimulation test (Addison \200\231s disease); lumbar puncture (VDRL, Lyme antibody, cell count, chemistry, protein electrophoresis); CT/MRI, EEG. 1 The Zung Self-Rating Depression Scale is copyright free and one version can be found a t: M http://healthnet.umassmed.edu/mhealth/ZungSelfRatedDepressionScale.pdf 2 The Zung Self -Rating Anxiety Scale is also copyright free and can be found at: M http:// healthnet.um assmed.edu/mhealth/ZungSelfRatedAnxietyScale.pdf 07_Semple_Chap07.indd 249 12/10/2012 6:36:08 PM CHAPTER 7 Depressive illness 250 Course and prognosis Points to note \200 Depression may occur at any age, although late onset depression may be milder, more chronic , more likely to be associated with life events, and more likely to have a subclinical prod rome. Depressive episodes vary from 4 \200\22330wks for mild \200\223moderate cases, to an average of about 6mths for severe cases (25% will last up to 1yr). Episodes of recurrent de pression tend to be shorter (4 \200\22316wks). 10 \200\22320% of patients will have a chron ic course, with persistent symptoms lasting over 2yrs. The majority of patients experiencin g a depressive episode will have further episodes later in life (risk of recurrence is 30% at 10yrs, 60% at 20yrs), but inter-individual variation makes it impossible to predict th e likely period of time before future episodes, although, as with bipolar disorder, the gre ater the number of recurrences, the shorter the time between episodes. Risk of recurrence i s greater when there are residual symptoms after remission (about a third of cases), e.g. l ow mood, anxiety, sleep disturbance, reduced libido, and physical symptoms (headache, fatig ue, GI upset). There is good evidence that modern antidepressant treatments impact signi \201 cantly upon all these quoted \201 gures, reducing the length of depressive episodes; and if treatment is given long term, the incidence of residual symptoms is less, there are fewer recurrent episodes, and chronicity may be as low as 4%. \200 Mortality \200 Suicide rates for severe depressive episodes vary, but may be up to 13% (i.e. up to 20 time s more likely than the general population), with a slightly higher rate for those who have required hospital admission (12 \200\22319%). For less severe episodes rates are much lower . The overall death rate for patients with depression is higher than the general population (SMR 1.37 \200\2232.49) with the cause of death usually due to suicide, drug and alcohol p roblems, accidents, cardiovascular disease, respiratory infections, and thyroid disorders. Prognostic factors \200 Good outcome: onset. Poor outcome: symptoms, neuroticism, low self-con \201 dence, comorbi dity (alcohol or drug problems, personality disorders, physical illness), lack of social su pports. acute onset, endogenous depression, earlier age of insidious onset, neurotic depression, elderly, residual 07_Semple_Chap07.indd 250 12/10/2012 6:36:08 PM This page intentionally left blank CHAPTER 7 Depressive illness 252 Management principles and outpatient treatment Initial assessment \200 History: \200 \200 \200 \200 key areas of enquiry include: any clear psychosocial precipitants; current social situation ; use of drugs/alcohol; past history of previous mood symptoms (including \200\230subclini cal \200\231 periods of low or elevated mood, previous DSH/suicide attempts); previous effe ctive treatments; premorbid personality; family history of mood disorder; physical illnesse s; current medication. \200 \200 \200 \200 (see b p. 249): focused enquiry about subjective mood MSE sympt oms, somatic symptoms, psychotic symptoms, symptoms of anxiety, thoughts of suicide. Object ive assessment of psychomotor retardation/agitation, evidence of DSH, cognitive functioning (MMSE). Physical examination: (see b p. 248). Baseline investigations focused on possible differential diagnoses (see b p. 249). Questions of severity and initial treatment options1 \200 When depressive symptoms are mild, of recent onset, and there is no previous history of mor e severe mood disorder, most guidelines suggest refraining from use of antidepressants. Clo se, active monitoring is advised and, depending on patient preference, the use of individua l guided self-help (based on CBT principles), computerized cognitive behavioral therapy (CC BT), or structured group physical activity programs. Antidepressants may be considered wher e there is: \200 a past history of moderate or severe depression; an initial presentation of subthreshold depressive symptoms that \200 have been present for a long period (typic ally at least 2yrs); subthreshold depressive symptoms or mild depression that persist(s) af ter other interventions. Treatment for moderate or severe depression combines antidepressant medication (see b pp. 2 56 \200\2239) and a high-intensity psychological intervention (e.g. CBT or IPT \200\224see b p. 256). Usually pharmacological treatment can be initiated on an outpatient basis (sever e cases may require admission \200\224see b p. 254). \200 Choice of antidepressant is guided by anticipated safety and tolerability, physician famili arity (which allows for better patient education in anticipation of adverse effects), prese nting symptoms, and history of prior treatments (see b p. 266). 