Major Depression..The Story and Treatment Prof. Yaser Abdel Razek Professor of Psychiatry Institute of Psychiatry, Ain Shams University WHO Collaborative center for training and research
Unipolar Major Depression /2010 • Number of 6,865,820,500 population• Life time prevalence 1,513,322,000 of UMD • Point prevalence 450,088,420 UMD (WHO- 2008 )• 15% will try suicide 67,513,263 • Died by suicide 426.463 (2010) www.peterrussell.com/WorldClock
• Worldwide, 450 million patient, with high comorbid, social and economic costs ( WHO 2008) • Prevalence of Unipolar depressive disorders is 17% (NCS-R Kessler et al, 2003)• Average life time prevalence from studies 19-21% ( Kaplan and Sadock, 2005)
• In the UK and in 2005 there were in excess of 29 million prescriptions for ADD.• The direct cost of treatment for depression in the National Health Service (£887 million) > both that for hypertension and diabetes combined (£439 and £300 million respectively).• In 1994 an estimated 1.5 million disability- adjusted life years were lost each year in the developed world as the result of depression.
• In the U.S., more than 21 million adults suffer from some kind of depressive disorder, according to the National Institute of Mental Health. • Most patients who have one major depressive episode are likely to have another within 5 years.• Overall, as many as 20% of patients with major depression do not respond to 2 or more adequate treatment regimens for depression.
Prevalence of depressive disorders will increase !!!!!!! • More industrialization and urbanization • Globalization • Increasing Stress ( education , competition, unemployment, delayed marriage, economic problems) • Increase life span • Genetic anticipation • Substance abuse
That’s Why Finding an effective treatment for depressionis therefore a key consideration for the health service
Some Facts and Figures about Depression • 3/10 employees will have a mental health problem in any one year, mainly depressive and anxiety disorders.• By the year 2020, major depression will be second only to chronic heart disease as an international health burden (this is measured by its cause of death, disability, incapacity to work and the medical resources it uses).
L e a d in g C a u s e s o f D A L Ys in 2020 ( D is a b ilit y A d ju s t e d f o r L if e Ye a r s ) Both sexes Males Females Disease or injury Disease or injury Disease or injury All causes All causes All causes Ischaemic heart Ischaemic heart Unipolar major1- disease disease depression Unipolar major Road traffic Ischaemic heart2- depression accidents disease Road traffic Cerebravascular Cerebravascular3- accidents disease disease Chronic Chronic Cerebravascular obstructive obstructive4- disease pulmonary pulmonary disease disease Chronic obstructive Unipolar major Road traffic5- pulmonary disease depression accidents Ustun et al (2004) Brit. J. Psychiat.
Why depression? (cont.) • 15% of depressive disorders cases attempt suicide• 50% of completed suicidal cases are major depression • Prevalence of depressive disorders is 20% in women and 12% in men • Prevalence of Unipolar Major depressive disorder is increasing – 1% for those born before 1905 – 6% for those born after 1955• Many persons with Depression are disabled and have a bad quality of life • It is an expensive disorder
Recognition of general practice patients Up to 50% of general practice patients may have some depressive symptoms. Approximately 5% of these will have major depression defined by DSM-III-R criteria.Freeling and Tylee (1992); Regier et al (1988); Vazquez-Barquero et al (1987)
M Depression Dysthymia Mixed anxiety depression Adjustment disorders with depressive symptomsDepressive symptoms
Prevalence of depressive disorders will increase due to: • More industrialization and urbanization • Globalization • Increasing Stress ( education , competition, unemployment, delayed marriage, economic problems) • Increase life span • Genetic anticipation • Substance abuse
Bed days: depression vs chronic medical condition No chronic condition Back problem Lung problem GI problem Arthiritis Angina onlyCoronary artery disease Diabetes Hypertension Depressive symptoms 0 0.5 1 1.5 2 2.5 Bed days / past month Wells et al., 1989
The Effects of Depression Beyond Symptoms Disability of Daily Functioning: Depression Compared with Chronic Medical Conditions Physical Social Role Bed Days Hypertension Diabetes Heart Arthritis LungDepression has more disability (P < 0.05)Depression has less disability (P < 0.001)No difference (P > 0.05) Wells et al. JAMA. 1989; 262 (7): 914-919
Work-Loss Days by Health Condition 3 2.77 2.5 1.78 2 1.74 1.6 1.41Days 1.5 1.21 0.83 1 0.5 0 Depression Diabetes History of Immune Heart isease Disorder Grzywacz JG. SL. TEN. 2000; 2(6): 41-46.
