Charles B. Nemeroff, MD, PhD
Leonard M. Miller Professor and Chairman
Department of Psychiatry and Behavioral Sciences
Director, Center on Aging
University of Miami, Miller School of Medicine
Miami, Florida 33136

CHARLES B. NEMEROFF, M.D., PH.D.
DISCLOSURES
• Research/Grants: National Institutes of Health ( NIH), Agency for Healthcare Research and Quality (AHRQ)
•
Speakers Bureau: None
•
Consultant: Xhale, Takeda, SK Pharma, Shire, Roche, Lilly
•
Stockholder: CeNeRx BioPharma, Inc., PharmaNeuroBoost, Revaax Pharma, Xhale
•
Other Financial Interest: CeNeRx BioPharma, PharmaNeuroBoost
• Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1),
Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2)
• Scientific Advisory Board: American Foundation for Suicide Prevention (AFSP),
CeNeRx BioPharma, National Alliance for Research on Schizophrenia and Depression
(NARSAD), PharmaNeuroBoost, Anxiety Disorders Association of America (ADAA),
Skyland Trail
• Board of Directors: AFSP, Gratitude America
3

Canst thou not minister to a mind diseased?
Pluck from the memory a rooted sorrow,
Raze out the written troubles of the brain,
And with some sweet oblivious antidote
Cleanse the stuffed bosom of that perilous
Stuff which weighs upon the heart?
4

William Manchester,
The Last Lion, Winston Spencer Churchill, Vol. I: Visions of Glory
(New York: Little, Brown & Company, 1989, p. 23)
5

Characterized by clinically significant distress and/or impairment in social, occupational, or other important areas of functioning
Symptoms must persist for most of day, nearly every day, for

2 consecutive weeks
DSM-IV. 1994.
6

•

5 symptoms including depressed mood and/or anhedonia
–
Other symptoms may include:
–
Significant weight change
–
Psychomotor agitation/retardation
–
Pervasive loss of energy/fatigue
–
Feelings of worthlessness/excessive or inappropriate guilt
–
Difficulty concentrating
–
Sleep disturbance
–
Recurrent thoughts of death/suicide
•
Symptoms present for

2 weeks
DSM-IV. 1994.
7

Prevalence of Depression in United States
Katon W. Schulberg H. Gen Hosp Psychiatry. 1992; 14: 237-247
8

Global Burden of Disease and Injury Series
A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020
EDITED BY
CHRISTOPHER J. L. MURRAY
Harvard University
Boston, MA, USA
ALAN D. LOPEZ
World Health Organization
Geneva, Switzerland
Published by The Harvard School of Public Health on behalf of The
World Health Organization and The World Bank
Distributed by Harvard University Press
4/13/2020
9

Depression —A Major Cause of Disability Worldwide
DALYs —2000 and 2020
Rank 2000 1 2020 (Estimated) 2
1 Lower respiratory infections Ischemic heart disease
2 Perinatal conditions
3 HIV/AIDS
Unipolar major depression
Road traffic accidents
4 Unipolar major depression Cerebrovascular disease
5 Diarrheal diseases Chronic obstructive pulmonary disease
1.World Health Report 2001. Mental Health: New Understanding, New Hope. Geneva, World Health Organization, 2001.
2. Murray CJL, Lopez AD, eds. The Global Burden of Disease. Boston: Harvard University Press; 1996.
DALYs=disability-adjusted life-years.
10

The leading causes of disease burden for women, aged 15-44, 1990
Percent of all causes in developed or developing regions
CAUSES
Unipolar major depression
Schizophrenia
Road traffic accidents
Bipolar disorder
Obsessive-compulsive disorder
Alcohol use
Osteoarthritis
Chlamydia
Self-inflicted injuries
Rheumatoid arthritis
Tuberculosis
Iron-deficiency anaemia
Obstructed labour
Maternal sepsis
War
Abortion

†
*Stowe and Nemeroff. Am J Obstet Gynecol. 1995; 173: 639-645.
†
Troutman and Cutrona. J Abnorm Psychol. 1990; 99: 69.
13