07_Semple_Chap07.indd 252 12/10/2012 6:36:09 PM MANAGEMENT PRINCIPLES AND OUTPATIENT TREATMENT 253 Initially follow-up will usually be fairly frequent (1 \200\2234wks) to monitor treatment r esponse and assess for any unwanted side-effects. Once treatment is established (and is eff ective) the time between appointments may be increased (see b p. 255 and b pp. 256 \200\223 9 for further guidance). 1 See NICE (2009) Depression: the treatment and management of depression in adults. Clinica l Guideline CG90 (this is a partial update of NICE clinical guideline 23). M http://www.nic e.org.uk/ nicemedia/live/12329/45888/45888.pdf 07_Semple_Chap07.indd 253 12/10/2012 6:36:09 PM CHAPTER 7 Depressive illness 254 Hospital admission Sometimes acute episodes of depressive disorder are severe enough to req uire hospital admission (which may be on a compulsory basis). As for all psychiatric disord ers, issues of safety and the provision of effective treatment will govern the decisions ab out whether a patient can remain in the community. Points to note \200 Due to symptoms of low self-esteem or guilt, some patients may refuse admission to hospital because they feel unworthy or they are \200\230using up a valuable bed \200\231. Sympathe tic reassurance that this is not the case and that the clinician believes they are suf \201 ciently ill to bene \201 t from hospital admission may avoid unnecessary detention. S ome patients (or relatives) may demand admission to hospital. Although this usually is due to personality factors, it may also be due to (sometimes erroneous) ideas of what may be re asonably achieved in a hospital setting (e.g. intensive psychotherapy for one speci \201 c issue), or re \202 ect undisclosed factors that have created a social crisis. A non-confr ontational approach in eliciting the reasons behind such demands may reveal other important issues that may help the decision-making process (including those which may be dealed with by other agencies, e.g. emergency accommodation/refuge). Common reasons for hospital admission \200 \200 \200 \200 \200 \200 \200 \200 b p. 51). Serious risk of suicide (see Serious risk of harm to others (esp. children \200\224see Sign i \201 cant self-neglect (esp. weight loss). Severe depressive symptoms. Severe psychotic symptoms. Lack or breakdown of social supports. Initiation of ECT. Treatment-resistant depr ession (where inpatient monitoring may be helpful). A need to address comorbid conditions ( e.g. physical problems, other psychiatric conditions, inpatient detoxi \201 cation). b p. 663). Suitable environment? Where there is signi \201 cant risk of harm to self (or others), adm ission should be to a ward where close observation and monitoring are possible. Observation levels ought to be regularly reviewed. The ward environment is often not the quiet sanctua ry patients hope for and this may lead to dif- \201 cult decisions in balancing the risk of self-harm against the use of compul- sory admission. Careful assessment of a patient \200\231s insight into their illness, issues of comorbid substance misuse, and clear eviden ce of their ability to seek additional support when symptoms are worse, may allow for a mor e \202 exible approach in permitting time out from the ward environment (per- haps in the company of a responsible relative or friend). 07_Semple_Chap07.indd 254 12/10/2012 6:36:09 PM HOSPITAL ADMISSION 255 Aftercare following discharge Following hospital discharge, or for outpatients started on a ntidepres- sant treatment, initial follow-up should be regular (2 \200\2234 wks) to monitor progress, ensure treatment response is maintained, and to allow time for other supports (e .g. CPN services, crisis/home treatment services, day hospitals, speci \201 c psychotherap ies) to become established. 