Public perceptions of Mental • 71% Due to emotional weakness illness • 65% Caused by bad parenting • 43% Incurable • 35% Consequence of sinful behaviour• 10% Has a biological basis; Involves the brain
Etiology of major depression • Major Depression has no environmental cause or disproportional to the cause • Neurotransmitter disturbance • Genetic factors • Neuroendocrinal disturbance • Disturbed immune function • Disturbed sleep cycle• Environmental stressors may play role but alone are not enough to cause depression
Treatable DiseaseDepression is one of the most treatable untreated diseases80% can be successfully treated with medication, psychotherapy or a combination of the two
Treatment of depression Depressed Patients (100%) Receive Untreated patients antidepressant (95.6%) (4.4%) - Do not seek help Adequately - Undiagnosed treated - Diagnosed but untreated (?%) - Treated but non compliant *Tylee A et al, Int Clin Psychopharmacol,1999,14(3):139–51;Lépine, JP etal., Int Clin Psychopharmacol, 1997,12:19–29.
cost of not treating Mood Disorders Dysfunctional families Absenteeism Decreased productivity Job-related injuries Adverse effect on quality control in the workplace• Although suicide is rare in our countries it is common in depression
Clinical features• To diagnose depression We should have two criteria out of each group of the following symptoms
First group 1-Depressed mood • Continuous unexplained bad mood with spontaneous crying from time to time 2-Loss of interest • Loss of all pleasurable activities like sports, watching TV, reading, spending, visiting friends, etc. 3-Easy fatigability• patients complained of inability to do anything with marked reduction of energy and easy fatigability on minor effort
Second Group • 1-Change of appetite • 2-Change of sleep • 3-Change of psychomotor activity • 4-Guilt • 5-Death wishes• 6-Lack of concentration, indecisiveness • 7-Loss of confidence
Other key symptoms – Irritability and anxiety in addition or instead of pure depression symptoms – Predominant somatic symptoms – Headache – General aches and pains – Libido decrease
How do patients with major depression usually present in primary care? Presenting complaint % patients 0 10 20 30 40 50 60 Cardiological Chest painTachycardia/irregular heart beat Neurological Headache Dizziness Syncope/seizures Gastrointestinal Epigastric pain Diarrhoea Pulmonary Dyspnoea ‘Asthma’* DSM-IV-TR™ 2000 Wa yn e K a to n
Types of depression• There are more than 50 type of depressivedisorder, all types share some symptoms and differ in some other symptoms
Different forms Unipolar Bipolar Major depressive Bipolar I disorder Dysthymia Bipolar II Cyclothymia Mixed statesAdjustment disorder with American Psychiatric Association (1994) depressive sym
Dysthymia • A less severe type of depression. • It involves long-term, continuous symptoms• However, people with dysthymia do not function well • Many people with dysthymia also experience major depressive episodes at some time in their lives.
Bipolar depression• Depression is alternating with episodes of hypomania or mania.
Major depression Adjustment disorder• Previous manic features (BP) • No manic F • Stress May not present • Stressor Must be present • Early morning awakening 2 • Delayed sleep onset hours • Diurnal variation (bad at • May be worst at the night morning) • Marked Change of • Not marked psychomotor activity • No delusions or• Delusions and hallucinations hallucinations • Worse just before menses • Not related to menses • Post partum attacks • No postpartum attacks • Recovery may be delayed • Recovery within 6 months
Debilitating physical illness ascancers may be presented by • Loss of weight • Easy fatigability • Disturbed sleep • Somatic symptoms
Medical disorders with Depression (organic) • AIDS • Cancer – Intracranial tumors, Pancreatic Ca., and others • Diabetes • Heavy metal toxicity – Lead, Mercury etc • Hypo and hyperthyroidism • Hyperadrenalism (Cushing’s disease) • Adrenocortical insufficiency (Addison’s disease) • Hypoparathyroidism • Pernicious anaemia • Systemic lupus erythemetosis • Viral infections; Hepatitis, Pneumonia.
