How Stress ProducesMajor Depressive Disorder

How Stress ProducesMajor Depressive Disorder

Ron Sterling, M.D.December 12, 2006

www.MindMatters.wswww.Hippocampus.us

www.BellevuePsychiatry.com

Conflicts of Interest StatementConflicts of Interest Statement

This presentation contains many referencesto medications. I should note that I am neithera “pill pusher” nor a “therapy pusher.”Additionally, I have no financial interest in anymedical supply or pharmaceutical company,nor do I accept or utilize medication samplesin my practice. I do not allow myself to visitwith or be influenced by drug companyrepresentatives and I receive no gifts or otherbenefits from any pharmaceutical company.

AcknowledgmentsAcknowledgments

I am not a research scientist.Data, concepts and other materialpresented in this lecture come primarilyfrom research papers and writings that areposted on the Internet.I particularly acknowledge a colleague inCorvallis, Oregon, Jim Phelps, M.D., whois responsible for a very informative Website at PsychEducation.org.

Objectives of PresentationObjectives of Presentation

Learn new acronyms..... heehee... CRF,HC, BDNF, SSRI, and others!Learn long “chemical” names like brainderived neurotrophic factorUnderstand neurotransmitter functionLearn about significant aspects of thebiological basis of major depressionLearn about sunny, pink, and blue people

What Major Depression is NotWhat Major Depression is Not

It’s not a bad hair day....

It’s not your average reaction to a minorloss, which is more short-lived.

It’s not usually part of a more majorloss, or the grieving process associatedwith it.

Depression as a SymptomDepression as a Symptom

The mood of depression can exist inmany disorders including:– Major Depressive Disorder– Bipolar Disorder– Posttraumatic Stress Disorder– Dysthymia– Adjustment Disorder– Substance abuse disorders– Other medical conditions (diabetes,

hypothyroidism, Parkinson’s, etc.)

What is Major Depression?What is Major Depression?

Major Depressive Disorder (MDD) isdescribed and defined in a book calledthe Diagnostic and Statistical Manual ofMental Disorders 4th Edition (DSM4).In the DSM4, there are several MDDDisorder categories such as singleepisode, recurrent, mild, moderate andsevere. Severe may have psychoticfeatures.

What is Major Depression?What is Major Depression?

The diagnosis of MDD requires– Five (or more) of the following symptoms

have been present during the same 2-weekperiod and represent a change fromprevious functioning; at least one of thesymptoms is either

– (1) depressed mood or– (2) loss of interest or pleasure.

5 needed (nearly every day)5 needed (nearly every day)(1) depressed mood most of the time, most every day(2) markedly diminished interest or pleasure in daily activities(3) significant weight loss when not dieting or weight gain, orappetite loss(4) insomnia or hypersomnia(5) psychomotor agitation or retardation (observable by others)(6) fatigue or loss of energy(7) feelings of worthlessness or excessive or inappropriate guilt(8) diminished ability to think or concentrate(9) recurrent thoughts of death (not just fear of dying), recurrentsuicidal ideation without a specific plan, or a suicide attempt or aspecific plan for committing suicide

In Addition, for MDD, Note:In Addition, for MDD, Note:– The symptoms cause clinically significant distress or

impairment in social, occupational, or other important areasof functioning.

– The symptoms are not due to the direct physiological effectsof a substance (e.g., a drug of abuse, a medication) or ageneral medical condition (e.g., hypothyroidism).

– The symptoms are not better accounted for by bereavement.MDD can be a result of the shock of a significant loss and isthought of as “complicated bereavement” as opposed to a“simple bereavement.” MDD symptoms that persist for about2 months or longer and are characterized by continuingfunctional impairment constitute complicated bereavement.

Serendipity and ResearchSerendipity and Research

Note: Much of what we have learnedabout the biological bases ofdepression and antidepressantsoriginated “accidentally.”One early antidepressant was iproniazid(an MAOI), originally developed to treattuberculosis.Then came MAOIs, tricyclics, SSRIs,and SNRIs.

