Financial Disclosures. objectives. Outline. Psychiatry for the Practicing Neurologist. Focus on mood disorders. none

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1 Psychiatry for the Practicing Neurologist Focus on mood disorders Financial Disclosures none Descartes Li, M.D. Clinical Professor University of California, San Francisco By Max Halberstadt - Public Domain, objectives Critique the criteria for normal sadness (per Horwitz+Wakefield) Define Trap of Meaning, and note its impact on treatment adherence Apply antidepressant treatment algorithm as described in STAR*D study List risk factors for conversion to bipolar disorder Outline Introduction and Epidemiology Normal sadness Trap of Meaning Stepped pharmacotherapy of depression (STAR*D) Using side effect profile to choose an Antidepressant Four Tips Diagnosis of Bipolar Disorder 1

2 Outline Introduction and Epidemiology Normal sadness Trap of Meaning Stepped pharmacotherapy of depression (STAR*D) Using side effect profile to choose an Antidepressant Four Tips Diagnosis of Bipolar Disorder Depression Prevalence 1 year = 6.6% (14 million) lifetime = 16.2% (35 million) 50% rated as severe or very severe 75% with co-morbid psychiatric dx The Epidemiology of Major Depressive Disorder: Results From the National Comorbidity Survey Replication (NCS-R). Kessler, RC et al. JAMA. 2003;289: glut-of-antidepressants/?_r=0 Is there a glut of coffee, alcohol? How about insulin, Lipitor? 2

3 Outline Increased antidepressant usage may decrease overall suicide rates Olfson M, Shaffer D, Marcus SC et al. (2003), Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 60(10): Gunnell D, Middleton N, Whitley E et al. (2003), Why are suicide rates rising in young men but falling in the elderly?--a time-series analysis of trends in England and Wales Soc Sci Med 57(4): Introduction and Epidemiology Normal sadness Trap of Meaning Stepped pharmacotherapy of depression (STAR*D) Using side effect profile to choose an Antidepressant Four Tips Diagnosis of Bipolar Disorder Case Vignette A 72yo man is depressed in the context of the death of his wife. How long would you wait before diagnosing MDD? Assume he meets DSM-5 criteria for MDE. A. Two weeks B. One month C. Two months D. Six months E. One year or more T w o w e e k s 10% 11% O n e m o n t h T w o m o n t h s 12% S i x m o n t h s 48% O n e y e a r o r m o r e 19% Mourning and Melancholia Outwardly can look the same Melancholia: No conscious object loss Loss of self-regard, but not ashamed Difficulty with nourishment, digesting Difficulty with sleeping 3

4 Normal Sadness Per Horvitz and Wakefield, 3 criteria: 1. Has an environmental trigger 2. Roughly proportionate in intensity to loss 3. Ends when loss situation ends Horwitz AV, Wakefield JC. The Loss of Sadness: How Psychiatry Transformed Normal Sorrow into Depressive Disorder. New York, NY:Oxford University Press; (p.16) Problems with normal sadness 1. What constitutes a trigger? 2. When is the response proportionate to the loss? 3. Does the presence of a recent major loss somehow make it more likely that depression will spontaneously resolve? Resilience to Spousal Loss Depression vs. Grief New York Times online Accessed October 8, resilience in the face of spousal bereavement is less common than previously thought Individuals who fulfill MDD criteria after loss of significant other have NOT been shown to recover at a greater rate than MDD alone -Only 8% showed resilience across all five indicators of life satisfaction and general health functioning Infurna FJ and Luthar SS. Resilience to Major Life Stressors Is Not as Common as Thought. Persp Psychol Sci Mar;11(2): doi: /

5 What the DSM-5 says about bereavement Depression vs. Grief Grief is still exists, but depressive episodes must be diagnosed independently of loss Grief and MDD are different and therefore they should be distinguished separately %20Fact%20Sheet.pdf Case Vignette A 72yo man is depressed in the context of the death of his wife. How long would you wait before diagnosing MDD? Assume he meets DSM-5 criteria for MDE. A. Two weeks B. One month C. Two months D. Six months E. One year or more T w o w e e k s 16% O n e m o n t h 26% T w o m o n t h s 25% S i x m o n t h s 17% O n e y e a r o r m o r e 15% Outline Introduction and Epidemiology Normal sadness Trap of Meaning Stepped pharmacotherapy of depression (STAR*D) Using side effect profile to choose an Antidepressant Four Tips Diagnosis of Bipolar Disorder 5