The association betweendepression and medical illness M e d ic a l F r equenc y of C o n d it io n M a j o r De p r e s s io n x Coronary Artery Disease 30-60% x Emphysema 20-40% x HIV infection 20-35% x Hypothyroidism 10-30% x Stroke 10-25% x Diabetes Mellitus 10-20% x Renal Failure 5-20%Kaplan HI, 1994
Neurological disorders • Parkinson’s 50% • Post stroke 20% • Dementia 20-30% major depression• Seizure 20-50% in recurrent seizure • Huntington’s 30% • Multiple sclerosis 50%
Drugs that can cause depression • All substances of abuse • Beta blockers • Some antihypertensive drugs • Contraceptive pills
Comorbid major depression and INTRODUCTION TO ANXIETY DISORDERS anxiety disordersLifetime comorbidity48% of patients with PTSD1 50% to 65% of patients with PD2 PTSD Panic disorder Major depression GAD SAD 8% to 39% of patients with GAD5 OCD34% to 70% ofpatients with SAnD4, 6 67% of patients with OCD3 1. Kessler et al (1995); 2. APA, DSM-IV; 3. Rasmussen & Eisen (1988); 4. Van Ameringen et al (1991); 5. Brawman-Mintzer & Lydlard (1996); 6. Stein & Kean (2000)
What are symptoms of anxiety?Anxiety can be experienced in a number of different ways. • Psychological symptoms – Inner tension. – Agitation. – Fear of losing control. – Dread that something catastrophic is going to happen, such as a blackout, seizure, heart attack or death. • Physical symptoms – Racing heart beat (palpitations). – Breathing fast, feeling short of breath or finding it hard to get breath. – Chest tightness. – Dry mouth, butterflies in the stomach, feeling sick. – An urge to pass urine. – Tremors – Sweating.
Treatment of depression Hospitalization May be necessary if patient has • Suicidal• Severe psychomotor retardation or agitation • Absolute insomnia
Major depressive episodeEuthymiaSymptoms MajorSyndrome depressive episodeCriteria and Severity Adapted from Thase and Kupfer (1996)duration
treatmentEuthymia Remission RecoverySymptoms Recurrence Response MajorSyndrome depressive episode Maintenance treatment MaintenanceRecurrence Predictors Adapted from Thase and Kupfer (1996) treatment
Maintenance Treatment Maintenance treatment85% remain well 15% Recurrence No Maintenance Treatment (drug stopped after patient responded to drug) 50% remain well 50% Recurrence (more difficult to treat)
Predictors of long-term, maintenance antidepressant therapy • At least three episodes Two episodes and potential risk factor • late onset (at age 60 years or over) • early onset (before 40 years of age) • short interval between episodes • rapid onset of previous episodes • positive family history with affective disorders • co-morbidity • severity of index episode • poor symptom control in continuation phase • low work adjustment
What to say to patient? • You have depression • Depression is a chemical disorder • You are not sin or kafer. You are ill• Drugs will take time to improve your condition • Drugs are not addictive • Drugs have no marked side effects
What to say to patient? (Cont.) • First to improve is your sleep and appetite • The last to improve is your mood • Recovery is expected within 2-3 months • One drug is enough in most of cases• There are many effective drugs . if one failed we will try another • Drugs should be continued till 1 year from recovery • ECT is not a bad choice
In elderly • Take care of• Comorbid physical disorders • Drug selection • Drug interactions • Suicide
During Pregnancy • Take care of • No drugs in first trimester Psychotherapy for mild cases ECT for severe cases • Second and third trimester consent from patient most of drugs are not injurious but frequent ultrasonography for fetus
Breast Feeding • Most of drugs secreted in breast milk• Follow up the baby for any anticholinergic effects or sedation
In Children• Assessment by psychiatrist is a must • Depression may take different faces • Phobic depression • Enuretic depression • Conduct depression • Somatic symptoms • School refusal
Treatment of depression Depressed Patients (100%) Receive Untreated patients antidepressant (95.6%) (4.4%) - Do not seek help Adequately - Undiagnosed treated - Diagnosed but untreated (?%) - Treated but non compliant *Tylee A et al, Int Clin Psychopharmacol,1999,14(3):139–51;Lépine, JPet al., Int Clin Psychopharmacol, 1997,12:19–29.
