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A Tale of Two (Hundred Twenty Seven) Depressions: Melancholic Versus Atypical Subtypes
David J. Scheiderer, MD, MBA, DFAPADirector of Education – Integrative Psychaitry
Sarasota, [email protected]
540-342-2844
Faculty Disclosure• David J. Scheiderer, MD has served as a member of the
Speakers Bureau and/or Advisory Board for the following: Lilly USA, LLC; Merck; Takeda, PamLab, Otsuka; Lundbeck; and Forest.
• Statements about supplements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.
As chronic degenerative illnesses (Diseases of Civilization – DOCs) become more common, so too do disorders affecting the brain: depression, anxiety, ADD, autism, Alzheimer’s, PTSD, chronic fatigue, and fibromyalgia.
Depression is the most common psychiatric disorder in the world.
“Descriptivist Methodology for Psychiatric Nosology”
Bjorklund P.. Nurs Philos. 2005 Apr;6(2):131-43.
“Given that our current descriptivist methodology for psychiatric nosology does not in fact establish causes, it is insufficient for determining what depression is. We can talk about what depression does, but not about what it is.”
Receiving less than minimally adequate
treatment
32%
Receiving at least minimally adequate
treatment
20%
Receiving no
treatment
48%
% of Patients
Nearly half of patients with Depression are not receiving any treatment.
Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication.Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Arch Gen Psychiatry. 2005 Jun;62(6):629-40.
STAR*D Study: 2/3 of Patients Remained Symptomatic Following Antidepressant Treatment
Perc
ent o
f Pat
ient
s
~67%
Mild symptoms
~28%
Moderate symptoms
~23%
Severe symptoms
~12%
Very severe symptoms
~4%
Depressive Symptoms (QIDS-SR score) After up to 12 Weeks of Antidepressant Treatment
Remission~33%
0
1
2
3
4
5
6
7
8
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
QIDS-SR, Quick Inventory of Depressive Symptomatology Self-Report; STAR*D, Sequenced Treatment Alternatives to Relieve Depression. Trivedi MH et al. Am J Psychiatry. 2006;163(1):28-40.
Significant Individual Differences in 20 Subjects Treated With An Antidepressant:
Or, in Other Words, It’s a Crapshoot.
40
20
10
00
30
Dep
ress
ion
Seve
rity
(MAD
RS)
1 2 3 4 5 6 7 9 11 12Time From Treatment Start (weeks)
8 10
MADRS = Montgomery-Asberg Depression Rating Scale. Uher R. Harv Rev Psychiatry. 2011;19(3):109-124 .
Complex Neurobiological Underpinnings of Mood Disorders
Multiple Symptom Domains
• Emotional• Cognitive• Behavioral• Physical
System-Wide Manifestations
“Network” Level: Dysregulation of Neural Circuitry
• Functional Changes• Structural Changes
Psycho-Neuro-Immunological (PNI) Disturbances (cortisol, serotonin, dopamine, norepinephrine, hormones)
Cellular and Subcellular LevelImpact on• Intracellular Signaling• Gene Transcription• Neurotrophic Support
Injury
Stress
Based on Maletic V, et al. Front Biosci. 2009;14:5291–5338.
GULCH*
*GULCH – Genes, Uterine environment, Life experiences particularly early life adversity, Choices, Habits
4
Depression is a geneticallycomplex disorder
• There is no single “depression gene”• Most likely there are mutations in multiple genes, coupled with
environmental causes1
• Gene alterations interact with each other and with the environment to influence vulnerability or resilience toward a specific disease2
• Examples of other genetically complex disorders:2
– Heart disease– Type II diabetes– Many forms of cancer
1. Kendler KS, et al. Am J Psychiatry. 2000;157:1243-1251.
2. National Human Genome Research Institute. Available at: www.genome.gov/10000865. 6
Childhood Adversity Represents a Risk for Adulthood Disease
Major depression (panel 1): z=4.94, P<.001. High-sensitivity C-reactive protein (hsCRP) level > 3 mg/L (panel 2): z=3.24, P=.001. Clustering of metabolic risk markers (panel 3): z=4.58, P<.001. ≥1 age-related disease risks (panel 4): z=5.66, P<.001. Adapted from Danese A, et al. Arch Pediatr Adolesc Med. 2009;163(12):1135-1143.
32-year prospective study.