6 Case vignette B Case vignette 28yo man, recently married 6m ago, appears well, but quickly breaks down: He says he s made a terrible mistake for imposing himself on his wife. I m a terrible person who cheated on my wife and on my taxes. He reports two months of depressed mood, crying spells, as well as oversleeping and not being able to get out of bed. In addition, his energy has been low, he has no appetite, and he can t focus at work. Would you diagnose him with Major Depressive Disorder? Would you prescribe an antidepressant? I cheated on my wife and on my taxes. Do we accept his reasons as the causes of his depression? Even when confronted with an intuitively plausible set of reasons, we must look for objective causes. Reason vs. Cause The Trap of Meaning What the difference? Reason : (noun) ( 1 ) Motive or justification for something Give me the reason for your going. He has adequate reason for doing so. Cause : (noun) ( 1 ) That which produces an effect, thing, event, person, etc make something happen What was the cause of the fire? Smoking is one of the causes of heart disease. Finding an explanation that appears meaningful and adopting it as causal. Lyketsos CG, Chisolm MS. The trap of meaning: a public health tragedy. JAMA Jul 22;302(4): doi: /jama

7 "...humans are incredibly good at linking cause and effect sometimes too good..." Life Events have NOT been associated with MDD "in general, MD can be diagnosed independently of the psychosocial context in which it arises." Kendler KS, Gardner CO. Dependent Stressful Life Events and Prior Depressive Episodes in the Prediction of Major Depression: The Problem of Causal Inference in Psychiatric Epidemiology. Arch Gen Psychiatry. 2010;67(11): "... it means that when you see something occur in a complex adaptive system, your mind is going to create a narrative to explain what happened even though cause and effect are not comprehensible in that kind of system." Embracing Complexity, An interview with Michael Mauboussin by Tim Sullivan Harvard Business Review 2011 Kendler KS, Myers J, and Halberstadt LJ. Do reasons for major depression act as causes? Molecular Psychiatry (2011) 16, ; doi: /mp ; published online 8 March Kendler KS, Myers J, and Halberstadt LJ. Should the Diagnosis of Major Depression made Independent of or Dependent upon the Psychosocial Context? Psychol Med May ; 40(5): doi: /s Lyketsos CG, Chisolm MS. The trap of meaning: a public health tragedy. JAMA Jul 22;302(4): doi: /jama What are the Validated Risk Factors for Depression? Take Home Messages Be aware of "explaining away" mood episodes. Anticipate patient s explanatory model and adherence implications Lyketsos CG, Chisolm MS. The trap of meaning: a public health tragedy. JAMA Jul 22;302(4): doi: /jama

8 Outline Introduction and Epidemiology Normal sadness Trap of Meaning Stepped pharmacotherapy of depression (STAR*D) Using side effect profile to choose an Antidepressant Four Tips Diagnosis of Bipolar Disorder Disclosures still none STAR*D Sequenced treatment alternatives to relieve depression 2,876 outpatients started on citalopram exclusions: schizophrenia, bipolar disorder, eating disorders, OCD Not placebo-controlled, therefore unblinded Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:

9 STAR*D Sequenced treatment alternatives to relieve depression Step 1 - citalopram Obtain Consent Level 1 Step One: citalopram up to 60mg/d CIT Satisfactory Response Follow-up Reminder: Black box warning for QTc prolongation Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163: Level 2 *Defined as nonremission Unsatisfactory Response* Level 1 STAR*D Results Medication Average dose N, number of subjects Citalopram 41.8mg/d 2,876 Remit rate QIDS-SR < 5 33% 47% Response rate 50% reduction of baseline QIDS-SR STAR*D Sequenced treatment alternatives to relieve depression Step 2 Step Two: switch to venlafaxine (Effexor) XR, bupropion (Wellbutrin) SR, sertraline (Zoloft) or cognitive therapy OR augment with buspirone (Buspar), bupropion SR or cognitive therapy Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:

10 Randomize SER BUP-SR VEN-XR CT Switch Options Level 2 CIT + BUP-SR CIT + BUS Augmentation Options CIT + CT Level 2 Medication Average dose N, number of subjects Switch Buproprion-SR 283mg/d 239 Augme nt Sertraline 136mg/d 238 Venlafaxine XR 194mg/d 250 Bupropion SR 268mg/d 279 Buspirone 40.9mg/d 286 Remit rate QIDS-SR < 5 Response rate 50% reduction of baseline QIDS-SR 25.5% 26.1% 26.6% 26.7% 25.0% 28.2% 39.0% 31.8% 32.9% 26.9% Sequenced treatment alternatives to relieve depression (STAR*D) Step 3 Step Three: One of the following options: switch to mirtazapine (Remeron) or nortriptyline OR Augment with lithium or Cytomel (T3) Evaluation of Outcomes with Citalopram for Depression Using Measurement- Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:

11 Level 3 MRT NTP L-2 Tx + Li Switch Randomize L-2 Tx + THY Augmentation Level 3 Medication Average dose N, number of subjects Switch Mirtazapine 42.1mg/d 114 Augme nt Nortriptyline 96.8mg/d 121 Lithium carbonate 900mg/d 69 Triiodothyronine T3 50mcg/d 73 Remit rate QIDS-SR < 5 Response rate 50% reduction of baseline QIDS-SR 12.3% 13.4% 19.8% 16.5% 13.2% 16.2% 24.7% 23.3% Sequenced treatment alternatives to relieve depression (STAR*D) Step 4 Level 4 Step Four: Switch to tranylcypromine (Parnate) or venlafaxine (Effexor) XR + mirtazapine (Remeron) Randomize TCP VEN-XR + MRT Switch Evaluation of Outcomes with Citalopram for Depression Using Measurement- Based Care in STAR*D: Implications for Clinical Practice. Trivedi et al. Am J Psychiatry 2006; 163:

12 Level 4 Medication Average dose N, number of subjects Tranylcypromine 36.9mg/d 58 Venlafaxine+mirtazapine 210.3mg/d+35.7mg/d 51 Remit rate QIDS-SR < 5 Response rate 50% reduction of baseline QIDS-SR 13.8% 12.1% 15.7% 23.5% Level 1 Medication Average dose N, number of subjects Citalopram 41.8mg/d Level 2 Switch Buproprion-SR 283mg/d Augment 2, Sertraline 136mg/d 238 Venlafaxine XR 194mg/d 250 Bupropion SR 268mg/d 279 Buspirone 40.9mg/d Level 3 Switch Mirtazapine 42.1mg/d Level 4 Augment Nortriptyline 96.8mg/d 121 Lithium carbonate 900mg/d 69 T3 50mcg/d 73 Tranylcypromine 36.9mg/d 58 Venlafaxine+mirtazapine 210.3mg/d+35.7mg/d 51 Remit rate QIDS-SR < 5 33% 47% 25.5% 26.1% 26.6% 26.7% 25.0% 28.2% Response rate 50% reduction of baseline QIDS-SR 39.0% 321.8% 32.9% 26.9% 12.3% 13.4% 19.8% 16.5% 13.2% 16.2% 24.7% 23.3% 13.8% 12.1% 15.7% 23.5% Conclusions from STAR*D Switching to Bupropion-SR, Sertraline, or Venlafaxine XR equally efficacious (remit rate for all: about 25%); No difference between different classes of antidepressants Augmentation with Bupropion (39% remission rate) slightly better than buspirone (33%) Third and fourth level remission rates less than 20%, except T3 augmentation. Outline Introduction and Epidemiology Normal sadness Trap of Meaning Stepped pharmacotherapy of depression (STAR*D) Using side effect profile to choose an Antidepressant Four Tips Diagnosis of Bipolar Disorder 12

13 The person who takes medicine must recover twice, once from the disease and once from the medicine. All antidepressants are equally efficacious. Cipriani et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009; 373: Gartlehner et al. Comparative Benefits and Harms of Second-Generation Antidepressants. Ann Intern Med. 2008;149: Attributed to William Osler How do you choose? Food Fast Good Cheap Meds Sedation Weight gain Sexual dysfunction (Cheap) By Unknown - [1], CC BY 4.0, Choosing an Antidepressant Side Effects Sedation/activation Weight gain Sexual dysfunction (cost) Kelly, K, Posternak, M, & Alpert, J E. (2008). Toward achieving optimal response: understanding and managing antidepressant side effects. Dialogues in clinical neuroscience, 10(4), For further review, plus tips on how to manage these side effects, check out: -to-choose-an-antidepressant/ Relative activation vs. Sedation modern antidepressants* Activating Neutral or mixed Sedating Sedating Strongly sedating [psychostimulants] Bupropion Fluoxetine, Sertraline Venlafaxine Escitalopram Citalopram Paroxetine Fluvoxamine Nefazodone Tricyclics Trazadone Mirtazapine** *based on personal experience, not clinically derived head-to-head data **higher dosage may be less sedating? 13

