psychiatry for the practicing neurologist - ucsf cme

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Psychiatry for the Practicing Neurologist

Descartes Li, M.D.Clinical ProfessorUniversity of California, San Francisco

[email protected]

By Max Halberstadt - http://politiken.dk/kultur/boger/faglitteratur_boger/ECE1851485/psykoanalysen-har-stadig-noget-at-sige-i-noejagtigt-betitlet-bog/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=5234443

Focus on mood disorders

Financial Disclosuresnone

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

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Depression Prevalence

1 year = 6.6% (14 million)lifetime = 16.2% (35 million)

50% rated as severe or very severe75% 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;289:3095-3105.

How about insulin, Lipitor?

Is there a glut of coffee, alcohol?

http://well.blogs.nytimes.com/2013/08/12/a-glut-of-antidepressants/?_r=0

http://psychcentral.com/blog/archives/2013/08/19/is-a-glut-of-antidepressants-really-so-bad/

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Increased antidepressant usage may decrease overall

suicide ratesOlfson M, Shaffer D, Marcus SC et al. (2003), Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 60(10):978-982.

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 1950-1998. Soc Sci Med 57(4):595-611




Case Vignette A72yo 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 monthC. Two monthsD. Six monthsE. One year or more T w

o we e k

sO n e

m on t h

T wo m

o n th s

S i x m o

n t hs

O n e y e

a r or m

o r e

10% 11%

19%

48%

12%

Mourning and MelancholiaOutwardly can look the sameMelancholia: • No conscious object loss

• Loss of self-regard, but not ashamed

• Difficulty with nourishment, digesting

• Difficulty with sleeping

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“Normal Sadness”Per Horvitz and Wakefield, 3 criteria:1. Has an environmental trigger2. Roughly proportionate in intensity to

loss3. Ends when loss situation endsHorwitz AV, Wakefield JC. The Loss of Sadness: How Psychiatry Transformed Normal Sorrow into Depressive Disorder. New York, NY:Oxford University Press; 2007. (p.16)

Problems with “normal sadness”

1. What constitutes a trigger?

2. When is the response proportionateto 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

New York Times onlineAccessed October 8, 2016http://nyti.ms/2cPiePQ

“…resilience in the face of spousal bereavement is less common than previously thought”

-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. 2016 Mar;11(2):175-94. doi: 10.1177/1745691615621271.

Depression vs. Grief

Individuals who fulfill MDD criteria after loss of significant other have NOT been shown to recover at a greater rate than MDD alone

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What the DSM-5 says about bereavement

Grief is still exists, but depressive episodes must be diagnosed independently of lossGrief and MDD are different and therefore they should be distinguished separatelyhttp://www.dsm5.org/Documents/Bereavement%20Exclusion%20Fact%20Sheet.pdf

Depression vs. Grief

Case Vignette A72yo 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 monthC. Two monthsD. Six monthsE. One year or more T w

o we e k

sO n e

m on t h

T wo m

o n th s

S i x m o

n t hs

O n e y e

a r or m

o r e16%

26%

15%17%

25%




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Case vignette B

http://commons.wikimedia.org/wiki/File:Portrait-as-an-artist-as-a-young-man.jpg

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?

Case vignette

http://commons.wikimedia.org/wiki/File:Portrait-as-an-artist-as-a-young-man.jpg

“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. CauseWhat 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.

The Trap of Meaning

“Finding an explanation that appears meaningful and adopting it as causal.”

Lyketsos CG, Chisolm MS. The trap of meaning: a public health tragedy. JAMA. 2009 Jul 22;302(4):432-3. doi: 10.1001/jama.2009.1059.

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"...humans are incredibly good at linking cause and effect—sometimes too good..."

"... 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 SullivanHarvard Business Review 2011

https://hbr.org/2011/09/embracing-complexity/

Life Events have NOT been associated with MDD

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):1120-1127.

Kendler KS, Myers J, and Halberstadt LJ. Do reasons for major depression act as causes? Molecular Psychiatry (2011) 16, 626–633; doi:10.1038/mp.2011.22; published online 8 March 2011.

Kendler KS, Myers J, and Halberstadt LJ. Should the Diagnosis of Major Depression made Independent of or Dependent upon the Psychosocial Context? Psychol Med. 2010 May ; 40(5): 771–780. doi:10.1017/S0033291709990845.

Lyketsos CG, Chisolm MS. The trap of meaning: a public health tragedy. JAMA. 2009 Jul 22;302(4):432-3. doi: 10.1001/jama.2009.1059.

"in general, MD can be diagnosed

independently of the psychosocial context in which it arises."

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. 2009 Jul

22;302(4):432-3. doi: 10.1001/jama.2009.1059.http://jama.jamanetwork.com/article.aspx?articleid=184281

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Disclosuresstill none

STAR*DSequenced 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; 163:28-40.

