Damage Control

May 01, 2006

Damage can take biologic, syndromic, social, and personal form, with correlations among the various levels of damage.

"Depression is the inability to construct a future.”-Rollo May

I spent the winter weekends of 2006 preparing 2 new series of lectures for our fourth-year psychiatry residents. One set of talks covered advanced psychopharmacology and the other set, humanities and psychiatry. The superficially parallel process of these 2 historically separate domains created a mild form of cognitive dissonance that when entertained, blossomed into new connections between the neurobiologic circuits of mental illness and their existential expression in the suffering of patients. One particular unassuming passage in a review of antidepressants and mood stabilizers crystallized these connections:

"In animal studies, repeated stresshas been shown to decrease levelsof BDNF [brain-derived neurotrophicfactor] mRNA [messenger RNA] inthe hippocampus. Conversely, studieshave shown that the display of 'behavioraldespair' in the forced swimtest can be alleviated by midbrain infusionof BDNF."1

Behavioral despair

The image of behavioral despair, evenif it was in the forced swim test of alaboratory rat, metaphorically capturedthe hopelessness and helplessness of thehundreds of depressed patients I treat.In this sterile experimental description,I saw the agonized nurse who, as a child,had found his father after he committedsuicide. Now, contemplating thebreakup of his fourth marriage and theimpotence of a plethora of psychosocialand pharmacologic treatments, he seemsdestined to repeat his parental demolitionin a tragedy as ineluctable as thatof Oedipus.

In the emotion of the denuded phrase"repeated stress," I felt the desperationof the woman who, after being sexuallyassaulted years earlier in the militaryand finally obtaining some measureof healing, was again violated andpleaded on the phone with me shortlyafter the rape to "give [her] just onegood shot of morphine to take the painof life away." I kept reading this paragraphagain and again, as I moved fromintellectual insight regarding the deepseateddestruction of serious mentalillness to a compelling sense of moralurgency and an even spiritual recommitment to my clinical mission ofdamage control.

Multilevel damage

In this essay, I will first explore theconcept of damage at multiple levels—biologic, syndromic, social, and personal—and our growing understandingof their correlations. My next columnwill turn to exciting new developmentsin psychopharmacology that hold thepromise of managing, and even repairing,this ruin. I will argue that thesescientific advances herald a reconfigurationof the philosophy of psychiatricpractice as a vigorous and empathicform of damage control. To delineatethe concept of damage control andbecause patients with mood disordersare the core population I treat, I willfocus primarily on unipolar and bipolardepression, while remaining consciousof the presence of even moredevastating disorders, such as dementiaand schizophrenia.

Emerging evidence from brain imaging,animal studies, and psychometrictesting converges on the dramatic andpreviously neglected points of howdepression corrupts genetic processes,depletes neurotransmitters, alters neuralfunctioning, distorts neuroarchitecture,and ultimately destroys neurons. Thisdestruction is found in the crucial areasof the brain that govern emotion, cognition,endocrine homeostasis, andvitality and thus provides a link to thesyndromic manifestations of poor concentration,depressed mood, insomnia,anhedonia, and even the psychic markersof guilt and pessimism.2,3

For example, one of the most replicatedfindings in depression is hypercortisolemia,particularly in the prefrontalcortex.4 These elevated cortisol levels, found most often in severe ormelancholic depression, may be relatedto reductions in hippocampal volume.Other studies show that there is a baselineincrease in activity and a correspondingdecreased responsiveness tostress in the amygdala and ventral striatum,areas that modulate emotion,psychomotor systems, and pleasurepathways. There are even suggestionsthat the loss of neuronal tissue is associatedwith the duration of untreateddepression.5

Persistence of deficits

What is even more disturbing is newlyemerging evidence that cognitive deficits in particular may persist even intoeuthymic states. While most biologicpsychiatrists readily accept that depressioncauses brain injury during moodepisodes, even we have been ignorant,or perhaps in denial, that this damagepersists into what is clinically deemedremission and recovery.6 This challengesKraepelin's classic and longliveddistinction that only dementiapraecox and not manic depression hasa degenerative trajectory.