•
>33% severely depressed*
•
 duration of pregnancy =
 risk of depressive disorder*
•
Treat depressive disorders if reaction beyond expected grief and bereavement
*from Janssen et al. Am J Psychiatry. 1996; 153: 226-30.
4/13/2020
14

Prevalence of Depressive Disorders in Children*
•
Preschool children – 0.8%
•
School-aged prepubertal children – 2.0%
•
Adolescents – 4.5%
Key Issues
†
•
Distinguish between depressive disorders and behavioral disorders
•
Depressive disorders before age 20 often associated with recurrent mood disorders in adulthood
•
30% of adolescents hospitalized with severe major depressive disorder develop bipolar disorder
*
Weller EB, Weller RA. In: Psychiatric Disorders in Children and Adolescents. 1990: 3-20.
†Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. 1993: 1-65.
Giles DE, Jarrett RB, Biggs MM, et al. Am J Psychiatry. 1989; 146: 765-767.
Strober M, Carlson G. Arch Gen Psychiatry. 1982; 39: 549-555.
15

•
Occur in approximately 15% of population >65 years old
•
May mimic dementia
•
Comorbid somatic symptoms
•
Not due to “old age”
•
Require appropriate treatment
Data from NIH Consensus Development Panel on Depression in Late Life. JAMA. 1992; 288: 1018-24.
16

• Less than 1/2 of patients with major depression are explicitly recognized as being depressed 1
• Only about 1/2 of all depressed patients receive some form of therapy for their illness 2
• Only about 1/4 of depressed patients receive an adequate dose and duration of antidepressant treatment 3
1. AHCPR. Rockville, Md: US Dept of Health and Human Services; 1993. Publication 93-0550.
2. Lepine JP, et al. Int Clin Psychopharmacol. 1997;12(1):19-29.
3. Katon W, et al. Med Care. 1992;30(1):67-76.
17

Cyclothymia Dysthymia
Bipolar I
Disorder
Bipolar II
Disorder
Unipolar
Depression
Normals
18

19

FACING THE FACTS…
 The suicide rate was 11.8/100,000 in
2008.
 It exceeds the rate of homicide greatly.
 Suicide is the 10 th leading cause of death in the United States.
 Of the 50 states, Florida is # 15 in suicide rate in 2007.
20

FACING THE FACTS…
21

FACING THE FACTS…
 Suicide is considered to be the second leading cause of death among college students. 1100 college students died by suicide in 2009.
 Suicide is the third leading cause of death for youth, 5-24 years old.
 Suicide is the fourth leading cause of death for adults between the ages of
18 and 65.
22

FACING THE FACTS…
Research shows that during our lifetime:
 20% of us will have a suicide within our immediate family.
 60% of us will personally know someone who dies by suicide.
23

SUICIDE DEATHS AND MAJOR PSYCHIATRIC SYNDROMES
<10% without
Major Psychiatric
Syndromes
>90% with Major
Psychiatric Syndromes
A number of psychological autopsy studies have found that approximately 90% of all completed suicides could be retrospectively diagnosed with a major mental disorder.
24

SUICIDE IS AN OUTCOME THAT REQUIRES SEVERAL THINGS TO GO
WRONG ALL AT ONCE.
-- There is no one cause of suicide and no single type of suicidal person.
Biological
Factors
Familial
Risk
Serotonergic
Function
Predisposing
Factors
Major Psychiatric
Syndromes
Substance
Use/Abuse
Proximal
Factors
Hopelessness
Intoxication
Immediate
Triggers
Public Humiliation
Shame
AccessTo
Weapons
Neurochemical
Regulators
Demographics
Personality
Profile
Abuse
Syndromes
Impulsiveness
Aggressiveness
Negative
Expectancy
Severe
Defeat
Major
Loss
Pathophysiology
Severe Medical/
Neurological Illness
Severe
Chronic Pain
Worsening
Prognosis
25