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depressionStep 1 - citalopram

Step One: citalopram up to 60mg/d

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; 163:28-40. *Defined as nonremission

Obtain Consent

Level 2

Follow-upSatisfactory Response

Unsatisfactory Response*

CIT

Level 1

STAR*D Results

MedicationAverage doseN, number of subjects

Remit rateQIDS-SR < 5

Response rate50% reduction of baseline QIDS-SR

Level 1

Citalopram41.8mg/d2,876

33% 47%


depressionStep 2

Step Two: switch to venlafaxine (Effexor) XR, bupropion (Wellbutrin) SR, sertraline (Zoloft) or cognitive therapy

ORaugment 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; 163:28-40.

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Randomize

SER BUP-SR VEN-XR CT CIT +BUP-SR

CIT +BUS

CIT +CT

Level 2

AugmentationOptions

SwitchOptions




Level 2

Switch Buproprion-SR283mg/d 239

25.5% 26.1%

Sertraline136mg/d238

26.6% 26.7%

Venlafaxine XR194mg/d250

25.0% 28.2%

Augment

Bupropion SR268mg/d279

39.0% 31.8%

Buspirone40.9mg/d286

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 ORAugment 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; 163:28-40.

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Level 3

MRT NTP L-2 Tx +Li

L-2 Tx +THY

Switch Augmentation

Randomize




Level 3

Switch Mirtazapine42.1mg/d114

12.3% 13.4%

Nortriptyline96.8mg/d121

19.8% 16.5%

Augment

Lithium carbonate900mg/d69

13.2% 16.2%

Triiodothyronine T350mcg/d73

24.7% 23.3%

Sequenced treatment alternatives to relieve depression (STAR*D)

Step 4

Step Four: Switch to tranylcypromine (Parnate)or venlafaxine (Effexor) XR + mirtazapine (Remeron)

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; 163:28-40.

Level 4

TCP VEN-XR + MRT

Randomize

Switch

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Level 4 Tranylcypromine36.9mg/d58

13.8% 12.1%

Venlafaxine+mirtazapine210.3mg/d+35.7mg/d51

15.7% 23.5%

Medication Average doseN, number of subjects



Level 1 Citalopram 41.8mg/d2,876

33% 47%

Level 2 Switch Buproprion-SR 283mg/d 239

25.5% 26.1%Sertraline 136mg/d238

26.6% 26.7%Venlafaxine XR 194mg/d250

25.0% 28.2%Augment Bupropion SR 268mg/d

27939.0% 321.8%

Buspirone 40.9mg/d286

32.9% 26.9%

Level 3 Switch Mirtazapine 42.1mg/d114

12.3% 13.4%

Nortriptyline 96.8mg/d121

19.8% 16.5%Augment Lithium carbonate 900mg/d

6913.2% 16.2%

T3 50mcg/d73

24.7% 23.3%

Level 4 Tranylcypromine 36.9mg/d58

13.8% 12.1%Venlafaxine+mirtazapine210.3mg/d+35.7mg/d51

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.




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“The person who takes medicine must recover twice, once from the disease and once from the medicine.”

Attributed to William Osler

By Unknown - [1], CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=33071914

All antidepressants are equally efficacious.

How do you choose?• Food

– Fast– Good – Cheap

• Meds– Sedation– Weight gain– Sexual dysfunction– (Cheap)

Cipriani et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet 2009; 373: 746–58.

Gartlehner et al. Comparative Benefits and Harms of Second-Generation Antidepressants. Ann Intern Med. 2008;149:734-750.

Choosing an AntidepressantSide Effects

• Sedation/activation• Weight gain• Sexual dysfunction• (cost)

https://prezi.com/wbdwrr1txias/how-to-choose-an-antidepressant/

For further review, plus tips on how to manage these side effects, check out:

Kelly, K, Posternak, M, & Alpert, J E. (2008). Toward achieving optimal response: understanding and managing antidepressant side effects. Dialogues in clinical neuroscience, 10(4), 409-18.

Relative activation vs. Sedation modern antidepressants*

*based on personal experience, not clinically derived head-to-head data**higher dosage may be less sedating?

Activating [psychostimulants]BupropionFluoxetine, Sertraline

Neutral or mixedSedating

VenlafaxineEscitalopramCitalopram

Sedating ParoxetineFluvoxamineNefazodoneTricyclics

Strongly sedating TrazadoneMirtazapine**

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Impact on weight*Weight loss (?) [psychostimulants]

BupropionNeutral or mixed Nefazadone

mild to moderate Ssri’s (fluoxetine < paroxetine)Maoi’sTricyclics

Significantmirtazapine

*based on personal experience, not clinically derived head-to-head data

SEXUAL DYSFUNCTION

DEPRESSION ANTIDEPRESSANTDECREASED

LIBIDO

AROUSALDISORDER

ORGASMDYSFUNCTION

Segraves. J Clin Psychiatry Monogr. 1993.