Threat Response SystemThreat Response System

“Flight or Fight” response to a threatHuman threat (stressor) response:– The brain releases CRF (corticotropin

releasing factor)– CRF travels to pituitary and triggers release of

ACTH (adrenocorticotropic hormone) whichtravels to the adrenal glands

– Adrenal glands secrete cortisol, epinephrine(adrenaline), and norepinephrine

Epinephrine and CortisolEpinephrine and Cortisol

Epinephrine increases heart rate andstroke volume, dilates the pupils, andconstricts arterioles in the skin and gutwhile dilating arterioles in leg muscles.

Cortisol increases blood pressure andblood sugar levels among other things.Unlike epinephrine, it can be damagingto the central nervous system.

The Relaxation ResponseThe Relaxation Response

After a perceived danger has passed, ourbody attempts to return to normal.Sometimes, this is not so easy and there isevidence that it becomes more difficult withage. Although the sympathetic nervoussystem jumps into action immediately, it isvery slow to shut down and allow thetranquilizing parasympathetic nervous systemto calm things down. Cortisol can stick aroundlonger than needed.

CRF, Cortisol, HippocampusCRF, Cortisol, Hippocampus

Perceived threats (stress) stimulateCRF. CRF not only produces theneeded human emergency response bygetting messages to the adrenals, but italso stimulates other parts of the brain.

Cortisol has been shown to be directlytoxic to hippocampus nerve cells.

Cortisol Damages HCCortisol Damages HC

Studies in rats have shown that thehippocampus of stressed rats areon average smaller andmicroscopic examination revealsthat there are far fewer dendritesand synapses than normal.

Importance of HCImportance of HC

Hippocampus (HC) helps with:

– Consolidation of new memories– Processing emotions, especially

emotional memory– Navigation– Spatial orientation

Emotion and MemoryEmotion and Memory

Emotion and memory are closelyrelated. For instance, after going to aparty, whose faces do you remembermost? The person who made youlaugh, made you embarrassed,complimented you, etc. -- in otherwords, the ones that had an emotionalimpact.

Known HC DamageKnown HC Damage

In Alzheimer's disease -- one of the firstregions to suffer damage resulting inmemory problems (especially newmemory) and disorientation.Evidence shows that the hippocampusin chronically depressed humans anddepressed rats is damaged.

HC’s Home -- Limbic SystemHC’s Home -- Limbic System

The limbic system (sometimes calledthe emotional system) includes thestructures in the human brain involvedin emotion, motivation, and emotionalassociation with memory.

Limbic system “old” part of brain, in allmammals and many reptiles

Some Limbic ComponentsSome Limbic Components

Amygdala: Involved in aggression, jealousy, and fearCingulate gyrus: Autonomic functions (heart rate,blood pressure), cognitive and attentional processingHippocampus: Required for formation of long-termmemories (emotional memories)Hypothalamus: Regulates autonomic system (bloodpressure, heart rate, hunger, thirst, sexual arousal,and sleep/wake cycle)Nucleus accumbens: reward, pleasure, addictionParahippocampal gyrus: formation of spatial memory.... and there is more... skip for now...

Limbic System and HCLimbic System and HC

The brain has two hippocampus areas just inside eachtemporal lobe on each side of the brain. Together theyare the hippocampus.

Lobotomy EvidenceLobotomy Evidence

Limbic system is tightly connected toprefrontal cortex. A very outdated method tocure severe emotional disorders, the“lobotomy,” was a surgical procedure thatsevered the connection. Post-operativepatients often became passive, lacking allmotivation. Many scientists concluded thelimbic connection to the cortex produces thepleasure humans obtain from solvingproblems (a very human trait).

Human & Rat HippocampusHuman & Rat Hippocampus

Dissection Showing Bilateral HCDissection Showing Bilateral HC

There are two HCstructures -- one oneach side ofthe brain, just insidethe temporal lobes.Together they are thehippocampus. (Thisview is looking downinto the brain fromabove.)