14 Impact on weight* SEXUAL DYSFUNCTION Weight loss (?) Neutral or mixed [psychostimulants] Bupropion Nefazadone mild to moderate Ssri s (fluoxetine < paroxetine) Maoi s Tricyclics Significant mirtazapine DEPRESSION DECREASED LIBIDO AROUSAL DISORDER ANTIDEPRESSANT ORGASM DYSFUNCTION *based on personal experience, not clinically derived head-to-head data Segraves. J Clin Psychiatry Monogr Effect on sexual functioning* Increased? Neutral or mixed Common [Psychostimulants] Bupropion Nefazadone Mirtazapine Duloxetine Ssri s Venlafaxine Maoi s Tricyclics cost Use generics Split pills Check out GoodRx. com *based on personal experience, not clinically derived head-to-head data 14

15 Cost cost Summary Choosing an Antidepressant Sedation/activation Weight gain Sexual dysfunction (cost) For further review, plus tips on how to manage these side effects, check out: -to-choose-an-antidepressant/ Outline Introduction and Epidemiology Normal sadness Trap of Meaning Stepped pharmacotherapy of depression (STAR*D) Using side effect profile to choose an Antidepressant Four Tips Diagnosis of Bipolar Disorder 15

16 Tip#1 of 4 Remember Tricyclics amitriptyline (Elavil) imipramine (Tofranil) Tip#2 of 4 Thyroid augmentation T-3, (Cytomel) Dosing schedule: 12.5mcg/day x2days 25mcg/day x2days 37.5mcg/day x2days 50mcg/day x2days nortriptyline (Pamelor) desipramine (Norpramin) In STAR*D, T3 was started at 25 µg/day for 1 week and then increased to the recommended dose of 50 µg/day. Li v T3 in STAR*D Tip#3 of 4 Light Therapy STAR*D Level-3 intervention Results: Remission rates were 15.9% with lithium augmentation and 24.7% with T3 augmentation Check out the Center for Environmental Therapeutics: 16

17 Tip#4 of 4 Bibliotherapy: Feeling Good, by David Burns Mind Over Mood, by Greenberger and Padefsky Lam RW et al. Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive Disorder A Randomized Clinical Trial. JAMA Psychiatry. 2016;73(1): doi: /jamapsychiatr y Outline Introduction and Epidemiology Normal sadness Trap of Meaning Stepped pharmacotherapy of depression (STAR*D) Using side effect profile to choose an Antidepressant Four Tips Diagnosis of Bipolar Disorder Cyclothymic Disorder Bipolar I Disorder Bipolar II Disorder Major Depressive Disorder Dysthymic Disorder 17

18 National Comorbidity Study (NCS) 2007 Lifetime (and 12-month) prevalence estimates: [9282 Respondents] for BP-I 1.0% (0.6%), for BP-II, 1.1% (0.8%) Merikangas, K. R. et al. Arch Gen Psychiatry 2007;64: Bipolar Disorder Symptoms Are Chronic and Predominantly Depressive 146 Bipolar I Patients followed 12.8 yrs 9% 32% 6% Study 1 53% 46% % of Weeks 50% Asymptomatic Depressed Hypo/manic Cycling/mixed 1. Judd LL, et al. Arch Gen Psychiatry : Judd LL, et al. Arch Gen Psychiatry 2003;60: Bipolar II Patients followed 13.4 yrs 1%2% Study 2 DSM-IV Diagnostic Criteria Hypomanic Episode: A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 4 days. Video vignette from The Fly 18

