藥 理 新 进 展 訓 練 課 : 抑 郁 症

New Psychopharmacology :

Major Depression as an example

A Training Session for AsCNP, China September 12th ₂₀₁₃

藥理新进展訓練課

:

抑郁症

Professor SW Tang

University of California, Irvine, USA

Honorary Professor of Anatomy, University of Hong Kong Director , Institute of Brain Medicine

Q:

What is the purpose of life for

all life forms ?

Purpose of Life for all life forms :

(

生命之意義

)

“Eat well, then Reproduce”

“

不孝有三，無後為大”

Eating & Sex

Known for thousands of years:

a. “The desire for eating and sex is basic to animals, & is human nature” ; “When I was small, I adored my parents, Now I understand sex, I adore women”

(Mencius)

孟子 (告子)：“人少则慕父母，知好色则慕少艾。”

告子曰：“食色性也”

b. “Eating and Sex are human wants” (Confucius)

Brain is NOT necessary

in the preservation of species originally

Intact

Emotional & Cognitive functions

are especially important for

Q:

which 2 chemicals play

important roles in emotional &

cognitive functions ?

Dopamine

DA

and Serotonin

5HT

are ancient and were present

in the primitive brain

Sub serving 2 fundamental purposes in Life

Sex, Eating and Reproduction

DA

5HT

5HT and DA evolved and bundled into

important pathways, extensively

innervating the higher brain to serve

complex functions in a complex society

Development and Refinement

in the roles of DA and 5HT to subserve the meaning of life have continued to evolve over the past

millions of years

The Human Brain has many more new roles in addition to sex and eating living in a complex 一

modern society

Reward and Pleasure have to be

5HT and DA pathways co-evolve

into two highly sophisticated

systems :

wiring for our complex feelings,

judgment and higher thinking

5HT

受體

1

e.g. Many 5HT receptors

in higher life forms in a complex society serving different purposes

Genetic or other Pathological changes in these two neurotransmitters (or their

functions/pathways) therefore may have grave consequences , manifested in symptoms of

“altered experience in Reward & Pleasure ” e.g. anhedonia, apathy, inappropriate or

disproportionate emotional and cognitive responses to stimuli

Q:

What do antidepressants do ?

Major Depression is not unhappiness

Sustained impairment (almost every day) > 2 weeks

Not only depressed mood > 5 symptoms ( significant impairment in social, work, or other important areas of functioning

1. Depressed mood most of the day

2. Diminished interest or pleasure in all or most activities 3. Significant unintentional weight loss or gain

4. Insomnia or sleeping too much

5. Agitation or psychomotor retardation noticed by others 6. Fatigue or loss of energy

7. Feelings of worthlessness or excessive guilt

8. Diminished ability to think or concentrate, or indecisiveness 9. Recurrent thoughts of death

Q:

Comment on the

pharmacology & neuroanatomy

of happiness and depression

Unhappiness

(a mood state)

or an unhappy character

is often mistaken

as the mood disorder (an illness)

** Very important concept

Drugs for treating depression are not drugs inducing happiness

Happiness and Major Depression

Recent Clinical Neuroscience research showed

Neuroanatomical and Neurochemical substrates for “unhappiness” and for “Major Depression ” may have evolved together but distinguished

themselves for different purposes over evolution These new data may help us to understand the

differential effects of drug & non-drug treatment in reversing major depression and in creating

happiness and also many long standing confusion in treatment targets and treatment end points

Drugs inducing pleasure may not be

true antidepressants ?

Pleasure and Mood may involve separate neuropathways/circuits ?

Major Depression is NOT unhappiness

But inducing pleasure/optimism may mask depression symptoms or give temporary relief in short term ( ? Apparent and transient effects of certain talk, music,

aromatic therapies and basis of various addiction in patients)

Compounds and other procedures

with fast mood actions

Drug of abuse (e.g cocaine…)

Ketamine, sleep deprivation, brain stimulation ……….

NA

VTA

ACC

快感的神經線路

NA

PFC

VTA

ACC

Neuro- Circuit for Pleasure/Reward

Addiction

DBS A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression . Lozano et al., J Neurosurg. 2012;

Deep brain electro-stimulation

Rat

Depressed patients

NeuroCircuits in Major Depression Frontal Cognitive Input Dorsal Raphe Amygdala Hippocampus Stress Inflammatory -ve Antidepressants + ve

Some Important

Hypothesis/Theories of Major

Depression

&

Q: WHICH PART(S) OF OUR

BRAIN MAKE US HUMAN ?

The PreFrontal Lobes

The New Man’s Pre-Frontal Cortex

A brain lacking the human brain (frontal) to control the animal (limbic) brain

or

A brain with pathological animalistic brain parts

Amygdala Weak Frontal Cortex 修養 Over-active Animalistic drives : Impulsive Strong Frontal Cortex Controlled limbic Un-buffered emotions Solution direct, e.g. physical Highly Buffered Calculated Solution Strategies Strong Limbic

Dogs could be trained to delay gratification before certain age

Animal Brain Limbic Human Br ai n Fr o n tal cort ex 我們的野獸冲動受制于前腦 Emotions : Happiness, Anger, Rage, Sadness, Lust, Bonding, Love, Trust, …..

