lecture 4 major depression -...

Lecture 4Major Depression

David Saffen, Ph.D.Principal Investigator

Department of Cellular and Genetic MedicineFudan University, Shanghai, China

Email: [email protected]

OutlineA. Introduction

- A brief history of major depression- Core clinical features - Diagnosis (DSM-5)- Epidemiology and societal burden - Famous individuals with major depression

B. Causes of major depression: pharmacology, neurobiology, environment, genetics

- Current drugs therapies and potential mechanisms - Brain regions implicated in major depression

C. Developing new therapies to treat major depression- Ketamine- Deep brain stimulation

D. References, major depression internet resources

A. Introduction

“Sorrowing Old Man”Vincent van Gogh (1890)

HippocratesAncient Greek physician

described a type of “melancholia” as a distinct disease

Sigmund FreudAustrian Neurologist

Founder of “psychoanalysis”emphasized theimportance of

unconscious processes in the development of

depression

Nathan S KleinAmerican Physician

Lasker Award Winner (2x)Conducted research on

and promoted the use of drugs, including iproniazid,

for the treatment of depression

Important figures in the history of thediagnosis and treatment of depression

Core characteristics• Sadness, dejection, despondency, feeling of guilt, worthlessness,

emptiness, helplessness and/or pessimism that last for extended periods of time, in a manner that disrupts family and social interactions.

• Inability to work, sleep, study eat or enjoy once-pleasurable activities

• Fatigue and decreased energy; physical ailments

• Difficulty concentrating, remembering details, making decisions

• Commonly accompanied by feelings of fear, anxiety, irritability, restlessness, anger, or delusions and obsessions, thoughts of suicide

Note: clinical depression is distinct from mourning and other “normal” sadness responses to personal loss (bereavement).

Subtypes of Depressive

Disorders (DSM-5)

- Major Depressive Disorder

- Disruptive Mood Dysregulation Disorder- Persistent Depressive Disorder (Dysthymia)- Premenstrual Dysphoric Disorder- Substance/Medication-Induced Depressive Disorder- Depressive Disorder Due to Another Medical Condition- Other Specified Depressive Disorder- Unspecified Depressive Disorder

Clinical features of MDD (DSM-5)

1) Depressed mood, most of the day nearly all day(In children and adolescents, can be irritable mood.)

2) Markedly diminished interest of pleasure in all, or almost all, activities

3) Significant weight loss when not dieting or decrease or increase in appetite(In children, consider failure to make expected weight gain.)

4) Insomnia or hypersomnia

5) Psychomotor agitation or retardation

6) Fatigue or loss of energy

7) Feelings of worthlessness or excessive or inappropriate guilt

8) Diminished ability to think or concentrate; indecisiveness

9) Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan ora suicide attempt or a specific plan for committing suicide.

Major Depression Episode (DSM-5)

A) Five or more of the “depressive” symptoms listed above have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure

B) The symptoms cause clinically significant distress or impairment in social, occupational or other areas of functioning.

C) The episode is not attributable to the physiological effects of substance or another medical condition.

Depressive disorder specifications (DSM-5):

With: - anxious distress - mixed features- melancholic features- atypical features- psychotic features (previously “psychotic depression”)

mood-congruent psychotic featuresmood-incongruent psychotic features

- catatonia- peripartum onset- seasonal pattern [previously “seasonal affective disorder” (SAD)]

Frequent comorbidities

• Anxiety disorders

• Personality disorders

• Alcohol or substance abuse

• Metabolic syndrome (obesity, diabetes)

• Coronary heart disease

• Stroke

• Cancer

• HIV infection

• Parkinson’s disease

Instruments for clinical assessment

• Hamilton Rating Scale for Depression

• Beck Depression Inventory

Current Therapies1) Psychotherapy

- Cognitive behavioral therapy (CBT)- Rational emotive behavior therapy- Mindfulness-based cognitive therapy - Psychodynamic psychotherapy- Interpersonal psychotherapy (IPT)- Family therapy

2) Pharmacotherapy- Monoamine oxidase inhibitors- Tricyclic antidepressants- Selective serotonin reuptake inhibitors (SSRIs)- Serotonin and norepinephrine inhibitors reuptake (SNRIs)- Norepinephrine or NE/dopamine reuptake inhibitors