Some Studies Found That• ADD Are of value in severe depression more than in mild to moderate cases. As difference from placebo effect is not significant
Half empty or half full?• Most of depressed patients treated with ADD get better• But fewer get entirely well Trivedi et al, Am J Psychiatry 2006: 163, 28-40
Definitions• Response: 50% or greater decrease in score of any depression rating scales• Remission : – Symptom free – HAM-D 17 less than 8 – Good functions
Is there a price to pay for a partial response?
Residual symptoms and quality of life• Poor function• More recurrence• More treatment discontinuation• Chronicity is related to loss of employment, loss of social relations, marital troubles, etc. Fava et al, 2007 Psychol med 37;307-317 Bocking et al 2006; J Clin Psychiatry 67;747-755
STAR*D Project• Naturalistic study• 6-year duration• $35 million• "next best" steps for patients with major depressive disorder.
If My patient is better but not well Should we Switch Augment or Combine?
Importance of remission from STAR D Relapse rate of Relapse rate of non remitted remitted Level I 59% 34% Level II 68% 47% Level III 76% 43% Level IV 83% 50%
TIME TO RELAPSE FROM STAR D non remitted remitted Level I 3.6 4.4 M Level II 3.2 4.5M Level III 3 3.9 M Level IV 3.5 2.5 M
Factors associated with greater chance for remission STAR*D• Employment• Greater income• Greater education• Caucasian• Female gender• No Comorbidity• Greater functioning• Married• private insurance• Fewer concurrent general medical and psychiatric conditions• A shorter index episode Trivedi et al, 2006 Am J psychiatry 163;28-40 Cohen et al 2006 Arch Gen Psychiatry 63;50-56
To what extent this remission is attributed to the drug?• No placebo group• Excellent patient characteristics
Problems with STAR*D• No placebo arm• No ECT group• Selection of drugs did not based on wisdom clinical experience• Did not discuss the issue of generic drugs• Little Number of cases in subgroups
46% of cases did not complete the studyLevel Non remitted Dropped cases casesI (3671) 2325II ( 1439) 1000 886III (390) 337 610IV (123) 107 214Total 1710 (46%) Non compliance and intolerable side effects
Lessons from STAR D• Only about one third of depressed patients remit (30%) with a first ADD trial.
Lessons From STAR*D• None of the late-sequence STAR*D options emerged as a miracle intervention for patients with treatment-resistant depression.• Clearly, one take-home message is that after patients with depression fail to obtain adequate benefit from two treatment trials only modest responses can be expected from each subsequent treatment trial.
Lessons from STAR*D• Even after four sequential trials, 49.5% of the patients – Did not achieve remission ( resistant depression) – Intolerable side effects – Non compliant• Clearly, we urgently need more effective treatments for depression.
Lessons from STAR*D• First and second drug are the best chance for a patient to remit so proper selection from the start is very important.
Maintenance Electroconvulsive Therapy• 2 years before ECT, 26 m during mECT, and up to 4 years after cessation of mECT.• The findings suggest that mECT – Increases remission rate – Reduces rate of hospitalization – Reduces duration of stay in each hospotaization Kellner et al, 2007 Evidence-Based Mental Health 2007;10:79 Susham et al 2008 Journal of ECT. 24(3):191-194
Factors with poor response• More score of HAMD• More Duration of current episode• Fatigue• Retarded depression• HAMD anxiety/somatization subscale• Anxiety related comorbid conditions• overall pain• Medical comorbidity• Atypical depression Howland et al, 2008 Ann Clin Psychiatry. 2008 Oct-Dec;20(4):209-18
20% reduction at day 14 may predict remission• A 20% reduction of HAMD total baseline is a sensitive predictor for remission (80%). 795 Henkel et al 2008 J Affect Disord. 2008 Nov 21
Clinical predictors• Lithium has a place in bipolar depression• TCA and SNRI for depression with painful physical symptoms• ECT or additional antipsychotic drugs are frequently necessary in very severe and delusional depressions.• MAOIs for atypical and anergic depression Thase ME 2004, CNS Spectrum 9:818-821 Joyce et al Arch Gen Psychiatry. 1989 Jan;46(1):89-99.