Panel 1:Major
Depression
Panel 2:hsCRP >3 mg/L
Panel 3:Clustering of
Metabolic Risk Markers
Panel 4:≥1 Disease Risk
Number of Adverse Childhood Experiences
% o
f Stu
dy M
embe
rs W
ith th
e C
ondi
tion
≥2 (n=98)
70
60
50
40
30
20
10
0
0 (n=502)1 (n=253)
5
Early Life Adversity Interaction with MTHFR Alleles
BD
I (to
tal s
core
)
MTHFR C/C
MTHFR C/T
MTHFR T/T
5
35
30
20
0
10
2 4Childhood Trauma (total score)
1 3
25
15
5
P=.0027.BDI, Beck Depression Inventory; MTHFR, methylenetetrahydrofolate reductase.Lok A, et al. Transl Psychiatry. 2013;3:e288.
Subjects With Depression Had an Attenuated Ventral Striatal (Nucleus
Accumbens) Response to Positive Stimuli
SD=standard deviation. BOLD=blood-oxygen-level dependent.Adapted from Epstein J, et al. Am J Psychiatry. 2006;163(10):1784-1790.
Subjects With Depression
Healthy Comparison
Subjects
Healthy Comparison
Subjects
Subjects With Depression
Left Ventral Striatum(-15, 15, -6)
Right Ventral Striatum(15, 6, -3)
Mea
n (±
SD) B
OLD
Res
pons
e (%
)
NegativeNeutralPositive
Valence6
4
2
0
-2
-4
-6
8
Melancholic Versus Atypical Depression
Gili M, Roca M, Armengol S, Asensio D, Garcia-Campayo J, Parker G.PLoS One. 2012;7(10):e48200.Lamers F et al. Mol Psychiatry. 2013;18(6):692-699.
• “Our study supports a different clinical pattern and treatment outcome for melancholic and atypical depression subtypes.”
• “The data provide further evidence that chronic forms of depressive subtypes differ not only in their symptom presentation, but also in their biological correlates.”
“For the diagnosis at least five of nine symptoms including at least one of the two core symptoms must be present. It follows that there are 227 possible combinations of symptoms leading to the diagnosis.”
A Tale of 227 Depressions
Data-driven subtypes of major depressive disorder: a systematic review. van Loo HM, de Jonge P, Romeijn JW, Kessler RC, Schoevers RA. BMC Med. 2012 Dec 4;10:156. doi: 10.1186/1741-7015-10-156
RDoC: Cognitive Systems, Neural Circuits, and Dimensions of Behavior• “Although many important discoveries have been made in
the study of cognition, neuroscience, and mental illness, there is growing frustration with the rate of translation of these efforts into understanding of etiological foundations and new treatments.”
• “Progress toward understanding and treating mental illness has been hindered by the scientific focus on diagnoses that do not reflect the organization of neural circuits and their associated behaviors.”
• As such, “… novel approaches to treatment and prevention may benefit from alternative conceptualizations of mental disorders.”
• The RDoC initiative is part of the NIMH’s strategic plan to classify mental disorders based on dimensions of observable behavior and neurobiological measures
RDoC, Research Domain Criteria.Morris SE, Cuthbert BN. Dialogues Clin Neurosci. 2012;14(1):29-37.
Biomarker Panels
• There are no clear single biomarkers• We have, however, mounting evidence of multiple
dysregulated contributing and perpetuating factors:– Growth factors– Pro-inflammatory cytokines– Endocrine factors (HPATG)– Metabolic factors (insulin resistance)
• Thus, a viable alternative to the single-biomarker approach could be the development and implementation of biomarker panels
HPATG, hypothalamus, pituitary, adrenal, thyroid, gonadal, gut.Schmidt HD et al. Neuropsychopharmacology. 2011;36(12):2375-2394; Castrén E, Rantamäki T. Dev Neurobiol. 2010;70(5):289-297.
The Promise of “Pathophysiology-Specific Biomarkers”
Miller AH et al. Biol Psychiatry. 2009;65(9):732-741.
“The availability of peripheral biomarkers that can both identify patients with specific pathophysiologic processes and serve to objectively monitor therapeutic responses within relevant pathways is truly unique and may represent a major advance in the personalization of the treatment of depression.”
