Goals of the talk PSYCHOPHARMACOLOGY FOR DEPRESSION AND MOOD DISORDERS: TIPS FOR SUCCESS. Conflict of Interest: last 12 months. Mark Hyman Rapaport MD

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1 PSYCHOPHARMACOLOGY FOR DEPRESSION AND MOOD DISORDERS: TIPS FOR SUCCESS Mark Hyman Rapaport MD Conflict of Interest: last 12 months Consultant/Advisor: Braincells Inc, AffectisPharma, Cypress, Johnson and Johnson, Funding: NCCAM, NIMH Goals of the talk To present a conceptual framework for Psychopharmacologic management To remind clinicians of practices that will: Facilitate greater diagnostic precision Enhance patient engagement Guide rapid assessment of progress

2 Depression: Breadth and Depth of Problem Lifetime prevalence Gender differences Age distribution 1 in % of men 10-20% of women 7-14% of children 15-20% of people age 55 Prevalence in primary care setting Remission Recurrence Every day, 20-30% of patients visiting primary care physicians have clinical significant symptoms of depression With appropriate therapy, 60-70% improve 50% experience 1 episode Depression can be a lifelong, recurrent illness Depression Rates Associated with Physical Illness Physical Illness Rate of Major Depression (%) Cancer Cerebrovascular accident Chronic pain Myocardial infarction Multiple sclerosis 50 Parkinson s disease 40 Adapted from Ballenger JC, et al, J Clin Psychiatry 1999;60(Suppl. 7):54

3 World Health Organization Findings Depression is the world s fourth greatest health problem Depression will be the second greatest problem by 2020 Depression is already the world s greatest source of disability among adults Murray, Lopez, 1996 Disability With Non-Major Depression By Number of Symptoms % Maier, Gansicke, Weifenbach, J Affect Disord 1997;45:41-51 The Prognosis and course of depression is heterogeneous (epidemiology) Fifty percent of subjects have a single episode of MDD with no subsequent episodes over 20 years of follow-up Fifteen percent of subjects have an unremitting course without any true periods of remission after an index episode Thirty-five percent of subjects have a recurrent disorder with a variable course Eaton et al Arch Gen Psychiatry 2008

4 Recurrence After Recovery from Index Episode of Major Depression Cumulative probability of recurrence (%) Time to recurrence (y) N=555; Kaplan-Meier Life-Table Estimate Judd et al, Arch Gen Psychiatry 1998;55: Patients Expected to Experience Recurrence of Depression within 5 Years from recovery of Previous Episode ~50% ~70% >90% % of Patients Keller MB & Boland RJ, Biol Psychiatry 1998;44: Chronicity May Be Stronger Predictor of Relapse Than Response Pattern MDD patients with acute response to 12-week course of fluoxetine (N=292) either continued treatment or were switched to placebo; followed prospectively for 1 year Greater chronicity of illness was strongly associated with relapse in both groups Cumulative Proportion Without Relapse Nonchronic (n=99) Chronic (n=163) Time Since Randomization (weeks) Other predictors included symptom severity, neurovegetative symptoms, female gender Contrary to previous retrospective findings, acute response pattern did not predict relapse MDD = major depressive disorder. McGrath PJ, et al. Am J Psychiatry. 2006;163:

5 Sustained Response/Remission Rates at 12 Months for Nonpsychotic MDD in TMAP (ALGO Patients) LOCF (n=118) IDS-C 30 Sustained Response IDS-C 30 Sustained Remission Note: Not all patients in this study were treatment resistant, as TMAP permitted entry at any stage of resistance. LOCF=last observation carried forward. Rush AJ, et al. Biol Psychiatry. 2004;56: Failure to Achieve Initial Remission Produces Worse Long-Term Outcomes Survival Distribution Function Asymptomatic recovery (n=155) Residual SSD recovery (n=82) Median Weeks Well (95% Confidence Interval) ( ) (49 88) 0 Weeks to First Relapse Into Major Depressive Episode (MDE) SSD=subsyndromal depression; subthreshold depressive symptoms. Reprinted from Judd LL, et al. J Affect Disord. 1998;50:97-108, with permission from Elsevier Month Outcomes in TRD Patient Population Response Remission 40 % of Patients % 13% 4% 7% 0 IDS-SR (n = 112) HRSD 24 (n = 104) IDS-SR (n = 112) HRSD 24 (n = 104) TAU Study TAU Study HRSD 24 =24-item Hamilton Rating Scale for Depression. George MS, et al. Biol Psychiatry. 2005;58: Evaluable Observed 15