TRIGGERING EVENTS
― Loss of social support (friends, family)
― Loss of identity/meaning (job, career, financial, legal problems)
― Loss of independence/autonomy, or function (major health problem)
― Acute psychiatric symptoms (psychosis, depression, panic…)
― Loss of hope/Sense of failure
― Date of a significant past interpersonal loss: Anniversary reaction
26

27

Lifetime comorbidity of mood and anxiety disorders
48% of patients with PTSD 1 Up to 65% of patients with Panic
Disorder 2
Post-Traumatic
Stress Disorder
Panic
Disorder
DEPRESSION
Social
Anxiety
Disorder
GAD
OCD
Up to 70% of patients with
Social Anxiety Disorder 5
67% of patients with
Obsessive
–Compulsive
42% of patients with
Generalised Anxiety
Disorder 4 Disorder 3
Kessler et al. Arch Gen Psychiatry 1995; DSM-IV-
TR™ 2000; Brawman-Mintzer et al. Am J Psychiatry 1993;
Rasmussen et al. J Clin Psychiatry 1992 ; Dunner, Depression and Anxiety 2001
28

The Five Rs
Reproduced with permission from Kupfer DJ. J Clin Psychiatry.
1991;52(suppl 5):28-34. Copyright 2002, Physicians Postgraduate
Press.
29

30

• Over a third of the liability for developing MDD comes from genetic factors
• Genes likely mediate risk as well as resilience
• Environmental stressors interact with genes to influence the likelihood of developing MDD
31

• Studies of identical twins have revealed that some conditions, such as psoriasis, have a strong genetic
Strong
Genetic
Influence component and are less influenced by environmental and lifestyle factors —identical twins are more likely to share these diseases; but other conditions, such as MS, are only weakly influenced by genetic makeup and therefore twins may show differences depending on their exposure to various environmental factors
Psoriasis
Bipolar disorder
Schizophrenia
Neurotic/ extrovert
Diabetes
Cardiac conditions
MDD
IQ
Asthma
Cancers
• “We used to think our fate was in
Multiple sclerosis our stars. Now we know, in large measure, our fate is in our genes.”
—J. D. Watson
Chakravarti A, Little P (2003), Nature 421(6921):412-414
Weak Genetic
Influence
32

Depression and anxiety are ultimately about how the brain responds to the environment cognition
The Wisconsin Card Sorting Task
Genes: sequence variants and variable gene processing
Cells: molecular pathways
Systems: activity in emotion processing circuitry mood and anxiety disorders
Behavior: temperament
Clinical phenotype
33

•
Family History of depressive disorders
•
Prior personal history of a depressive disorder
•
Female gender
•
Life stressor (eg, bereavement, chronic financial problems)
•
Certain personality traits
•
Loss of parents at an early age
•
Childhood abuse
•
Alcohol or drug abuse
•
Anxiety disorders
• Neurologic disorders (eg, Parkinson’s, Alzheimer’s, stroke)
•
Primary sleep disorders
Hirschfeld RMA, Goodwin FK. In: The American Psychiatric Press Textbook of Psychiatry. 1987: 403-441
Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. 1993: 1-65
34

Stress is an important risk factor for depression
Early life stress is an important risk factor
Genes account for a substantial variation in risk
Brain systems related to the regulation of emotion are functionally impaired during an episode
Monoaminergic drugs are therapeutic
35

• There are disturbances in the monoamine systems
– Serotonin (5-hydroxytryptamine, 5-HT)
– Norepinephrine (NE)
– Dopamine (DA)??
• There are also disturbances in other neurotransmitter systems (e.g., corticotropinreleasing factor [CRF] and substance P)
• Serotonin and norepinephrine have been the most extensively studied in the clinical setting
36

Axon Terminals of Serotonergic Neurons
Project to Virtually All Portions of the Brain
Thalamus
Striatum
Neocortex
Cingulum
Cingulate Gyrus
To Hippocampus
Ventral Striatum
Amygdaloid Body
Hypothalamus
Cerebellar Cortex
Olfactory and Intracerebellar Nuclei
Entorhinal
Cortices Hippocampus
Rostral Raphe Nuclei
Caudal Raphe Nuclei
To Spinal Cord
Kaplan HI, Sadock BJ (1991), Synopsis of Psychiatry: Behavioral Sciences, Clinical Psychiatry, 6th ed. New York: Lippincott Williams & Wilkins
37

