Setting ambitious goals for patients with depression with a focus on functional recovery The role of the overlooked cognitive symptoms in the treatment of depression Dr Andreas Papadopoulos Locum Consultant Psychiatrist AWP NHS Trust Honorary Senior Lecturer University of Bristol apapadopoulos@nhs.net
MAJOR DEPRESSIVE DISORDER Depression is the leading cause of global disease burden among mental, neurological and substanceuse disorders 1 Burden of disease: leading causes (DALYs) 5 10. Road traffic accidents 2.6 9. Trachea, bronchus, lung 3. 8. Diabetes mellitus 3. The total annual cost of depression in Europe was estimated at 118 billion in 2004, which corresponds to a cost of 253 per inhabitant 2 7. COPD 6. Hearing loss, adult onset 5. Alcohol use disorders 4. Alzheimer and other dementias 3. Cerebrovascular disease 2. Ischaemic heart disease 3. 3.4 3.4 3.6 3.9 6.3 1. Unipolar depressive disorders 8.2 The WHO predicts that depression will be the leading cause of disease burden globally by 20303 0. 2.3 4.5 6.8 9. Total DALYs: High-income countries (%) 1. Collins et al. Nature 2011;475:27 30; 2. Sobocki et al. J Ment Health Policy Econ 2006;9:87 98; 3. WHO. Global burden of mental disorders and the need for a comprehensive, coordinated response from health and social sectors at the country level. Report by the Secretariat 2011; 5. WHO Global Burden of Disease 2004
FUNCTIONAL RECOVERY WHY IS IT IMPORTANT? The ultimate treatment goal in depression is functional recovery 1,2 Functional recovery: resolution of symptoms and return to optimum mood and function The aim of an intervention should be the complete relief of symptoms, 1,2 associated with; Improved functioning 3 Better overall quality of life 3 Lower likelihood of relapse 4 1. Borolato B et al. CNS Neurol Disord Drug Targets 2014; 13: 1804-1818; 2.Stotland NL.. Psychiatr Clin N Am 2012; 35: 37-49; 3.Greer TL, Kurian BT, Trivedi MH. CNS Drugs 2010; 24(4):267 284; 4.Tranter RT et al.. J Psychiatry Neurosci. 2002; 27(4): 241-7
DIFFERENT PATIENT GROUPS Responders GREAT!!! Non Responders + Chronic depression Persistent depressive episode Arbitrarily >2 years No assumption about the adequacy of treatment + Treatment resistant depression Failure to respond to at least 2 antidepressants from different classes 1 TRD may be stigmatising; encourage helplessness Partial or inadequate responders Patients treated with an antidepressant who have only partially responded i.e. they have residual symptoms NO FUNCTIONAL RECOVERY 1. Rizvi SJ et al (2014). Can J Psychiatry; 59(7): 349-57.