19 DSM-IV Diagnostic Criteria Hypomanic Episode: B. At least three of the following symptoms are present during mood disturbance (four if mood is irritable): 1. inflated self-esteem or grandiosity 2. decreased need for sleep 3. increased talkativeness 4. flight of ideas or racing thoughts 5. distractibility 6. increase in goal-directed activity or psychomotor agitation 7. increase in risky behavior Reminder for Bipolar Disorder: DIG FAST Mnemonic D Distractibility I Insomnia G Grandiosity (or inflated self esteem) F Flight of Ideas (or racing/crowded thoughts) A Activities (increased goal directed activities) S- Speech (pressured) T- Thoughtlessness (impulsivity, ie, increased pleasurable activities with potential for negative consequences: sex, money, traveling, driving) DSM-IV Diagnostic Criteria Hypomanic Episode: (continued) C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. D. The disturbance in mood and the change in functioning are observable by others. APA Diagnostic and Statistical Manual DSM-IV Diagnostic Criteria Hypomanic Episode: (continued) E. The episode is not severe enough to cause marked impairment in social or occupational functioning, or to necessitate hospitalization, and there are no psychotic features. F. The symptoms are not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism) APA Diagnostic and Statistical Manual

20 Diagnostic Criteria Compared Hypomanic Episode: Manic Episode A. at least 4 days. at least 1 week B. See DIGFAST same C. unequivocal change Not a Mixed Episode D. observable by others. E. not severe enough to cause marked impairment F. are not due to a substance or a general medical condition D. marked impairment or hospitalizaton or psychosis E. are not due to a substance or a general medical condition Does the Trap of Meaning occur with mania or hypomania? Yes! Conversion refers to when individuals previously diagnosed with unipolar depression develop a mania or hypomania. The individual converts to bipolar disorder. Different from St Paul s Conversion! Case Vignette C A 22yo woman is admitted to the hospital for severe depression with suicidal ideation. What is the likelihood that she will have a hypomanic or manic episode in the next 15 A. 5% B. 10% C. 20% D. 40% E. 65% years? 11% 24% 40% 20% 4% 5 % 1 0 % 2 0 % 4 0 % 6 5 % 20

21 Risk of Bipolar Illness (Goldberg) Risk of Bipolar Illness (Goldberg) Goldberg JF had a small group (n=74) of subjects who were more severely ill (hospitalized) and who were younger (all were less than 25) The conversion rate in the next 15 years was pretty high: 41% Goldberg JF et al. Risk for Bipolar Illness in Patients Initially Hospitalized for Unipolar Depression. Am J Psychiatry 2001; 158: Goldberg JF et al. Risk for Bipolar Illness in Patients Initially Hospitalized for Unipolar Depression. Am J Psychiatry 2001; 158: Summary Rate of Conversion from Depression to Bipolar disorder is about 1-2% per year indefinitely study n Conversion rate: (per year) Akiskal HS; et al 1995 Coryell et al Goldberg JF et al Angst J et al % (1.1%) % (1.0%) 74 41% (2.7%) % (3.0%) Years of f/u comment 11 Mood lability predictive 10 Avg. age >35 15 Younger pts (<25yo) and hospitalized 13 Linear rate of conversion, severely ill Angst J et al. Diagnostic Conversion from depression to bipolar disorders: results of a long term prospective study of hospital admissions. J Affect Disord 2005; 84:

22 DSM-5 Episode Specifiers (that are risk factors for bipolar disorder) Atypical Catatonia Melancholic (not a risk factor) Mixed features Postpartum onset Psychotic features Summary Patients initially diagnosed with unipolar depression are at high risk for converting to bipolar disorder. Several risk factors are associated with conversion: Age of onset (ie, <25yo) Family history of bipolar disorder Number of depressive episodes (ie, > six) Post-partum onset Psychotic features Severity (eg, hospital admission) The conversion rate is about 1-2% per year, perhaps slightly higher in the first 4 years, but really no obvious plateau ing of risk (see Angst) Take home message Suspect bipolar disorder in the following situations: Unclear history How to interview for bipolar disorder, see Patient is not improving, or worsening, with standard antidepressant treatment Patient has multiple risk factors for conversion What to do about Bipolar depression? Controversial area in psychiatry Avoid antidepressants, unless clear evidence of benefit Prevent mania: start mood stabilizers: lithium or divalproex Depression and Bipolar Support Alliance ( ; 22

23 Outline Phelps, J. (2006) Why am I Still Depressed? Recognizing and Managing the Ups and Downs of Bipolar II and Soft Bipolar Disorder. McGraw-Hill Education. 92 Introduction and Epidemiology Normal sadness Trap of Meaning Stepped pharmacotherapy of depression (STAR*D) Using side effect profile to choose an Antidepressant Four Tips Diagnosis of Bipolar Disorder 23