3) Electroconvulsive therapy (ECT)

Antidepressants approved by the FDA

Kupfer DJ, Frank E and Phillips ML, 2012

Epidemiology and societal burden

• Twelve-month prevalence: 6.6%; lifetime prevalence: 16.2%; Prevalent for entire lifespan (USA)

• Twice as common in women as in men

• A significant source of disability; also worsens prognosis for comorbid physical diseases

• Major Depressive Disorder Disability-Adjusted Life Years(DALY), a measure of the burdenof disease; one DALY = one yearof “healthy” life lost, due to living with disability or earlydeath. (date from WHO) = 850 – 925 per 100,000

= > 1450 per 100,000

Famous individuals with major depression

William BlakeEnglish poet, painter,

Printmaker

Mark RothkoAmerican artist:

Died of suicide (1970)

Ernest HemingwayAmerican Author,

Nobel Prize in LiteratureDied of suicide

Sergei Rachmaninoff

Russian composer(attempted suicide)

Abraham LincolnAmerican president

Andrew Soloman,American author:

“The Noonday Demon”“Far From the Tree”

B. Causes of major depression: pharmacology, neurobiology,

environment, genetics

First-generation antidepressants(discovered and developed during 1950’s)

IsoniazidA “first-line”

medication forthe treatment of

tuberculosis”

Iproniazidfirst marketed “antidepressant”a non-specific,

irreversiblemonoamine

oxidase (MAO)inhibitor

Imipramineprototypic“tricyclic”

antidepressanta potent reuptake

inhibitor of serotonin,

norepinephrine and dopamine

Biosynthesis and metabolism of

serotonin(5HT:

5-hydroxy-tryptamine)

Serotonin-producing neurons

Serotonergic synapses

Serotonin interacts with 14 known subtypes of membrane receptors,

classified within 7 families: 5HTR1-7.Most of serotonin receptors belong

to the seven-transmembrane Gprotein-coupled receptor superfamily.

The exception, 5HTR3, is a ligand-gated ion channel.

The primary mechanism for thetermination of serotonergic

neurotransmission is the reuptakeof serotonin from the synaptic cleft

into the presynaptic nerve-endingvia the serotonin transporter (SERT).

Selective serotonin reuptake inhibitors

• Many drugs with anti-depressant effects influence the serotonergic neurotransmission. Among these, selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed drugs for depression.

• SSRIs comprise a major class of “second-generation” antidepressants, which are also used for the treatment of anxiety disorders, obsessive-compulsive disorders and eating disorders.

• Commonly prescribed SSRIs include:

- fluoxetine (Prozac)

- sertraline (Zoloft)

- paroxetine (Paxil)

- escitalopram (Lexapro)

- fluoxamine (Luvox)

- citolopram (Celexa)

Biosynthesisof dopamine

& norepinephrine

note:epinephrine

aka: adrenaline

norepinephrine aka: noradrenaline

catechol

VMA = vanilylmandelic acid

HVA =homovanillic acid

Dopamine-producing neurons

The dopaminergic synapse

The primary mechanism for thetermination of dopaminergic

neurotransmission is the reuptakeof dopamine from the synaptic cleftinto the presynaptic nerve-ending

via the dopamine transporter (DAT)

Dopamine interacts with 5 known subtypes of membrane receptors,

DR1-DR5, which are members of theseven-transmembrane G protein-

coupled receptor superfamily.DR1 and DR5 interact with Gs;

DR2, DR3 and DR4 interact with Go/i.

Norepinephrine-producing neurons

The noradrenergic synapse

Norepinephrine interacts with five subtypes adrenergic receptors, allseven-transmembrane G protein-

coupled receptors: alpha1 and alpha2 and beta1, beta 2 and beta3.Alpha1 receptors interact with Gq,

Alpha2 with Gi/o and Beta1-3 interact with interact with Gs.

The primary mechanism for thetermination of noradrenergic

neurotransmission is the reuptakeof NE from the synaptic cleft

into the presynaptic nerve-ending viathe NE transporter (NET)

Dopamine and norepinephrine reuptake inhibitors

• Tricyclic antidepressants block the reuptake of dopamine, norepinephrine as well as serotonin.