PARTIAL RESPONDER & FUNCTIONAL RECOVERY These patients are: Real and recognisable Feel hopeless and project hopelessness Often fail to recognise any improvement in mood or functionality 1.2 million patients in primary care (difficult to assess as GPs are likely to continue treating) 40-60% of patients with a primary diagnosis of depression in secondary care
DEPRESSION: FOUR CLINICAL DIMENSIONS dysphoria hopelessness suicidality anhedonia anxiety Mood change Cognitive impairment ````````````` apathy poor attention ST memory exec function ruminations slow movement restlessness agitation Motor deficits Circadian dysregulation low drive energy appetite sleep libido Helen Mayberg
British Columbia Cognitive Complaints Inventory items COGNITIVE COMPLAINTS IN DEPRESSED PATIENTS Percentage of individuals rating problems Quite a bit or Very much Memory problems Poor concentration Expressing thoughts Word finding Slow thinking Problem solving Depressed patients (n=62) Healthy individuals (n=112) 0 10 20 30 40 50 60 Individuals (%) Moderate cognitive complaints found in 27% of depressed patients (2% of control individuals) Severe cognitive complaints found in 13% of depressed patients (none in control individuals) Iverson GL, Lam RW. Ann Clin Psychiatry 2013;25:135-40
Mean proportion of time DSM-IV symptom cluster is present DEPRESSIVE SYMPTOMS PERSIST DURING PERIODS OF REMISSION AND SUBSEQUENT DEPRESSIVE EPISODES Mean proportion of time DSM-IV symptoms are present during 3-year follow-up period (n=267) 1.00 0.80 Cognitive problems Core symptoms: depressed mood/diminished interest Lack of energy Sleeping problems Worthlessness/guilt Eating problems Psychomotor problems Death ideations 0.60 0.40 0.20 0.00 Weeks of follow-up Conradi et al. Psychol Med 2011;41(6):1165 1174
NON-FUNCTIONAL RECOVERY SUBJECTIVE COGNITIVE SYMPTOMS PERSIST Patients with cognitive symptoms a Patients with cognitive symptoms Presenting cognitive symptoms during depressive episodes Presenting cognitive symptoms during depressive episodes Residual cognitive symptoms in between depressive episodes Residual cognitive symptoms in between depressive episodes 94% 44% a Diminished ability to think or concentrate, or indecisiveness. Prospective study (n=267) assessed 12 times over 3 years Conradi HJ et al. Psychol Med 2011;41:1165-74
COGNITIVE SYMPTOMS OF DEPRESSION HAVE A NEGATIVE IMPACT ON MANY ASPECTS OF THE PATIENT S LIFE 1,2 Cognitive dysfunction and general functioning are linked and both have an impact on clinical outcomes Find it difficult to maintain job performance Loss of focus Loss of productivity Experience household and financial strain Struggle with a variety of attention-related tasks Unable to fully participate in family life Exhibit social irritability Have problems meeting expectations from society Find it difficult to participate in social life 1. McIntyre RS, et al. Depress Anxiety. 2013;30(6):515-527; 2. Hammar A, Ardal G. Front Hum Neurosci. 2009;3:26.
COGNITIVE DYSFUNCTION OF DEPRESSION IMPACTS ON FUNCTIONAL RECOVERY In MDD, cognitive impairments in information processing, memory, and verbal fluency may impact upon educational, occupational, and daily functioning 1 Workplace functionality Government-commissioned research in 2010 found that people unable to work because of depression lose 8.97 billion of potential earnings per year in England 2 In the United States, the costs related to both absenteeism from work and presenteeism due to untreated depression are over $51 billion per year 3 1. Hammar A, Ardal G. Front Hum Neurosci. 2009;3:26; 2. All-Party Parliamentary Group on Wellbeing Economics: Cost of depression in England, 2010. Available at: http://wellbeingeconomics.files.wordpress.com/2012/02/costo fdepressionstats2010.pdf. Accessed September 2014; 3. Greenberg PE, et al. J Clin Psychiatry. 2003;64(12):1465-1475.
WHY DO SOME PATIENTS NOT ACHIEVE FUNCTIONAL RECOVERY WITH TREATMENT? Wrong diagnosis e.g. bipolar rather than unipolar Diagnostic comorbidities Pain, anxiety, substance misuse, personality disorder Biology of the disorder Depression is probably not a pathophysiologically homogeneous disorder Wrong (or not ideal) treatment for that patient Patient not adherent to treatment Treatment trials are inadequate Psychosocial maintaining factors
COMMON MISCONCEPTIONS
TIME TO ONSET OF ACTION Delayed onset of antidepressant action has become accepted law But does not fit with trial data Time to appreciable improvement not onset of action per se Meta-analysis (47 studies) 1 35% of eventual rating scale improvement occurred in 1 st week 1. Posternak MA, Zimmerman M. J Clin Psychiatry. 2005 Feb;66(2):148-58.