Can we Find Biomarkers that predict remission?• DST• Quantitative EEG and REM latency• Imaging• Genetics
Early Normalization of DST• Remitters were characterized by a more pronounced early normalization of an 842 initially dysregulated HPA-axis.• Early partial response within 2 weeks is important positive predictor for achieving remission. Hennings et al, 2008 J Psychiatr Res. 2008 Jun 30.
Sleep Microstructure• REM latency and REM density changes are common in depressed patients.• Decreased amplitude of delta and theta waves during REM ( over temporal lobes).• These changes tend to improve rapidly in patients who respond to ADD. Liscombe et al , 2002 J Psychiatry Neurosci. 2002 January; 27(1): 40–46.
SPECT before and after treatment• Baseline rCBF was lower in depressed patients than in controls in the frontal cortex and subcortical nuclei bilaterally.• A response to medication was associated with normalization of rCBF deficits, Kohn et al, 2007 Journal of Nuclear Medicine Vol. 48 No. 8 1273-1278
Meta-Analysis of MRI Studies• Several studies have found reduced hippocampal volume in patients with depression.• A meta-analysis of the 12 studies of unipolar depression. The sample comprised 351 patients and 279 healthy subjects. The weighted average showed a reduction of hippocampal volume of 8% on the left side and 10% on the right side.• The total number of depressive episodes was significantly correlated to hippocampal volume reduction.• Effective ADD are associated with increased volume of hippocampus ( neurogenesis – animal studies) Videbech et al, 2004 Am J Psychiatry 161:1957-1966, November 2004
Genetics• STAR*D reported an association between genetic variation in the HTR2A gene and GRIK4 gene, outcome of citalopram treatment. Homozygote carriers of these markers were more likely to respond to citalopram.• GenPOD Trial , this study aims to investigate the influence of a polymorphism in the 5HT transporter in altering response to SSRI medication. Paddock et al, 2007 Am J Psychiatry 164:1181-1188, Thomas et al, Trials. 2008; 9: 29. Published online 2008 May 22
Before anything be sure that non remission is not due to• Non adherence• Latent bipolarity• Latent psychosis• Latent physical illness• Substance abuse
APA PRACTICE GUIDELINES• If a patient is considered medication resistant on the basis of unsatisfactory response to an antidepressant agent for 6-8 weeks, the preferred treatment is – A trial of alternative non MAO Inhibitor drug with a different chemical profile – Co administration of lithium or thyroxin – Co administration of a second antidepressant
Factors in choosing pharmacotherapy in major depression• Efficacy• Prior response• Pharmacokinetic profile• Affordability• Mechanism of action
Switch• Better between different classes• Better from mono to dual or triple action reuptake inhibitors.