WORK-RELATED
URBANICITY
POOR NUTRITION
LACK OF SLEEP
TOXINS
EMOTIONAL STRESS
HORMONAL IMBALANCE
INFECTION
PACE
DRUGS
CancerCHDDM
GERDDepression
MSAlzheimer’s
IBDPsoriasisArthritis
PainObesityAsthma
Genes
Uterine Environment
Life Experiences
Choices
Habits
Diseases of Civization
TriggersAntecendents“GULCH”
Adapted from Goldstein BI et al. J Clin Psychiatry. 2009;70(8):1078-1090; Szelényi J, Vizi ES. Ann N Y Acad Sci. 2007;1113:311-324; Chandra A, Lukaczer D. Functional Medicine: A Patient-Centered, Comprehensive Chronic-Care Model. http://courses.washington.edu/mhe501/Functional%20Medicine/UW_talk_3-2-09%5B1%5D.pdf. Accessed Oct. 2, 2012.
Mediators
Hormones
Neuro-transmitters
Immune Cells
Growth Factors
Metabolic Parameters
Stressor Response
Mediators –
A Closer LookHormones
Neuro-transmitters
Immune Cells
Growth Factors
Metabolic Parameters
The Study of which is called Psycho-Neuro-
Immunology (PNI).
Psycho-Neuro-Immunology
Defined“Psychoneuroimmunology is a convergence of disciplines – namely, the behavioral sciences, the neurosciences, endocrinology, and immunology –intended to achieve a more complete understanding of the way the interactions among these systems serve homeostatic ends and influence health and disease.” -Robert Ader
Building a Better Biomarker Panel: Allostatic Load
HPA, hypothalamic-pituitary-adrenal. Sterling P, Eyer J. In: Fisher S, Reason J, eds. Handbook of Life Stress, Cognition and Health. New York, NY: John Wiley & Sons; 1988; McCaffery JM et al. PLoS One. 2012;7(10):e47246.
Allostasis
The process of achieving stability through physiologic and behavioral change. This is carried out by alterations in HPA axis hormones, autonomic nervous system, cytokines, and other regulatory systems and is generally adaptive in the short term.
Allostatic load is a commonly utilized metric of health risk based on the hypothesis that recurrent stress engenders progressive dysregulation of multiple physiological systems.
Biomarkers Repeatedly Used in Studies of AL
AL, allostatic load; DHEA-S, dehydroepiandrosterone; IL-6, interleuken-6; TNF-α, tumor necrosis factor-alpha; CRP, C-reactive protein; IGF-1, insulin-like growth factor-1.Juster RP et al. Neurosci Biobehav Rev. 2010;35(1):2-16
Neuro-endocrine
Immune Metabolic CV and Respiratory
Anthro-pometric
Cortisol IL-6 HDL Systolic BP Waist-HipRatio
DHEA-S TNF-α LDL Diastolic BP BMI
Epinephrine Hs-CRP Triglycerides Peak Expiratory Flow
Norepinephrine IGF-1 HgbA1C Heart Rate
Dopamine Fibrinogen GlucoseInsulin
HRV
Aldosterone Vitamin D AlbuminCreatinineHomocysteine
Cortisol as Proxy for Allostatic Load
Juster RP et al. Psychoneuroendocrinology. 2011;36(6):797-805.
0
0.1
0.2
0.3
0.4
0.5
0.6
Cor
tisol
μg/
dl
Low ALHigh AL
“Chronic stress causes stress hormones to strain many biological systems in a process referred to as allostatic load that is measurable using an index of biomarkers.”
Subtypes of Major Depression
• Subtypes of major depressive disorder were found to be stable across a 2-year follow-up and to have distinct determinants, supporting the notion that the identified subtypes are clinically significant1
• Significant heterogeneity in depressive symptomatologyexists in United States samples. Profiling symptom patterns is potentially useful as a first step in developing tailored intervention and treatment programs2
• In the National Comorbidity Survey, 36% of individuals with MDD had atypical features and 53% had melancholic features3
1Lamers F et al. Psychol Med. 2012;42(10):2083-2093; 2Carragher N et al. J Affect Disord. 2009;113(1-2):88-99; 3Matza LS et al. Arch Gen Psychiatry. 2003;60(8):817-826.
“Biological Correlates” in Melancholic vsAtypical Depression
AUCg, area under the curve with respect to the ground; AUCi, area under the curve with respect to the increase.Lamers F et al. Mol Psychiatry. 2013;18(6):692-699.
hs-CRP
IL-6
TNF-α
Metabolic Syndrome Components
BMI
Saliva Cortisol Awakening Curves (AUCg & AUCi)
Diurnal Cortisol Slope
Melancholic vs Atypical Depression
Juruena MF, Cleare AJ. Rev Bras Psiquiatr. 2007;29(Suppl 1):S19-S26.