DOSE INCREASE No evidence of dose response for most antidepressants Most commonly used strategy in practice BAP recommends 1 considering dose increase especially if: minimal side effects and/or, some improvement on the antidepressant and/or, the current antidepressant has a possible dose response there is modest evidence for venlafaxine, escitalopram, TCAs. 1. Cleare A et al (2015). J Psychopharmacol. 29(5):459-525.
SWITCH: BUT TO WHAT? There is evidence of differences in efficacy between antidepressants But the effect size is very small Meta-analysis provides support for 1,2 Venlafaxine (>150mg) Escitalopram (20mg) Sertraline Amitriptyline Mirtazapine In addition >1 RCT showing benefit over another AD for 3,4,5 Agomelatine, clomipramine and vortioxetine Theoretical support for blockade of both 5-HT and NA 5 1. Anderson et al. 2000 J Affect Disord. 58(1):19-36; 2. Cipriani et al. 2009 Lancet. 373(9665):746-58; 3. Montgomery et al. 2007 Int Clin Psychopharmacol. 22(6):323-9; 4. Hale et al. 2010 Int Clin Psychopharmacol. 25(6):305-14; 5. Nelson JC, et al. Biol Psychiatry. 2004;55:296 300; Montgomery et al., (2014). Hum Psychopharmacol Clin Exp 29: 470 482.
COMBINATION/AUGMENTATION STRATEGIES 1. Rush AJ, Trivedi MH, Stewart JW, et al. (2011). Am J Psychiatry 168: 689 701. Only Li and SGAs are supported by meta-analysis of placebo controlled RCTs Other augmentation strategies have: inconsistent data e.g. antidepressant combinations, T3 augmentation or limited preliminary data e.g. pramipexole, ketamine Data for using antidepressant combinations is relatively weak CO-MED study conducted in chronically unwell patient group 1 No difference in outcome at 12 weeks or 7 months between: escitalopram bupropion combination venlafaxine mirtazapine combination escitalopram placebo
AUGMENTATION WITH ATYPICAL ANTIPSYCHOTICS Meta-analysis: 16 placebo-controlled double-blind RCTs of adjunctive atypical antipsychotics for treatmentresistant major depression (non-psychotic) Trials 4 to 12 weeks duration Largely SSRI/SNRI non or partial responders (3480 patients) Agents evaluated*: aripiprazole, olanzapine, quetiapine, risperidone Atypical antipsychotics significantly improved response & remission compared to placebo *Not all agents, including aripiprazole, are licenced for augmentation in depression 1. Nelson JC & Papakostas GI (2009). Am J Psychiatry 166: 980-991
CBT IN PARTIAL RESPONDERS CoBalT study compared 469 primary care patients with at least mild depression after 6 weeks of adequate antidepressant treatment Randomised to add-on CBT or TAU 1 Response rate (50% reduction in BDI) at 6 months: 46% intervention group vs 22% TAU (NNT 4). Remission rates were 28% vs 15% (NNT 7) Weaknesses are not blinded and no active control Suggests CBT is of additional benefit in antidepressant nonresponders Unclear how CBT compares with other next-step treatments. One blinded study suggested Li augmentation in partial responders to antidepressants was superior to CBT 2 1. Wiles et al (2013) Lancet 381: 375 384 2. Kennedy et al (2003) J Clin Psychiatry 64: 439 444
ECT VS PHARMACOTHERAPY 1. UK ECT Review Group 2003, Lancet
REALISTIC GOALS Goal functional recovery Recognising partial response Residual symptoms can be mood, cognitive or physical Advising primary care management of partial responders Reduce waiting times for medication to take effect 1ary and 2ary HCP need to work systemically and with synergy Information sharing on new treatment options available New medications/ combinations available - SCP? Joint formularies?
TREATING COGNITIVE DYSFUNCTION Assessment of cognitive deficits by GP, Psychiatrist, Nurse, OT, Psychologist Three ways to treat: (1) using remediation techniques, (2) compensatory strategies, or (3) adaptive approaches. The approaches to be used (remediation vs. compensation vs. adaptation) would be determined by the individual's relative strengths and weaknesses. Medication
NICE CG90
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