38

39

123

5-HTT
5-HTT
Sagittal Image Through
Brainstem and Basal
Ganglia
SPECT = single photon emission-computed tomography
Coronal Image
40

4
5
6
123
Drug free
Drug naive
3
2
1
Healthy Depressed
*p=0.02; V3" = [brainstem-occipital]/occipital; Malison RT et al. (1998), Biol Psychiatry 44(11):1090-1098
41

• Results of regression analysis estimating the association between childhood maltreatment
(between the ages of
3-11) and adult depression (ages 18-
26), as a function of
5-HTT genotype
0.7
0.6
0.5
0.4
0.3
0.2
s/s s/l l/l
0
No
Maltreatment
Probable
Maltreatment
Severe
Maltreatment
Caspi A et al. (2003), Science 301(5631):386-389
42

43

• Role of dopamine neurons in behavioral and physiological areas altered in depression
• High rate of comorbidity of Parkinson’s disease and depression
• Pathophysiological involvement of DA systems in depression
Imaging Studies Postmortem Studies Biological
Fluids Studies
• Role of DA circuits in the actions of antidepressants
 MAOIs
 Effects on the DA transporter
44

6.5
• Dopamine transporter
6.0
binding potential in bilateral striatum is lower 5.5
in depressed patients.
5.0
Data was analyzed using analysis of covariance with age as a covariate, examining effect of diagnosis (effect of diagnosis: F1,29 = 7.1, p=0.01)
4.5
4.0
3.5
3.0
2.5
15 Age 35
Healthy
Depressed
Linear (healthy)
Linear (depressed)
55
Meyer JH et al. (2001), Neuroreport 12(18):4121-4125
45

Recovery With SSRI
FDG PET
R
F9
Transient Sadness
CBF PET
Cg25 Cg25
Cg25 +4z
Cg31 Cg31
- 4z
Cg25
Depressed Patients
Cg25
Cg25
Healthy Volunteers
FDG = [ 18 F] fluorodeoxyglucose; Numbers (i.e., 25, 31) are Brodmann area designations; Mayberg HS et al. (1999), Am J Psychiatry 156(5):675-82

Paroxetine
(Paxil)
N=13
Age 36+10
HAM 22+3 post 6+4
F9
P40 th hc
Cg25 th +inc
CBT
N=14
Age 41 ±9
HAM 20 ±3 post 6.7
±4
F9 mF9
F9 pCg vF hc
Cg24 hc mF9
Cg24 pCg mF10
F11
- dec
Different Treatments; Different Targets
HAM = HAM-D Score; P = inferior parietal; th = thalamus; hc = hippocampus; pCg = posterior cingulate; mF = medial frontal; vF = ventral prefrontal; Goldapple K et al. (2004), Arch Gen
Psychiatry 61(1):34-41

Miller et al (2009) Biol Psychiatry 65:732-741.
48

Goal = reduce symptoms of depression and return patient to full, active life
Nonpharmacologic
•
Psychotherapy
-
Cognitive behavioral therapy
-
Interpersonal therapy
-
Psychodynamic therapy
•
Electroconvulsive therapy
•
Phototherapy
Pharmacologic
•
Antidepressant medications
Depression Guideline Panel. Depression in Primary Care: Vol 1.
Detection and Diagnosis. Clinical Practice Guideline No. 5. 1993.
49
Binder et al (Submitted)

• Increased risk relapse and treatment resistance
• Continued psychosocial limitations
• Decreased ability to work and decreased workplace productivity
• Increased cost for medical treatment
• Sustained risk suicide, substance abuse
• Sustained depression can worsen morbidity/mortality of other conditions
Paykel ES, et al. Psychol Med . 1995;25:1171-1180; Thase ME, et al. Am J Psychiatry . 1992;149:1046-1052.
Judd LL, et al. J Affect Disord . 1998;59:97-108; Miller IW, et al. J Clin Psychiatry . 1998;59:608-619.
Simon GE, et al. Gen Hosp Psychiatry . 2000;22:153-162; Druss BG, et al.
Am J Psychiatry. 2001;158:731-734.
Frasure-Smith N, et al. JAMA. 1993;270:1819-1825; Penninx BW, et al. Arch Gen Psychiatry . 2001;58:221-227.
Rovner BW, et al. JAMA . 1991;265:993-996.
50