1 Risk of suicide is increased at this time as energy and motiv ation improve and the patient struggles with the consequences of being unwell. Key aims for follow-up \200 \200 \200 Establishing and maintaining a therapeutic alliance. Monitoring the patient \200\231s psych iatric status. Providing education regarding depressive disorder and the treatment options. Enhancing treatment compliance. Monitoring side-effects of medication. Identifying and add ressing any signi \201 cant comorbidity. Promoting regular patterns of activity and rest. Identifying unmet needs for speci \201 c (practical) support, counseling, (bereavement, st ress management), or psychotherapy. Promoting understanding of and adaptation to the psycho social effects of symptoms. Identifying new episodes early. Reducing the morbidity and sequ elae of depressive disorder. \200 \200 \200 \200 \200 The ultimate aim is a return to normal activities (academic, employment, home life, social activities), usually in a graded way as the resolution of symptoms allows, using a collabor ative approach. Maintenance treatment (see b pp. 255 \200\2239) will usually be monitored i n the primary care setting, with speci \201 c advice about continuation of medi- cation an d what to do should symptoms recur. 07_Semple_Chap07.indd 255 12/10/2012 6:36:09 PM CHAPTER 7 Depressive illness 256 Treating depressive illness (without psychotic features) First-line treatment \200 \200 Antidepressant drugs are effective in 65 \200\22375% of patients. For mild \200\223moderate episodes, or where antidepressants are contraindicated (e.g. recent MI), CBT or other psyc hotherapies may have a role (see b p. 252 for NICE recommendations CG90). The combination o f psychological approaches and pharmacotherapy may be synergistic, but in severe cases trea tment \200\224at least initially \200\224is almost exclusively pharmacological or physical (e.g. ECT). Choosing an antidepressant The decision about which antidepressant to choose will depend up on: \200 Patient factors: liver, neurological) \200\224see b pp. 972 \200\2237), previous response t o antidepressants. Issues of tolerability: Symptomatology: hypersomnia (more adrenergic/sti mulatory agent), mixed (e.g. with anxiety/panic \200\224SSRI/imipramine), OCD symptoms (clo mipramine/ SSRI), risk of suicide (avoid TCAs). age, sex, comorbid physical illness (cardiac, renal, \200 see b p. 266. sleep problems (more sedative agent), lack of energy/ Adequate trial Generally an adequate trial of an antidepressant is de \201 ned as at least 4wks of the highest tolerated dose (up to BNF maximum). 1 Suicide risk The risk of suicide may actually be increased in the early stages of treatment. Often patients with previous m arked antidepressant psychomotor retardation have been unable to act upon their thoughts of self-harm. Partial treatment response may \200\230free \200\231 them to do this, hence ca reful monitoring is critical (and admission to hospital may be indicated). Treatment failure \200\224second-line treatment Failure of an adequate trial of an antidepr essant may occur in 25% of cases. A similar number of patients will experience unacceptabl e side- effects, leading to the withdrawal of the agent without completing an ade- quate tr ial. For these patients, second-line treatment is with an alternative agent usually from a different class of antidepressant, or from the same class but with a different side-effect pro \201 le. Partial responders (see also b p. 260) 50% of patients who have only partial ly responded to a TCA, SSRI, or MAOI may bene \201 t from the addition of lithium (usual d ose 600 \200\223900mg/d). Treatment response is generally observed within 2wks. Alternative \200\230augmentative \200\231 strategies include the use of triiodothyronine (T3), or L-t ryptophan. 07_Semple_Chap07.indd 256 12/10/2012 6:36:09 PM TREATING DEPRESSIVE ILLNESS (WITHOUT PSYCHOTIC FEATURES) 257 ECT1 (see b p. 284) \200 ECT may be considered as a \201 rst-line therapy when there are severe biological feature s (e.g. signi \201 cant weight loss/reduced appetite) or marked psychomotor retardation. I t is sometimes used when the patient is at high risk of harming themselves or others (where there is clear evidence of repeated suicide attempts or signi \201 cantly aggressive beha vior) or where psychotic features are prominent (see b p. 258). Under these circumstances i ssues of consent to treatment must be considered (see b p. 284). It may also be considered as a second- or third-line treatment for non-responders to pharmacotherapy. Maintenance therapy First episode \200 A collaborative approach with the patient should emphasize compliance (even when feeling \200\230better \200\231) with advice