MRI - 3 Views of HCMRI - 3 Views of HC

Dark areas at greencrosshairs are the body of the hippocampus

MRI -- Temporal Lobe, HCMRI -- Temporal Lobe, HC

HC

Temporal lobe outlined in red

Neurons, Axons, DendritesNeurons, Axons, Dendrites

A neuron has a cell body with a central area (the largebulb) with larger stems which are called axons and thereare branches from both the body and the axons calleddendrites. Synaptic areas where nerve cells connectto each other can be found mostly on the dendrites.

Dendrites -- before and afterDendrites -- before and after

Picture of rat hippocampus dendrites, before and after.The right picture shows more spikes or buds off of thedendrites. This is from a research study of estrogeneffects on rat hippocampus dendrites.

Dendrites and SynapsesDendrites and Synapses

Synapses

Dendrites

Vulnerability to CRF, CortisolVulnerability to CRF, Cortisol

Some people are more vulnerable tostress than othersSome rats are more vulnerable to thestress than othersWe can study the rat hippocampusmuch more easily. What do we know?

Rats, Prozac, and ExerciseRats, Prozac, and Exercise

You can’t stress damage thehippocampus of a rat on ProzacYou can’t stress damage thehippocampus of a rat who getsconsistent exerciseYou can repair a damaged rathippocampus with ProzacNot clear if exercise alone can repair adamaged hippocampus

How does repair take place?How does repair take place?

The hippocampus is one of the very fewparts of the brain where nerve cells canrepair and regrow (neurogenesis)Repair can be stimulated by manyantidepressants (not just Prozac) but noother medications that we yet knowRepair is mediated by an intracellularhormone called brain derivedneurotrophic factor (BDNF)

BDNFBDNF

Discovered during neural developmentstudies in animalsAssists survival of existing neurons, andencourages growth and differentiation of newneurons and synapsesKnown to be higher in rats who are givenProzac or who exercise consistentlyLower in humans with MDDProtects hippocampus nerve cells fromdamaging effects of CRF and cortisol

BDNF -- Vulnerability Factor?BDNF -- Vulnerability Factor?

High BDNF produced by ingestion ofProzac or exercise protects againststress-related damageIndividual variation of BDNF may beone key to understanding why somepeople are more vulnerable to stress-induced hippocampus damage (MDD)

CRF Cortisol Dysfunction ExistsCRF Cortisol Dysfunction Exists

Early trauma such as abuse leads toapparent permanent changes– Increased number of CRF neurons are produced– Hypersensitive and increased CRF and cortisol

responsiveness– Thus, even mild stress can lead to exaggerated

CRF and cortisol responses– Chronic exposure to above-normal cortisol levels

leads to hippocampus damage– Hippocampus damage positively correlated to

MDD

What About Serotonin?What About Serotonin?

As you may know, Prozac and many othermodern antidepressants are called SSRIs- Selective Serotonin Reuptake InhibitorsThey increase serotonin in spaces outsidenerve cells by preventing nerve cells fromreabsorbing the serotoninNerve cells produce their own serotonin(mostly in synaptic areas)It is a neurotransmitter

What is a Neurotransmitter?What is a Neurotransmitter?

It is a chemical bridge between nerve cellsIt relays, amplifies and/or modulateselectrical signals between a neuron andanother cell, usually another neuron (nervecell)Many types of neurotransmittersVery specialized and often located only incertain parts of the brainSerotonin concentrated in limbic system

Types of NeurotransmittersTypes of Neurotransmitters

Serotonin - memory, emotions,wakefulness, sleep and temperatureregulationNorepinephrine - wakefulness or arousalDopamine - voluntary movement andemotional arousalAcetylcholine - voluntary movement of themuscles... and there is more... skip for now...

Neurotransmitter PathwaysNeurotransmitter Pathways

Diseases may affect specificneurotransmitter pathways. For example,Parkinson's disease is at least in partrelated to failure of dopamine producingcells to produce dopamine in thesubstantia nigra. Treatments whichincrease dopamine can alleviate somesymptoms (but have many side effectsbecause not all the “ingested” dopaminegets into the nerve cells)

“Reuptake” - What is it?“Reuptake” - What is it?