THE NEED FOR OUTREACH TO COLLEGE STUDENTS
 Only 15-19% of students who die by suicide had been treated at campus counseling center (Gallagher, Annual
Survey of Counseling Center
Directors, 1995-2006)
 Why is this figure so low?
51

BARRIERS TO HELP-SEEKING
 Negative attitudes toward treatment
 Fear of negative reactions from parents, friends
 Concerns about confidentiality and potential impact of treatment on academics and career
 Concerns about administrative sanctions
 Worries about costs/issues with parents’ insurance
 Beliefs that problems will resolve on their own
 Perception that problems don’t impact functioning
 Resistance to giving up “control” of own choices
 Too overwhelmed to take necessary steps
52

CONFIDENTIALITY AND NEGATIVE CONSEQUENCES
 “This may sound silly but it has held me back from trying to talk to someone earlier: are there any repercussions for coming in? Last year I overdosed on a bunch of pills and I cut up my body. My father flew down here to kind of help me out…he said that it was probably a good thing that I did not go to the hospital because they would have to report a suicide attempt or something and it could get me kicked out of school. If I admit to that or talk about my depression will I get in trouble?”
53

COST
 “I wouldn’t mind meeting you…One thing is bothering me, though: my parents used to pay for my therapists back home, but if I tell them now that I’m thinking of going back to therapy they would get really worried about me and might want me to withdraw or something…But then, I wouldn’t be able to pay on my own if it’s as expensive as seeing private psychiatrists were…What do you think I should do?”
54

DIALOGUE AS THERAPY
 ”I’ve had a really bad year and it seems like I am either super happy or super sad, like right now I am sitting here crying on my bed and I couldn’t even tell you why exactly…I think what I am most stressed out [about] (which makes me contemplate whether I should even live any more or not) is really stupid and even I can recognize that it is dumb. I feel like I am so lost because I am so undecided about my future that I lose sleep at night. My parents will not stop bugging me about a major or a career and I’m beginning to think that no matter what major or career I choose I will hate it. My friends would probably never guess I’m depressed. I try very hard to hide it…but in the end it makes it worse because I feel like I’m not being who I really am. I think the depression questionnaire was a God-send before I did something stupid. People looking at my life from the outside in would see a very normal happy childhood and I have a great family and people who love me, so I almost feel guilty about being so sad. I don’t have a real reason to be I guess... This is really long, but it’s nice to get it all out. Thanks for listening.”
55

STUDENTS CAN COME BACK FOR HELP AT LATER DATE
 I filled out your survey last semester. You emailed me multiple times, but I thought I had a handle on things and was starting to feel better.
My friend committed suicide last week and I am finding it really hard to even get out of bed. It’s just,… I don't know. I thought I could handle this on my own, but I may need help.
56

•
S afety
-
Drug-drug interaction potential
•
T olerability
-
Acute and long term
•
E fficacy
-
Onset of Action
-
Treatment and prophylaxis
•
P ayment (cost-effectiveness)
•
S implicity
-
Dosing
-
Need for monitoring
Preskorn SM. J Clin Psychiatry. 1997; 58(suppl 6): 3-8.
58

Antidepressant agent classes
•
Monoamine oxidase inhibitors (MAOIs)
•
Tricyclic (TCAs) and tetracyclic antidepressants
•
Selective serotonin reuptake inhibitors
(SSRIs)
•
Atypical antidepressants
-
Bupropion
-
Venlafaxine
-
Nefazodone
-
Mirtazapine
Rossen EK, Buschmann MT. Arch Psychiatr Nurs. 1995; 9: 130-136.
59