6 TRD Morbidity TRD is associated with Increased economic burden Greater healthcare utilization and costs 1-3 Patients with depression made more than 3 the number of doctor visits than those without depression 2 Hospitalized TRD group had 7 the annual health care costs of the outpatient group and 19 the costs of the comparison group 3 1. Russell JM, et al. J Clin Psychiatry. 2004;65: Lépine J-P, et al, on behalf of the DEPRES Steering Committee. Int Clin Psychopharmacol. 1997;12: Crown WH, et al. J Clin Psychiatry. 2002;63: Treatment of TRD Patients is Costly $50,000 $42,344 Year 2000 $US Annualized Year 2000 Dollars/Person $40,000 $30,000 $20,000 $10,000 $6,512 $10,241 0 Mean* Control Group (n=7,335) Outpatient Group (n=2,887) Hospitalized Group (n=483) *All pairwise tests P < Crown WH, et al. J Clin Psychiatry. 2002;63: Healthcare Utilization Increases With Greater Degrees of Treatment Resistance Healthcare Costs per Month ($) 1,400 1,200 1, Inpatient Outpatient Pharmaceutical Total Number of Depression Medication Regimen Changes Russell JM, et al. J Clin Psychiatry. 2004;65:

7 STAR*D Study Design Level 1 CIT Unsatisfactory Level 2 SER BUP VEN CT Switch Strategy CIT CIT CIT BUP BUS CT Augment Strategy Level 2 A Switch Strategy Unsatisfactory BUP VEN Level 3 Level 4 MRT NTP Switch Strategy Switch Strategy SER + Li or THY Unsatisfactory VEN + TCP MRT BUP + Li or THY VEN + Li or THY Augment Strategy CIT + Li or THY CIT=citalopram. SER=sertraline. BUP=bupropion. VEN=venlafaxine. CT=cognitive therapy. BUS=buspirone. MRT=mirtazapine. NTP=nortriptyline. Li=lithium. THY=thyroid hormone. TCP=tranylcypromine. Rush AJ, et al. Control Clin Trials. 2004;25: STAR*D Results Demonstrate Diminishing Effectiveness of TRD Treatments % of Patients Remitting % (n=790) 30.1% (n=86) 29.7% (n=83) 24.8% (n=62) 21.3% (n=51) 17.6% (n=42) 24.7% (n=18) 15.9% (n=11) *Remission rates are after 12 weeks of treatment and are based on the HRSD % (n=24) 12.3% (n=14) 13.7% (n=7) 6.9% (n=4) 5 0 Citalopram Buspirone Bupropion Venlafaxine Bupropion Sertraline (n=2,876) (n=286) (n=279) (n=250) (n=239) (n=238) T 3 (n=73) Lithium Nortriptyline Mirtazapine Venlafaxine Tranylcypromine (n=69) (n=121) (n=114) + Mirtazapine (n=51) (n=58) Level 1 Level 2 (Augment) (n=2,876) 1 (n=565) 2 Level 2 (Switch) (n=727) 3 Level 3 (Augment) (n=142) 4 Level 3 (Switch) (n=235) 5 Level 4 (Switch) (n=109) 6 1 Trivedi MH, et al. Am J Psychiatry 2006;163:28. 2 Trivedi MH, et al. N Engl J Med 2006;354: Rush AJ, et al N Engl J Med 2006;354: Nierenberg AA, et al. Am J Psychiatry 2006;163: Fava M, et al. Am J Psychiatry 2006;163: McGrath PJ, et al. Am J Psychiatry 2006;163: Remission Rate Decreases With Each Treatment Level The overall cumulative remission rate (QIDS-SR 16 ) after 4 treatment steps was 67%* *This estimate assumes no dropouts, and assumes that those who exited the study would have had the same remission rates as those who stayed in the protocol. Rush AJ, et al. Am J Psychiatry. 2006;163:

8 Treatment Intolerance Increases With Each Treatment Level Percentage of Patients Intolerant to Treatment *Participants were considered to have intolerable side effects if they left the treatment level prior to 4 weeks for any reason or left thereafter citing treatment intolerance as the reason. Rush AJ, et al. Am J Psychiatry. 2006;163: Relapse Rate Increases With Each Treatment Level *Relapse rate calculated from those who made at least 1 postbaseline call to the interactive voice response system. Treatment step pairwise comparisons showed only Step 1 to be significantly different from the rest (p<0.0001). Rush AJ, et al. Am J Psychiatry. 2006;163: Depression is Common Heterogenoius Recurrent Complicated to treat

9 Older Conceptualization of MDD Discrete Illness Predominantly Single Episodes Full Recovery The Fluidity of the Spectrum After an index episode of MDD: 75% of patients will have a recurrence within 10 years Patients spend 58% of their lives suffering from Min D, depressive symptoms or MDD Patients shift back and forth from MDD through the spectrum to euthymia Judd et al, Arch Gen Psychiatry 1998;55: One size does not fit all when considering long term treatment of complex heterogeneous syndromes

10 Know the facts Ask the right questions Think about the causes Measure your outcomes Healing takes time Remember old friends Potential Causes of Treatment Failure Misdiagnosis Inadequate treatment, undertreatment, or starting treatment too late 1 Failure to achieve initial remission 2 Nonadherence Failure to address concurrent disorders 1 Occult substance abuse Occult general medical conditions (GMCs) Concurrent Axis I or II disorders 1. Thase ME, Rush JA. J Clin Psychiatry. 1997;58(suppl 13): Judd LL, et al. J Affect Disord. 1998;50:

11 Factors Increasing Risk of Recurrence Frequent and/or multiple episodes Familial mood disorders Pre-existing dysthymia Long duration or severe index episode Onset after age 60 Seasonal pattern Concurrent anxiety or substance abuse disorder Treatment-specific factors Inadequate treatment Poor medication adherence Keller MB, et al, J Clin Psychiatry 1999;60(suppl 17):41-45 Don t ask, don t tell If you do not perform a complete psychiatric history you will miss comorbidities: PTSD, substance abuse, bipolar disorder If you do not take a trauma history you will miss childhood and adult traumas that will complicate treatment response If you do not take a complete medical history you will miss complicating medical disorders cancer, head trauma, vitamin deficiencies

12 Don t ask, don t tell If you do not take a complete family history you will miss bipolar and substance use disorders, anxiety disorders and familiar medical conditions If you do not ask about life stressors you will miss confounds to treatment interventions If you do not ask a complete treatment history, you will be flying blind. Don t ask, don t tell Always ask your patients if there is something they think that you should know but have not covered. If you do not ask about what the patient and family s treatment expectations are.you may not know what to treat. Pearls to remember: PTSD and early life trauma complicate treatment of MDD and require intervention for the MDD to resolve Early onset MDD is frequently a precursor of bipolar disorder A pattern of antidepressant intolerance, particularly when it is associated with anxiety is often suggestive of bipolar disorder

13 The Depressive Disorders The pathogenesis of depressive disorders is complex and not fully understood: genetic factors epigenetic factors hormonal abnormalities disturbances in specific neurotransmitter systems and neural specific circuits early life trauma (eg, childhood physical or sexual abuse) recent life stressors Norepinephrine Energy Interest Motivation Anxiety Irritability Mood, Emotion Cognitive function Serotonin Impulsivity Sex Appetite Aggression Drive Dopamine

14 Dysregulation of nonmonoamine systems and depressive disorders Disturbances in: Corticotropin-releasing factor [CRF], and glucocorticoid receptors Glutamate Substance P and tachykinins Neurotrophins Pro-inflammatory cytokines Glutamatergic Modulation Glutamate implicated in neurobiology of depression 1 Glutamate receptors include ionotropic (NMDA, AMPA, kainate receptors) and metabotropic (g-protein coupled) subtypes Animal studies demonstrate that NMDA- R antagonists ( ketamine, MK 80) and Ro (an NR2B selective antagonist) increases glutamate and AMPA receptor throughput 1 Zarate et al., Ann N Y Acad Sci, 2003; 2 Kos et al., J Pharmacol Exp Ther, 2006; 3 Zarate et al., Arch Gen Psychiatry, 2006; Maeng et al., Biol Psychiatry 2008 Much more preclinical and clinical work is needed investigating glutamatergic systems

15 Inflammation and Depression Immune-Edocrine-Monoamine Pathways "We used to think our fate was in our stars. Now we know, in large measure, our fate is in our genes."j. D. Watson Studies of identical twins have revealed that some conditions, such as psoriasis, have a strong genetic component and are less influenced by environmental and lifestyle factors identical twins are more likely to share these diseases. But other conditions, such as multiple sclerosis, are only weakly influenced by genetic makeup and therefore twins may show differences depending on their exposure to various environmental factors. Chakravarti & Little (2003) Nature 421: There is more than one way to skin a cat

16 Why should we measure our outcomes? It helps us know if our treatment is working It helps our patients know if our treatment is helping them Most of of our colleagues measure their outcomes The regulatory agencies will be requiring it The payers will be requiring it How can we assess outcomes Clinician-rated symptom measures: Hamilton Depression Scale, the IDS-C, the QIDS-C Patient report symptom measures: BDI, QIDS-SR, PHQ-9 Quality of Life Measures: QLES-Q, MOS Functioning: SDS, WSAS The Most Troubling Symptom Scales (MTS) Identify with the patient the symptoms or situations that are bothering that person the most ( up to 3). Quantify the degree of distress on a 10 likert scale Ask the patient to rate the symptoms daily and bring in the record Ask the patient to rate the intensity of the symptoms at the next visit, even if he/she does not bring in the record

17 Advantages to the MTS The patient understands that you know his/her treatment priorities The patient is more engaged in his/her therapy It helps to minimize the confusion that is sometimes caused by intercurrent life events One can rapidly assess treatment response Chronic syndromes like depression take a long time to heal from. Frequently patients and physicians get too impatient they declare both treatment successes and failures too rapidly

18 At first you do not succeed, try try again.. Be sure to Reassess your diagnosis Be sure you have enough data Remember that psychotherapy is powerful And that futility is doing the same experiment over and over again and expecting a different result We have many old friends MAOIs TCAs Lithium Benzodiazepines

19 In summary: Tips for success Take a full history: medical, psychiatric, and developmental Listen to your patients and their families, they will tell us a lot Patient engagement is critical for therapeutic success Measure your outcomes and use the data to inform your treatment decisions