SSx Melancholic AtypicalLevel of arousal Hyperaroused Hypo-aroused, apathetic
Anxiety level anxious Generally not anxious
Reactivity to environment Relatively unreactive Reactive to environment
Emotional memory Broods over painful past Emotionally detached
Cognition ↓ concentration, perseveration
Poor focus
Behavior Regression Unmotivated, inactive
Strong link to bipolar No Yes
Sleep Decreased, poor quality Increased, poor quality
Appetite Decreased with wt. loss Increased with wt. gain
Energy Variable “Leaden paralysis”
Diurnal variation Worse in morning Worse in evening
Melancholic vs Atypical Depression (cont’d)
Juruena MF, Cleare AJ. Rev Bras Psiquiatr. 2007;29(Suppl 1):S19-S26.
SSx Melancholic AtypicalHPA axis Centrally-activated Centrally-mediated hypo-
activityCortisol/ CRF output High/high Low/lowDST Low suppression High suppressionResponse to prednisone - Yes Sympathetic activity Increased Decreased BMI Normal HighLean body mass Decreased (sarcopenia) Normal Immune function Immunosuppressed,
increased infectionsImmuno-enhanced, increased inflammation
Heart disease Premature CHD Premature CHDBone Density Premature osteoporosis Normal bone
Either Road Leads to M
etabolic Syndrom
e
Chrousos GP. Organization and Integration of the Endocrine System. Sleep Med Clin. 2007 Jun;2(2):125-145.
Are People with Atypical Depression Sicker?
Blanco C, Vesga-López O, Stewart JW, Liu SM, Grant BF, Hasin DS. J Clin Psychiatry. 2012 Feb;73(2):224-32
“The presence of atypical features during an MDE was associated with greater rates of lifetime psychiatric comorbidity, including….”
• Alcohol abuse• Drug dependence• Dysthymia• Social anxiety disorder• Specific phobia• Any personality disorder
except antisocial • Female gender
• Younger age at onset• More MDEs• Greater episode severity
and disability• Higher rates of family
history of depression, bipolar I disorder, and suicide attempts
• Larger mental health treatment-seeking rates
Atypical Depression Associated With Obesity, Diabetes, and Metabolic Syndrome
Centers for Disease Control and Prevention. Healthy Weight – it’s not a diet, it’s a lifestyle. http://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html. Levitan RD, Davis C, Kaplan AS, Arenovich T, Phillips DI, Ravindran AV. J Clin Psychiatry. 2012 Aug;73(8):1119-24; Glaus J, Vandeleur C, Gholam-Rezaee M, Castelao E, Perrin M, Rothen S, Bovet P, Marques-Vidal P, von Känel R, Merikangas K, Mooser V, Waterworth DM, Waeber G, Vollenweider P, Preisig M.. Acta Psychiatr Scand. 2012 Dec 7..
“To conclude, results emphasize the need to subtype depression and to pay particular attention to the atypical subtype.”
HPA Axis Activity and DOCs
OCD, obsessive-compulsive disorder; PTSD, posttraumatic stress disorder; RA, rheumatoid arthritis.Juruena MF, Cleare AJ. Rev Bras Psiquiatr. 2007;29(Suppl 1):S19-S26; Hickman RJ et al. J Behav Med. 2013 Apr 30;[Epub ahead of print].
Increased HPA Axis Activity
Decreased HPA Axis Activity
Severe chronic disease Atypical depression Melancholic depression Seasonal depression
Anorexia nervosa Chronic fatigue syndrome
OCD FibromyalgiaPanic disorder PTSDChronic excessive exercise
Hypothyroidism
Malnutrition Adrenal suppressionHyperthyroidism AsthmaCentral obesity PostpartumPregnancy RA
“Individuals with atypical depression may be partially driving the overall depression-inflammation relationship and may be a subgroup at elevated risk for coronary artery disease.”