Once a neurotransmitter transmits theelectrical signal from one neuron to thenext neuron(s) it is reabsorbed by thesurrounding nerve cells so it can berecycled and so it quits transmittingFor serotonin, the system is called theSerotonin Transporter SystemThere are two genes that control theSerotonin Transporter

2 versions of transporter gene2 versions of transporter gene

Long gene and short geneLong gene has more potent manufacturingsignal -- in other words, it tells serotoninproducing nerve cells to make lots of it.The short gene is not as powerful.This leads to three groups of people --yellow [“sunny”] (two long genes), pink(one long, one short) and blue (two short)

Sunny, Pink, Blue... hmmm..Sunny, Pink, Blue... hmmm..

Research shows that it takes a lot ofstress to depress a sunny person (twolong genes) and not as much todepress a pink or blue personObviously, if you don’t produceserotonin well, you won’t have itavailable to process information with --transmissions will break down, chemicalbridges will be out

Do Meds Fix Low Production?Do Meds Fix Low Production?

Probably not.So, why does putting a lot of serotoninin the space between limbic nerve cellshelp? Wouldn’t that just confuseneurons? -- Disorganized, chaotictransmission, rather than targeted?It does -- many side effects of SSRIsprobably relate to that situation

So, What do SSRI Meds Fix?So, What do SSRI Meds Fix?

Most significant - many antidepressants(not just SSRIs) increase BDNF levelsIncreased BDNF repairs, grows, andprotects neurons from stress damageAND create more dendrites/synapses(increased sites of serotonin production)Probable reason why SSRIs don’tproduce significant changes for manyweeks or months (repair is slow).

BDNF and Production ProbsBDNF and Production Probs

The Serotonin production system is controlledby genes -- you either have good or poorproductionHowever, nerve cells produce most of theirserotonin in dendritic (synapse) areas ofneuronsGuess what, BDNF increases dendrite andsynapse density, so, production is increasedby having more sites for production(inefficient but numerous)

Medication for MDDMedication for MDD

Making the right choice is complexprocess. I can’t cover all aspects in onepresentation.It used to be that we thought thesignificant action of an SSRI, likeProzac, was to increase serotoninlevels -- a good thing, but if so, whydidn’t symptoms improve more rapidly?Now we know... repair takes time.

Role of Psychotherapy?Role of Psychotherapy?

Can you think yourself out of a majordepression? Probably not. It’s likebeing in a hole where more workproduces more stress which thenproduces more damage (used to betreatment consisted of long vacation atlocal sanitarium or similar)Understanding dynamics of MDD isimportant -- psychoeducation

Role of Psychotherapy?Role of Psychotherapy?

Once MDD is appropriately beingtreated with appropriate medication (nomean task), then work on learning howto reduce perceived stress (BIG role forpsychotherapy!)No MDD yet? If strong family history,psychotherapy might be very importantunless you just want to deal with theMDD when it arrives with medication

Risk of Waiting for MDDRisk of Waiting for MDD

When it arrives, it can be lethalWhen it arrives, it can really cause lotsof problems -- financial, marital, youname it...Prevention, as they say, is 9/10ths ofthe law (or is that possession?)... well,you know what I mean. A stitch in timesaves nine...

ConclusionsConclusions

Likely that individual baseline BDNF isgenetically determined (vulnerability)Low baseline BDNF may determinehigher vulnerability to stress-inducedhippocampus damage (MDD)Fix baseline vulnerability to stressdamage by increasing BDNF (severalantidepressants and exercise do it)

ConclusionsConclusions

Serotonin production system has significantgenetic control -- sunny, pink, and bluepeopleDon’t have a way to increase efficiency ofproduction but have a way to increase sites ofproductionLots of serotonin in space between neuronscreates side effects (must be tolerated to getthe desired effect -- increased BDNF)

The End. Some Books?The End. Some Books?

Since much of this information is fromrecent research, a lot of it is notshowing up in books yet, exceptprofession-related textbooks.Your best bet is to search atAmazon.com using “neurobiology ofdepression” and choose the mostrecent books.