• Better prognosis
• Better function
• Less treatment resistance
• Better outcomes in comorbid general medical conditions
• Fewer complications
– Substance abuse
– Relationship problems
– Lower morbidity from general medical conditions
60

1 Episode
50%
2 Episodes
80% - 90%
3 Episodes
>90%
Depression Guideline Panel. Depression in Primary Care, Volume 2: Treatment of Major Depression.
Clinical Practice Guidelines, Number 5. 1993.
Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.
61

• ECT effective for depression 1
– Limitations include side effects and high relapse rate (even with continuation ECT) 2
– Increasingly focal ECT may be efficacious with fewer side effects 3,4
• Magnetic seizure therapy
– Convulsive therapy with a very focal initial stimulation
– Preliminary efficacy suggested with fewer cognitive side effects than ECT 5,6
1The UK ECT Review Group, Lancet, 2003; 2Kellner et al., Arch
Gen Psychiatry, 2006; 3Sackeim et al., Arch Gen Psychiatry, 2000;
4Bakewell et al., J ECT, 2004; 5Lisanby et al.,
Neuropsychopharmacology, 2003; 6White et al.,
Anesth Analg, 2006
62

18
16
14
12
10
8
6
4
2
*
0
Persistent
†
Improved
†
Remission
†
*P <0.001
†Clinical depression status at 12-month assessment. Persistent = still meeting diagnostic criteria for MDD;
Improved = HAM-D

8, but not meeting diagnostic criteria; Remission = HAM-D

7
Simon GE, et al. Gen Hosp Psychiatry . 2000;22:153-162.
63

• Absenteeism may represent only a small fraction of the cost of depression in the workplace
• Persistently depressed workers are 7 times less productive on the job
• Impact of depression on function at work is substantially higher than its association with missed days at work
Druss BG, et al.
Am J Psychiatry. 2001;158:731-734.
64

• Depression worsens morbidity and mortality after myocardial infarction 1,2
• Depression increases risk for mortality in patients in nursing homes 3
• Depression worsens morbidity post-stroke 4
• Depression can worsen outcomes of cancer, diabetes, AIDS, and other disorders 5
1.Frasure-Smith N, et al. JAMA. 1993;270:1819-1825. 2. Penninx BW, et al. Arch Gen Psychiatry . 2001;58:221-
227. 3. Rovner BW, et al. JAMA . 1991;265:993-996. 4. Pohjasvaara T, et al. Eur J Neurol . 2001;8:315-319. 5.
Petitto JM, Evans DL. Depress Anxiety. 1998;8(suppl 1):80-84.
65

5
4
Nondepressed
Minor depression
Major depression
3
2
1
0
No pre-existing cardiac disease Pre-existing cardiac disease
Penninx BW, et al. Arch Gen Psychiatry . 2001;58:221-227.
66

• FDA-approved (1997) for treatment of medicationrefractory epilepsy
• FDA-approved (2005) for treatment of depression that has not responded to four or more medications
• Achieved by implanting a pulse generator attached to
(usually) the left vagus nerve
67

• Studied for treatment of depression since 1993
– Multiple open and sham-controlled studies have been performed; meta-analyses support antidepressant effects for high frequency left-sided rTMS 1,2
– Some studies have suggested a favorable comparison to ECT, but data are mixed 3,4
– Low frequency right-sided rTMS may also have antidepressant effects 5,6
• Side effects are generally mild; serious adverse events (seizures) from TMS performed within current safety guidelines are very rare 7
1Holtzheimer et al., Psychopharm Bull, 2001; 2Kozel et al., Journal of Psychiatric Practice, 2002; 3Grunhaus et al., Biol
Psychiatry, 2000; 4Eranti et al., Am J Psychiatry, 2007; 5Fitzgerald et al., Arch Gen Psychiatry , 2003; 6Januel et al., Prog
Neuropsychopharmacol Biol Psychiatry, 2006; 7Wassermann, Electroencephalogr Clin Neurophysiol, 1998
68
Geracioti et al (2006) AJP 163:637-643.

69