Effect on sexual functioning*Increased? [Psychostimulants]

BupropionNeutral or mixed Nefazadone

MirtazapineDuloxetine

Common Ssri’sVenlafaxineMaoi’sTricyclics

*based on personal experience, not clinically derived head-to-head data

cost• Use generics• Split pills• Check out GoodRx. com

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Cost cost

SummaryChoosing an Antidepressant

• Sedation/activation• Weight gain• Sexual dysfunction• (cost)

https://prezi.com/wbdwrr1txias/how-to-choose-an-antidepressant/

For further review, plus tips on how to manage these side effects, check out:




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Tip#1 of 4Remember Tricyclics

desipramine(Norpramin)

imipramine (Tofranil)

amitriptyline (Elavil)

nortriptyline (Pamelor)

Tip#2 of 4Thyroid augmentation

T-3, (Cytomel) Dosing schedule:12.5mcg/day x2days25mcg/day x2days37.5mcg/day x2days50mcg/day x2days

In STAR*D, T3 was started at 25 µg/dayfor 1 week and then increased to the recommended dose of 50 µg/day.

Li v T3 in STAR*DSTAR*D Level-3 intervention

Results: Remission rates were15.9% with lithium augmentation and24.7% with T3 augmentation

Tip#3 of 4Light Therapy

Check out the Center for Environmental Therapeutics: www.cet.org

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Lam RW et al. Efficacy of Bright Light Treatment, Fluoxetine, and the Combination in Patients With Nonseasonal Major Depressive DisorderA Randomized Clinical Trial. JAMA Psychiatry. 2016;73(1):56-63. doi:10.1001/jamapsychiatry.2015.2235 68

Tip#4 of 4Bibliotherapy:•Feeling Good, by David Burns•Mind Over Mood, by Greenberger and Padefsky




Dysthymic Disorder

Major Depressive Disorder

Cyclothymic Disorder

Bipolar I Disorder

Bipolar II Disorder

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National Comorbidity Study (NCS)

2007Lifetime (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;64:543-552.71

Bipolar Disorder Symptoms Are Chronic and Predominantly

Depressive

Study 1

AsymptomaticDepressedHypo/manicCycling/mixed

% of Weeks

146 Bipolar I Patientsfollowed 12.8 yrs

86 Bipolar II Patientsfollowed 13.4 yrs

Study 2

6%9%

32% 53% 46%50%

2%1%

1. Judd LL, et al. Arch Gen Psychiatry 2002.59:530-537.2. Judd LL, et al. Arch Gen Psychiatry 2003;60:261-269.

Video vignette from “The Fly”

DSM-IV Diagnostic CriteriaHypomanic Episode:

A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 4 days.

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B. At least three of the following symptoms are present during mood disturbance (four if mood is irritable):

1. inflated self-esteem or grandiosity2. decreased need for sleep3. increased talkativeness4. flight of ideas or racing thoughts5. distractibility6. increase in goal-directed activity or psychomotor agitation7. increase in risky behavior

Reminder for Bipolar Disorder: DIG FAST Mnemonic

D – DistractibilityI – InsomniaG – 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)


(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. 1994


(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. 1994

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Diagnostic Criteria ComparedHypomanic Episode: Manic Episode

A. at least 4 days. at least 1 weekB. See DIGFAST sameC. unequivocal change Not a Mixed Episode

D. observable by others.E. not severe enough to

cause marked impairmentD. marked impairment

or hospitalizaton or psychosis

F. are not due to … a substance … or a general medical condition

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.

Different from St Paul’s Conversion!

The individual “converts” to bipolar disorder.

Case Vignette CA 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

years?A. 5%B. 10%C. 20%D. 40%E. 65%

https://www.pexels.com/photo/blonde-haired-woman-in-blue-shirt-y-27411/

5 % 1 0%

2 0%

4 0%

6 5%

11%

24%

4%

20%

40%

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Risk of Bipolar Illness (Goldberg)

Goldberg JF et al. Risk for Bipolar Illness in Patients Initially Hospitalized for Unipolar Depression. Am J Psychiatry 2001; 158:1265-1270.

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%

Risk of Bipolar Illness (Goldberg)

Goldberg JF et al. Risk for Bipolar Illness in Patients Initially Hospitalized for Unipolar Depression. Am J Psychiatry 2001; 158:1265-1270.

Summarystudy n Conversion

rate:(per year)

Years of f/u

comment

Akiskal HS; et al 1995

559 12.5%(1.1%)

11 Mood lability predictive

Coryell et al. 1995

381 10.2% (1.0%)

10 Avg. age >35

Goldberg JF et al. 2001

74 41%(2.7%)

15 Younger pts (<25yo) and hospitalized

Angst J et al. 2005

309 39.2%(3.0%)

13 Linear rate of conversion, severely ill

Rate of Conversion from Depression to Bipolar disorder is about 1-2% per year

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; 84:149-157.

indefinitely

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DSM-5 Episode Specifiers(that are risk factors for bipolar disorder)

• Atypical• Catatonia• Melancholic (not a risk factor)• Mixed features• Postpartum onset• Psychotic features

SummaryPatients 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 messageSuspect bipolar disorder in the following situations:• Unclear history – How to interview for bipolar disorder, see http://thecarlatreport.com/free_articles/current-issues-bipolar-disorder-diagnosis-life-course-method-free-article

• 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 (800-826-3632; www.dbsalliance.org)

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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.