to continue the effective treatment for 6mths to 1yr a fter remission (particularly if there are residual symptoms). Discontinuation should be gra dual and if there is recurrence of symptoms revert to effective dose with further attempt a t withdrawal after at least a further 4 \200\2236mths. Often patients wish to continue medi cation inde \201 nitely (particularly after a severe episode) and reassurance should be gi ven that there is no evidence of any speci \201 c long-term problems with such a course of action. Recurrent episodes \200 If period between episodes is less than 3yrs, or with severe episodes (esp. with marked sui cidal thought/actions) prophylactic treatment should be maintained for at least 5yrs (often inde \201 nitely \200\224risk of relapse if medication stopped is 70 \200\22390% within 5 yrs). Otherwise treat as for \201 rst episode. ECT \200 If ECT has been used as a \201 rst-line therapy, and remission maintained with medication , treat as for \200\230First episode \200\231. If ECT has been used successfully as second - or third-line treatment, consider maintenance ECT as an option (note: not recommended in recent NICE guidelines \200\224see b p. 292) where there is evidence that ECT effectively t reats relapse of symptoms. There is some evidence that ECT every 2wks may be an effective p rophylactic (this does not preclude further trials of pharmacotherapy). 1 Recently published NICE guidelines (see b p. 285) do not allow for some of these uses of ECT. However, NICE guidance does not override the individual responsibility of health profe ssionals to make decisions appropriate to the circumstances of a speci \201 c patient (suc h action should be discussed, documented in the notes, and, where appropriate, validated by a second opinion). 07_Semple_Chap07.indd 257 12/10/2012 6:36:09 PM CHAPTER 7 Depressive illness 258 Treating depressive illness (with psychotic features) ECT (see b p. 284) \200 For depression with psychotic features, ECT should be considered as \201 rst-line therapy , as evidence supports the superior ef \201 cacy of ECT to pharmacotherapy in this patient group, with signi \201 cant bene \201 t in 80 \200\22390% of cases (note: current NICE g uidelines do not support this practice \200\224see b p. 285). Often issues of consent or re lative contraindications may preclude the immediate use of ECT and its role is often that o f a second-line treatment after partial response or failure of pharmacotherapy. Combination treatment (antidepressant plus antipsychotic) \200 It is usual to commence tr eatment with an antipsychotic agent (as for an acute psychotic episode, see b p. 192) for a few days before commencing an antidepressant. This allows for a period of assessment (to e xclude a primary psychotic disorder), may improve compliance (when psychotic symptoms clear ly improve with medication), avoids potential worsening of psychotic symptoms with an antid epressant (in some predisposed individuals), and may help identify the 30 \200\22350% of pa tients who do respond to an antipsychotic alone. This approach is effective in 70 \200\2238 0% of patients. There is no clear evidence for any medication being more ef \201 cacious, but the available evidence supports use of an atypical (SGA).1 However, it is not unusual f or low doses of older antipsychotics (FGAs) to be used, e.g. chlorpromazine (25 \200\223100 mg at night). The most studied is olanzapine \200\223 \202 uoxetine combination, mainly du e to the fact that it is available as a single capsule (OFC \200\224Symbyax ) in the USA.2 A recent meta-analysis suggests that starting an antidepressant \201 rst and adding the antipsychotic if necessary may be a better strategy as far as cost \200\223bene \201 t to the patient.3 particular combination of Additional practice points \200 Symptoms ought to be carefully monitored, as antipsychotic side- effects may mask improveme nt in depressive symptoms \200\224hence use of lowest effective dose is advocated (e.g. aro und 2 \200\2234mg haloperidol or equivalent). Combinations of antidepressant/antipsychotic may worsen side-effects common to both (e.g. sedation, anticholinergic effects) and careful dose titration is necessary. Once acute psychotic symptoms have resolved, a lower dose of antipsychotic (or withdrawal) may be indicated, particularly when patients begin to manifes t side-effects (which were not seen in the acute stages, even with higher doses) \200\224wi th careful monitoring for recurrence of psychotic symptoms. 