• Selective norepinephrine reuptake inhibitors (NRIs) comprise an additional class of “second-generation” antidepressants; these include:

atomoxetine (Strattera), reboxetine (Edronax) and viloxanzine (Vivalan)

• The widely prescribed “atypical” antidepressant bupropion (Wellbutrin, Zyban) inhibits the reuptake of both dopamine and norepinephrine

• Serotonin and norepinephrine reuptake inhibitors (SNRIs) are also commonly prescribed for depression. These include: duloxetine (Cymbalta), venlafaxine (Effexor), desvenlafaxine (Pristiq), milnacipran (Ixel, Savalla) and levomilnacipran (Fetzima)

New hypothesis: rather than resulting from of a simple

“imbalance” in biogenic amine neurotransmitters(serotonin, dopamine, norepinephrine),

major depression is caused by disruptions of functional and structural connections of the neural

circuits that underlie the regulation of mood.

Dunman RS et al, Nature Medicine 22, 2016

Heterogeneity of depression andinfluences on susceptibility to depression


Neural systems of relevance to major depressive disorder

Kupfer DJ, Frank E and Phillips ML, 2012

OFC: orbitofrontal cortex

mPFC: medial prefrontal cortex

ACC: Anterior cingulate cortex

DLPFC: dorsolateral prefrontal cortex

VLPFC: ventrolateral prefrontal cortex

mPFCACC

amygdala

serotonin

OFC

ventralstriatum

dopamine

MDD is characterized by high levels of stress, which together can adversely affect the

structure and function of the brain

• Depression is associated with neuronal atrophy and reduced synaptic connectivity in the medial prefrontal cortex (mPFC), hippocampus and anterior cingulate cortex (ACC).

• Also: loss of projection neurons, GABAergic interneuron and glial cells (astrocytes and oligodendrocytes) in PFC and hippocampus

• Also: reduced adult neurogenesis and gliogenesis in dentate gyrus of the hippocampal formation.

Effects of chronic stress on neurons and synapses


Many extracellular signaling molecules and multiple intracellular signaling cascades influence synapse formation and stability


Hypothesis: the efficacy of drugs used to treat depression is mediated by activation of PKA and increased production of brain-

derived neurotrophic factor (BDNF)

Duman and Voleti, 2012

Brain derived neurotrophic factor (BDNF) and major depression

Duman and Voleti, 2012

Advances in our understanding of the neurobiology of MDD

Genetics of major depressionGenetic heritability of variance in susceptibility to depressionIs estimate at ~ 35- 40%.

Small-scale, candidate gene-based association studies have often yieldedyielded association that could not be replicated.

To date may large-scale genome-wide association studies (GWS) have failed to identify common genetic variants that statisticallyassociate with depression. Large heterogeneity of depression disorders,Possible differences in susceptibility and/or diagnosis criteria among ethnic groups, and gene interactions with non-genetic factors (e.g., environment, epigenetic effect are suspected to play important roles in the inability to identify depression liability genes and genetic variants.)

A recent large-scale GWS of depression in Han Chinese population, however, reported the first statistically robust association depression for two genetic loci on chromosome 10. (Converge consortium, Nature523, 2015)

C. Developing new therapies totreat major depression

Controversy concerning the efficacy of antidepressants

Kirsch I et al, PLOS Medicine 5, e45, 2008

Note: NICE = National Institute for Clinical ExcellenceHRSD = Hamilton Rating Scale for Depression (< 18: mild depression; 19-22: severe depression , > 23 very severe depression)

Additional shortcomings of antidepressant medications

• Low response rates: ~1 of 3 patients respond to first medication prescribed; 2 of 3 respond after repeated testing

• Long lag time (several weeks to months) before therapeutic effect is attained (putting patients at risk for suicide in the interim)

• Reports that some SSRIs increase suicide ideation in young patients

Ketamine

• NMDA glutamate receptor antagonist; acts as a “dissociative” anesthetic; high doses mimic cognitive deficits observed in schizophrenia patients

• Rapidly acting antidepressant effect when used a low concentrations

• Effective even in patients who have not responded to two or more SSRIs

• Single low doses produce antidepressant effects that last for for up to one week.

Mechanism of action of ketamine in medial prefrontal cortex (mPFC)


Deep brain stimulationfor non-responsive depression

Targeted structures include: subgenual cingulate white matter (Cg25WM: within BA25),

ventral anterior internal capsule, ventral striatum, nucleus accumbens and lateral habenula.