“Weeping and A-wailing”
High Cortisol,
High Excitatory (Ex) NTs
“Doom, Despair, and
Agony on Me”
“Wired and Tired”
High Cortisol,
Low Ex NTs
Allergic and Infected
“Wired and Tired”
Low Cortisol,
High Ex NTs
Inflamed and in Pain
“Just Plain Tired”
Low Cortisol,
Low Ex NTs
Situation Critical
The 4 Faces of Depression
Depression With Excess Negative Emotions and Cognitions: Melancholia Elevated HPA Axis Activity: Cortisol
High Excitatory and Low Inhibitory NTs
Symptoms• Terminal insomnia• Decreased appetite• Ahedonia• Dread about the future• Sense of doom• Worthlessness, helplessness• Worse in the morning
“Internal Comorbidities”• OCD• Panic disorder• Severe chronic disease• Hyperthyroidism• Excessive exercise
Depression With Deficient Positive: Atypical
Decreased HPA Axis Activity: Cortisol
Low Excitatory NeuroTrasmitters
Symptoms• Excessive sleepiness• Increased appetite
with carb cravings• Fatigue• Anhedonia• “Leaden paralysis”• Rejection sensitivity• Symptoms worsen as
day progresses
“Internal Comorbidities”• PTSD• Fibromyalgia• Chronic fatigue• Heart disease• Metabolic syndrome• Obesity • Hypothyroidism
Pharmacogenetic Testing: How Far Are We From Clinical Application?• Pharmacogenetics studies how genetic variation influences the
response of patients to drugs. This discipline has a greater impact in those medical specialties that treat complex diseases in which the therapeutic response is insufficient and/or have high costs such as psychiatry.
• As such, there is again great potential for pharmacogenetics to facilitate improved and more effective pharmacotherapy. However, clinical implementation of these discoveries can only be realized with adequate assistance from the appropriate regulatory, professional, healthcare, and third-party payer organizations. Although not as quick as technology advancements, it seems that these agencies are at least making incremental strides to ultimately facilitate clinical pharmacogenetics into more routine patient care.
Dolgin E. Clinical efficacy data on gene tests trails marketing in psychiatry. Nat Med. 2012 Aug;18(8):1161; Scott, SA. Genet Med Genet Med. 2011 December; 13(12): 987–995; Daray FM, MaffiaPC, Rothlin RP, Errasti AE. Vertex. 2012 Jul-Aug;23(104):299-309.
Test Genes TendenciesOxidative Stress SOD1, SOD2,
SOD3, GPx1, CATHeart disease, Aging,Diabetes, Alzheimer’s
Vitamin D VDR, CYP27B1, GC Bone loss, MS, Heartdisease, Inflammation
NeurotransmitterSynthesis/ Folate Methylation
COMT, MTHFR Fibromyalgia, Fatigue, ADD, Autism, Depression, Anxiety
Celiac Disease HLA-DQ2.5, HLA-DQ8
Gluten sensitivity, brain fog, GI distress
Metal Detoxification
GSTM1 Chronic fatigue syndrome, Detox issues, Fibromyalgia,
Multiple Drug Resistance
MDR1 Altered response to drugs,Detox issues
Functional Genetics
MTHFR Polymorphism & Depression
• MDD is most likely a neurobiological, heterogeneous disorder.1
• Genome-wide association studies have so far failed to identify specific genes involved in etiology of MDD.2
• MDD is most likely a product of complex interactions between multiple genes, epigenetic changes, and environmental adversity.1,2
• MTHFR is associated with reduced antidepressant efficacy.3
• MTHFR polymorphism is associated with increasing the risk and severity of depression.4,5
• ELA interaction with MTHFR predicts increased risk of depression.6
1.Cohen-Woods S et al. Psychol Med. 2012 June 12:1-15. 2.Uher R et al. Harv Rev Psychiatry. 2011;19(3):109-124. 3.Lanctôt KL, et al. Brain Inj. 2010;24(7-8):959-69. 4.Gilbody S, et al. Am J Epidemiol. 2007 Jan 1;165(1):1-13. Epub 2006 Oct 30. 5.Słopien R, et al. Maturitas. 2008 Nov 20;61(3):252-5. Epub 2008 Sep 17. 6.Lok A, et al. Transl Psychiatry. 2013;3:e288.
BH4 - Tetrahydrobiopterin
TPHtryp
THtyr
PAHphe
NOSarg
Tyr
L-DOPA
5-HTP
NO
BH4BH2
XPH2Inflammation and
Oxidative Stress
Haroon E et al. Neuropsychopharmacology. 2012 Jan;37(1):137-62.
L-methylfolate
Summary
Phenotype: 4 Faces of Depression
“Internal Comorbidities”
Biological Correlates: PNI Perturbations