07_Semple_Chap07.indd 258 12/10/2012 6:36:09 PM TREATING DEPRESSIVE ILLNESS (WITH PSYCHOTIC FEATURES) 259 Dual-action agents There is some evidence that single agents with dual actions, such as amo xapine (a tetracyclic antidepressant with signi \201 cant D2 antagonism), or antipsychotic s, such as aripiprazole, clozapine, olanzapine, quetiapine, or risperidone may be effective in treating both aspects of depression with psychotic symptoms. To date, evidence does not exist to support use of these agents for long-term treatment: where there are issues of co mpli- ance/tolerability the utility of using a single agent is attractive, but should be co nsidered carefully.3 Maintenance therapy \200 When ECT has been used, maintenance usually involves the treatment of the underlying depres sive symptoms with an antidepressant (as in episodes without psychotic symptoms, see b p. 2 56). When combination treatment has been successful, maintenance often involves a clinicall y effective antidepressant with the lowest effective antipsychotic dose. As for dual-action agents, evidence is lacking with regard to long-term treatment and this tends to be pragma tic, on the basis of continued symptomatology. In view of the antidepressant and/or antipsy chotic is prudent (often inde \201 nitely, as for recurrent depressive episodes, see b p. 257). severity of the disorder, prophylactic use of an 1 Nelson JC, Papakostas GI (2009) Atypical antipsychotic augmentation in major depressive d isor- der: a meta-analysis of placebo-controlled randomized trials. Am J Psychiat 166: 980 \200\22391. 2 Recent RCT evidence actually suggests a combination approach is superior to a ntipsychotic alone for olanzapine vs. olanzapine/ \202 uoxetine: (Rothschild AJ, Williamso n DJ, Tohen MF, et al. (2004) A double-blind, randomized study of olanzapine and olanzapine / \202 uoxetine combination for major depression with psychotic features. J Clin Psychopha rmacol 24: 365 \200\22373), olanzapine/sertraline vs. olanzapine/placebo (Meyers BS, Flint AJ, Rothschild AJ, et al. (2009) A double-blind randomized controlled trial of olanzapine p lus sertraline vs. olanzapine plus placebo for psychotic depression: the study of pharmacot herapy of psychotic depression (STOP-PD). Arch Gen Psychiat 66: 838 \200\22347), and for OF C (olanzapine \200\223 \202 uoxetine) vs. olanzapine or \202 uoxetine alone (Trivedi MH, Thase ME, Osuntokun O, et al. (2009) An integrated analysis of olanzapine/ \202 uoxetine combination in clinical trials of treatment resistant depression. J Clin Psychiatry 70: 387 \200\22396). 3 Wijkstra J, Lijmer J, Balk FJ, et al. (2006) Pharmacological treatment for unipolar psychotic depres- sion: systematic review and meta-analysis. Br J Psychiat 188: 41 0 \200\22315. 07_Semple_Chap07.indd 259 12/10/2012 6:36:10 PM CHAPTER 7 Depressive illness 260 An approach to treatment-resistant depression Commonly de \201 ned as \200\230failure to respond to adequate (dose and dura- tion \200\224i.e. max BNF dose for at least 4 wks) cour ses of 2 antidepressants, or 1 antidepressant and ECT \200\231. The consequences of resista nt depression include reduced quality of life, excessive strain on relationships (which may lead to break-up of families), signi \201 cant personal economic impact, increased physic al comorbidity (e.g. malignancy, cardiovascular disease, even premature death), increased r isk of suicide, therapeutic aliena- tion (making further interventions dif \201 cult due t o dif \201 culties forming a therapeutic alliance), and high use of psychiatric services ( without clear bene \201 t). Differentiating treatment resistance It is important to distinguish actual treatment resist ance from chronicity of symptoms. Apparent treatment failure may also occur due to: incorre ct initial diagnosis (i.e. not depressive disorder in the \201 rst place), inadequate ini tial treatment, poor compliance, incomplete formulation (esp. role of maintaining factors), and issues of comorbidity (both physical and other psychiatric disorders). Risk factors for treatment resistance Concurrent physical illness, drug/alcohol abuse, pers onality disorder, high premorbid neuroticism, long period of illness prior to treatment. Management1 \200 Review diagnostic formulation: unaddressed maintaining factors (e.g. social, physical, psyc hological)? Note: a proportion of individuals with chronic, refractory depression will have unrecognized bipolar disorder. Check patient understanding/compliance: Continue monotherap y at maximum tolerable dose: BNF guidelines (esp. if there has been partial bene \201 t). Consider change in antidepressant: Consider augmentation with a mood stabilizer: Consider