Augmentation• No FDA approval• No washout• Faster mechanism of action• May be able to target residual symptoms• As – Lithium – T3 and T4 – APD – AED – Buspirone – Pindolol – Nutrients ( omega 3, folic acid)
The best evidence with T3 and T4• Well tolerated• Better in females more than males Nierenberg et al, 2006 Am J Psych 163:1519-1530
Mechanism of actions of ADD Transporter, Receptors G protein and cAMP ++ Calcium ++ Activate Protein kinase Phosphorylation of transcription factors as CREB and BDNF Gene product hippocampus receptors Trk B ADD effect
Future Expectations• All through 46 years we still working outside the cell• Within 30 years we have only two groups of ADD• At the last 15 years we have more than 10 new groups of ADD• So it is expected within 10 years to have additional groups with different mechanisms• Drugs working inside the cell are under trials
Three primary approaches are currently being taken• 1) optimizing the pharmacologic modulation of monoaminergic neurotransmission,• 2) developing medications that target neurotransmitter systems other than the monoamines• 3) directly modulating neuronal activity via focal brain stimulation. Holtzheimer AND Nemeroff Curr Psychiatry Rep. 2008 Dec;10(6):465-73
New Drugs• Triple monoamine reuptake inhibitors,• Dopamine receptor agonists• Corticotropin -releasing factor-1 receptor antagonists• Glucocorticoid receptor antagonists• N-methyl-D-aspartate receptor antagonists• Drugs that are selective to hippocampus• Drugs that directly increases cAMP, calcium• Drugs decrease breakdown of cAMP• Drugs that act directly on BDNF• Drugs directly act on Trk B receptors• omega-3 fatty acids, and melatonin receptor agonists
Focal Brain Stimulation• Vagus nerve stimulation• Transcranial magnetic stimulation• Magnetic seizure therapy• Deep brain stimulation ( phase I and II)
Please can you switch me on doctor?• Pulse generator• Programmed by telemetry using a control software on a PC• Approved by FDA July 2005• A treatment for medication- refractory epilepsy.• Physicians can adjust the timing and amount of stimulation• The therapy assures patient adherence.• No serious adverse• Decreased doses of common ADD Patel et al, 2007 MedGenMed. 9(4): 62 Matthews et al, 2003 The British Journal of Psychiatry 183: 181-183
Mechanism of action of VNS Afferent sensory fibres nucleus of the tractus solitariusraphe nucleus & locus coereuleus cortical and limbic structures
VNS IN REFRACTORY DEPRESSION• The response and remission rates were 55% and 27% respectively at 1 year.• "Thats an incredible response for this group (These are people who havent been well for years).• The most common side effect was voice alteration or hoarseness which was generally mild and related to output current intensity. Corcoran et al 2006, Br J Psych 189: 282-283. Sackeim et al, 2001 Neuropsychopharmacology 25 713-728 Patel et al, 2007 MedGenMed. 9(4): 62 Matthews et al, 2003 Br J Psych 183: 181-183
TMS• There is strong evidence of the safety and tolerability of TMS when standard protocols are used.• The efficacy of the stimulation of the dorsolateral prefrontal cortex in depression is well documented. lopez-ibor, 2008 Curr Opin Psychiatry. 2008 Nov;21(6):640-4
Magnetic seizure therapy• A new 100 Hz magnetic seizure therapy device• Seizures are elicited with a high-frequency magnetic field• Limited cognitive side-effects.• The mean duration of magnetically induced seizures is 30 sec• Exceptionally quick recovery time (mean 7-15 min) shorter than with ECT in the same patients Kirov et al , 2008 Br J Psychiatry. 2008 Aug;193(2):152-5
Therapeutic Nihilism• 55-year-old woman• Depression began at age 9• Adequate doses and durations of 15 different antidepressants• 10 diverse medications for augmentation• Bilateral ECT• No improvement and "incapacitated" by depression• Several suicide attempts Yudofsky June 2008 Am J Psychiatry 165:671-674
SURGERY• Bilateral stereotactic ablative cingulotomy.• Symptomatic improvement during the year following cingulotomy.• Deep brain stimulation in the Cg25 region of this patient’s brain.• Significant improvement till remission .• Currently celebrating two years in remission Yudofsky June 2008 Am J Psychiatry 165:671-674
What Therapy Doesnt Teach and Medication Cant Give ?
Talking and Pill Taking• Patients receiving any variant of psychotherapy were significantly more likely to remit.• Patients receiving CBT were significantly more likely than those receiving PDT or IPT . Churchill et al, 2001 Health Technology Assessment ; Vol. 5: No. 35
Cognitive therapy, STAR D level II• The best remission rate 41.9% BUT – Very expensive – need extensive training – Suitable only for certain types of patients
Psychosocial Interventions• Drugs can not solve problems• Drugs can not teach life• Drugs can not be prescribed in psychosocial vacuum• Effective drugs must be combined with effective psychosocial intervention
Conclusion • Depression is a common illness • Prevalence of depressive disorders will increase . • Depression is the worst illness as it lead to poor quality of life and suicide • Depression is under diagnosed . • Depression is one of the most treatable untreated diseases . • It represents an unmet need to come up with antidepressant drugs of greater efficacy and improved tolerability • A lot of new drugs are in trials • If we have The best drug we will take 20 years to know it. • Psychiatrists need to be aware of every treatment option available and to overcome resistance to change.03/19/12 116