References (1)• Duman RS, et al, Synaptic plasticity and depression: new insights from stress and rapid-acting

antidepressants, Nature Medicine 22, 238-249. 2016

• Kupfer D, Frank E and Phillips ML, Major depressive disorder: new clinical, neurobiological and treatment perspectives, Lancet 379, 1045-1055, 2012

• Youdim M, Edmondson D and Tipton KF, The therapeutic potential of monoamine oxidase inhibitors, Nature Reviews Neuroscience 7, 295-309, 2006

• Goldstein-Piekarski AN, et al, Human amygdala engagement moderated by learly life stress exposure is a biobehavioral target for predicting recovery on antidepressants, Proc. Natl. Acad. Science (USA), 2016

• Jian C and Salton SR, The role of neurotrophins in major depressive disorder, Translational Neuroscience 4, 46-58, 2013

• Banasar M, Dwyer JM, and Duman SR, Cell atrophy and loss in depression: reversal by antidepressant treatment, Current opinion in cell biology 23, 730-737, 2011

• Duman SR and Voleti B, Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents, Trends in Neuroscience 35, 47-56, 2012

• Miller AH and Raison CL, The role of inflammation in depression: from evolutionary imperative to modern treatment target, Nature Reviews Immunology 16, 22-34, 2016

• Kirsch I et al, Initial Severity and antidepressant benefits: a meta-analysis of data submitted to the food and drug administration, PLOS Medicine 5, 2008

• Duman RS et al, Signaling pathways underlying the rapid antidepressant actions of ketamine, Neuropharmacology 62, 35-41, 2012

References (2)

• Lener MS, et al, Glutamate and gamma-aminobutyric acid systems in pathophysiology of major depression and antidepressant response to ketamine, Biological Psychiatry, 20016

• Salvadore G and Singh JB, Ketamine as a fast acting antidepressant: current knowledge and open questions, CNS Neuroscience and therapeutics 19, 428-436, 2013

• Lapidus K, Soleimani L and Murrough JW, Novel glutamatergic drugs for the treatment of mood disorders, Neuropsychiatric Disease and Treatment 9, 1101-1112, 2013

• Kennedy et al, Deep brain stimulation for treatment-resistant depression: follow-up after 3-6 years, American Journal of Psychiatry 168, 502-510, 2011

• Williams NR and Oku MS, Deep brain stimulation (DBS) at the interface of neurology and psychiatry, J Clinical Investigation 23, 4546-4556, 2013

• Ledford H, First robust genetic links to depression emerge, Nature 523, 268-269, 2015

• Converge consortium, Spare whole-genome sequencing identifies two loci for major depressive disorder, Nature 523, 588-591, 2015

• Power RA et al, Genome-wide association for major depression through age at onset stratification, Biological Psychiatry, 2016

• Zeng Y et al, A combined pathway and regional heritability analysis indicates Netrin1 pathway is associated with major depressive disorder, Biological Psychiatry, 2016

Journal Presentations

Background Articles:

Loria K, Scientists are increasingly excited about ketamine, a party drug that could prevent depression, Business Insider, Oct 10, 2016

From Mice to Men: Can Ketamine Enhance Resilience to Stress? Biological Psychiatry , May 1, 2016

Research Article : Brachman RA, et al, Ketamine as a prophylactic against stress-induced depressive-like behavior, Biological Psychiatry , May 1, 2016

Internet resources

• National Institute of Mental Health (NIH)http://www.nimh.nih.gov/health/topics/depression/index.shtml

• National Alliance on Mental Illnesshttp://www.nami.org

• Depression and Bipolar Alliancehttp://www.dbsalliance.org/

http://www.nimh.nih.gov/health/topics/depression/index.shtml

http://www.nami.org/

http://www.dbsalliance.org/

Extra slides

Synapse and cellular alterations caused by stress and depression

Banasr, Dwyer & Duman, Current Opinion in Cell Biology, 2011

BDNF = brain-derived neurotrophic factorVEGF = vascular endothelial growth factorBcl2 = an anti-apoptotic proteinMKP-1 = MAPK phoshphatase-1

Duman RS, et al, Neuropharmacology 62, 2012VDCC = voltage-dependent calcium channelIRS = insulin receptor substrateeEF2K = eEF2 kinase

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