a dditional augmentative agents: Box 7.4). Consider combining antidepressants from different classes: caution is advised, due to possible serious adverse reactions (e.g. b p. 960). Con sider use of ECT: psychotic symptoms). Consider possibility of psychosurgery or other advan ced intervention: b pp. 296 \200\2239. is diagnosis correct? Are there any \200 serum levels may help. may mean exceeding \200 \200 try different class of antidepressant. e.g. lithium. e.g. T3, tryptophan (see see b p. 284 (esp. if severe biological features or see 1 Useful guidance and assessment tools for treatment-resistant depression including advice regard- ing criteria for \200\230adequate treatment \200\231 can be found on the Dundee Ad vanced Intervention Service website: M http://www.advancedinterventions.org.uk/library_tool s.htm 07_Semple_Chap07.indd 260 12/10/2012 6:36:10 PM AN APPROACH TO TREATMENT-RESISTANT DEPRESSION 261 Points to note \200 There is little de \201 nitive evidence to support any speci \201 c augmentative regime ( see Box 7.5). Spontaneous remission is possible: \200\230regression to the mean \200\231 s uggests that symptoms will improve; bear in mind that the natural life of depression is 6 \200\22318mths, even when untreated. Psychological and social interventions, particularly w hen psychosocial factors appear paramount, may be important (often overlooked or undisclose d) aspects of management. Box 7.4 Tryptophan (L-Tryptophan, Optimax ) \200 \200 Mode of action: Indications: resistant depression (lasting more than 2yrs). Usual dose: Com mon adverse effects: eosinophilia \200\223myalgia syndrome (rare, monitoring of FBC necessa ry). precursor for serotonin. restricted specialist use as an adjunct for treatment- \200 1g tds, increased to max 6g/day. drowsiness, headache, nausea, dizziness, Box 7.5 STAR*D trial The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial is one of the lar gest independent studies undertaken by the NIMH to examine the effectiveness of a variety o f treatments for non-psychotic major depression. The initial report was published in the Am erican Journal of Psychiatry in Nov. 2006.1 \200 A fairly representative outpatient sampl e ( steps: \200 \200 n = 3671) underwent 4 Level 1 Level 2 cognitive therapy) or combine (bupropion, buspirone, cognitive therapy); Le vel 2a switch to bupropion or venlafaxine XR; Level 3 lithium or T3); Level 4 \200\224 plus mirtazapine). \200\224citalopram; \200\224switch (to bupropion, sertraline, venlafaxine XR, or \200\224if cognitive therapy alone or plus citalopram add or \200\224switch (to nortriptyline or mirtazapine) or augment (with switch (to tranylcypromine) or combine (venlafaxine XR Remission rates were 37%, 31%, 14%, and 13% for each level, with an overall cumulative remi ssion rate of 67%. The trial highlighted patient preference for combinations/ augmentations and provided some evidence to support certain strategies: e.g. lithium or T3 augmentation; combining citalopram plus bupropion, buspirone, or venlafaxine plus mirtazapine. 1 Rush AJ, Trivedi MH, Wisniewski SR, et al. (2006) Acute and longer-term outcomes in depre ssed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiat 1 63: 1905 \200\22317. 07_Semple_Chap07.indd 261 12/10/2012 6:36:10 PM CHAPTER 7 Depressive illness 262 Atypical depressive episode Regarded as a subtype of depressive disorder, rather than a sep arate entity. Atypical features coded in DSM-IV as an \200\230episode speci \201 er \200 \231 (like melancholic, post-partum, catatonic). Listed under \200\230other depressive epi - sodes \200\231 in ICD-10. Clinical features \200 Mood is depressed, but remains reactive (able to enjoy certain experiences but not to \200 \230normal \200\231 levels). Hypersomnia (sleeping more than 10hrs/day, at least 3 days/wk, for at least 3mths). Hyperphagia (excessive eating with weight gain of over 3kg in 3mths). \200\230Leaden paralysis \200\231 (feeling of heaviness in the limbs, present for at leas t 1hr/day, 3 days/wk, for at least 3mths). Over-sensitivity to perceived rejection. Other i nfrequent symptoms may include: initial insomnia rather than early morning wakening (EMW); reversed diurnal mood variation (better in the morning); severe motor retardation; absence of feelings of guilt. \200 \200 1 Epidemiology Onset usually in late teens and early twenties, often (up to 30%) family histo ry of affective disorders. Comorbidity Higher rates of anxiety (esp. panic disorder and soc ial phobia), somatization disorder (see b p. 802), alcohol and drug misuse than in other de pressive disorders. Management \200 