Higher Thinking: Wisdom, Humor Strategy, delay gratification

ACC

vmPFC Amygdala

Hippocampus

前腦調節情緒的機制

Brain parts identified for emotions and the controls

Hypofrontality

Early childhood development

Resilience Training (修養, 毅力) Psychotherapy ,Talk Therapies Drugs

2. Amine Hypothesis :

Functional Impairment of

Aminergic Neuro-transmission

Increase functional Amines : e.g. Amine Reuptake Blockers

3. MAOI (A & B) 2. Auto-receptor Antagonist 1. Re-uptake Inhibitors all TCAs, SSRIs, SNRIs NRIs,NDRI

Current Antidepressant Drug

Targets _Examples: 1. Amitriptyline, Imipramine Fluoxetine (Prozac) Paroxetine (Paxil) Escitalopram (Lexapro) Venlafaxine and metabolites Duloxetine, Bupropion 4. 5HT2C 2.Mirtarzapine,Mianseri n 3. Pargyline, Phenelzine (Nardil) Selegiline (Deprenyl) Tranylcypromine (Parnate) Rasageline 4. Other compounds on 5HT receptors (e.g. 5HT2c) Agomelatine (antagonist) , trazodone (agonist)

Clinical reality

Irrespective of Dx

Categories Drugs

Current antidepressant treatable Current antidepressant compounds Augmentation needed Add Lithium, or other antidepressant (

e.g. escitalopram + mirtazapine), or antipsychotics (e.g. aripiprazole,

resiperidone), or thyroxin, estrogen, ……… Incomplete responses Polypharmacy, any new drug, ??????? Resistant cases Polypharmacy, any new drug, ??????? Unclear diagnosis Antidepressants , polypharmacy, & any

psychotropic drugs plus other compounds ? ??????

Reality in Clinic :

Recycling or Polypharmacy

TCAs, SSRIs, SNRIs, NDRIs, 5HT2c agents, Li, MAOIs,……

Ocean of compounds with antidepressant property or compounds with augmentation property

Q:

Have we reached the limit in

the development of DA/5HT

antidepressant drugs ?

or Have we fully exploited the Amine

Hypothesis of Depression in the development of antidepressant drugs ?

3. Depression as

a neuro-toxic disease

Hypothesis

3 a

.

Cortisol Toxicity Model

Stress (sustained & serious)  Cortisol  BDNF

suppression  Impairment/Damage of

spines/dendrtites/neruons  Depressive

symptoms

Antidepressant Treatment  BDNF gene

expression  elevated BDNF 

spinogenesis/dendritogenesis/neurogenesis

 _{Reversal of depression state}

Q:

Do antidepressant drugs work

through producing new neurons

Enhance Neurogenesis

Dendritogenesis & Synaptogenesis

Dendrtie with spines and synapses

3 b. Mitochondria Dysfunction

and Oxidative damage

Inflammatory

Neurodegenerative Hypothesis

Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders.

Gardner and Boles 2011, Prog Neuropsychopharmacol Biol Psychiatry 2011

Mitochondrial Complex I Activity and Oxidative Damage to Mitochondrial Proteins in the Prefrontal Cortex of Patients With Bipolar Disorder

Neuro-degeneration

Spine loss

Dendritic shortening and loss

Reduced neuronal & glial numbers

Reduced packing density and size of neurons Loss of prefrontal inhibitory circuits

Decrease pyramidal neuron soma size

All  reduced hippocampal & other brain area volume

Campbell 2004; Campbell and MacQueen 2006; Parashos et al., 1998; stockmeier et al., 2004; Steingard et al., 2002; Vasic et al., 2008; Zou et al., 2010

Mitochondria Pathology Model

A. Chronic Stress 

1.Chronic cortisol elevation  chronic increases in mitochondria activity & oxidative, Ca++

activities  impaired mitochondria function & mitochondrial DNA damages

2. Pro-inflammatory cytokines  impaired

mitochondrial functions

B. Mitochondrial defects from other causes C. Genetic mitochondrial defects

Beyond the serotonin hypothesis: mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Gardner and Boles 2011, Prog Neuropsychopharmacol Biol Psychiatry 2011 Impaired mitochondrial function in psychiatric disorders . Manji et al., Nature Reviews Neuroscience 2012

Q :

Why are there significant %

of depression cases not

responsive to antidepressant

treatment?

University based clinicians and

researchers emphasized the

importance of accurately diagnosing

“Depression” for good reasons

In reality, Depressions : A mixed bag

Cases Not fulfilling

DSM Diagnostic criteria Mixed features;

Unhappiness May or

May not respond to antidepressants

DSM but

Resistant cases

DSM & Rx

responsive cases

Q:

Only those fulfilling the DSM/ICD

Diagnostic criteria should go on

antidepressants?

or, Depression is only a symptom of a

variety of CNS/Mood/Cognitive

The Rippling Effects of

a Brain Disorder

The

Clinical Reality

after Initiation of

Rx

Current Antidepressant treatable

Augmentation needed

Incomplete response cases

However, Current Antidepressant drugs induced remission in a significant % of

depressed cases

Common Scenario

1

drug

~ 30-60 % patient responded

~ 10 % patient of the remaining responded 3rd _drug

~ 2- 5 % of remaining responded

Adding another drug to existing : ~ 5 -10 %

Though Resilience factor remains a difficult and significant problem when facing adversity

Or, perhaps after all, Depression

is only a symptom of a variety of