These neurobiologic underpinningsand their clinical articulates eventuatein the social and economic disturbancesall too familiar to psychiatric patientsand their providers and families: transgenerationalabuse, unemployment,homelessness, lack of education, andfailed domestic partnerships. Simon,7in a recent review, underscores the resultsof numerous cross-sectional studies that show large decrementsin the qualityof life of patientswith both unipolarand bipolar depression.This decline infunctioning is specificallydeleteriousto the emotional andsocial spheres that provide meaning andfulfillment.

In my own practice, healthy and lastingrelationships are the exception—this being an individual observationunfortunately supported by research.Statistical modeling of National ComorbiditySurvey data finds that prior psychiatric disorders are significantlyassociated with a higher risk of divorce,amounting to approximately 23 millionlost years of marriage among men and48 million lost years for women in theUS population in the age range coveredby the survey.8

The most poignant testimony to theburden that families of depressedpatients bear is a survey of patients withbipolar disorder and their spouses regardingtheir attitudes toward marriageand childbearing. Fifty-three percent ofthe spouses, in contrast to 5% of thepatients, would not have had childrenif they had known more about bipolardisorder.9

A poignant coda to these results occurredseveral months ago, when one ofmy patients with bipolar disorder cameto the clinic after having been almost beaten to death by his own depressedson, who refused treatment. The father,despite his injuries, begged the districtattorney not to sentence his son to prisonbut to mandate therapy.

Finally, there has also been an increasinginterest, partly economicallydriven, in the adverse effect of mooddisorders in the workplace. A 2002national survey found a 40% reductionin paid employment for those respondentsreporting a diagnosis of bipolardisorder.10

Epidemiologic and clinical recognitionof the enormous human andeconomic costs of psychiatric disordersis not a new discovery. What is unprecedentedis our ability to link neurobiologicdeficits to social impairmentsthrough the pathway of clinical signsand symptoms. The Table outlinesexamples of this integration of levelsof damage. Not only is there verticalmultiplication of the destructive sequelaeof mood disorders in a cascade fromcellular to societal, there is also verticalamplification of harm.

Frontal cortex deficitsAmotivation, cognitive impairmentUnemployment, educational underachievementLoss of purpose and self-esteem
Frontal cortex deficitsAmotivation, cognitive impairmentUnemployment, educational underachievementLoss of purpose and self-esteem


The hypothesis of kindling suggests thatwith each episode of depression (ormania, for that matter), the brain, like aloaded spring, is more tightly woundand thus, more easily and forcefullyresponds biologically to ever-weakerperturbations of the psychosocial dimension.Over 3 years, clinicians rated 258outpatients on the National Institute ofMental Health Life-Chart method. Anaverage of 4.1 psychotropic drugs wereprescribed for each patient. Despite theadequacy of pharmacotherapy and treatmentin specialty clinics, patients weredepressed 33.2% of the year; 62.8% ofpatients had 4 or more episodes per year;two thirds of patients were substantiallyaffected by their illness; and more thana quarter were ill for more than 9 monthsof the year.11

Clinically, kindling translates intoa course of affective disorder that appearsto increase in frequency, duration,severity, and treatment resistance witheach and every episode.


The noncomplianceand substance abuse soprevalent in patients with mood disordersonly accelerate this malignantcourse of disease, which reaches its nadirin rapid cycling.


While the content of this column mayat first seem oppressive and its messagedemoralizing, religious teachers of alltraditions have long known that therequisite prelude to healing is an austereinventory of distress. I encouragereaders to join me for the next essay,in which I will review the burgeoningevidence that our everyday antidepressants and old standby lithium maypossess the futuristic properties ofneuroprotection and neurogenesis. Farfrom being discouraging, the potentialfor the psychiatrist in his or her officeto intervene at the molecular level notonly to control but reverse the proteandamage of depression both signals andsummons us to an unparalleled galvanizationof our professional duty to patientswith putative chronic andpersistent mental illness.

Dr Geppert is chief of consultation-liaisonpsychiatry and chief ethics consultant at NewMexico Veterans Affairs Health Care System,Albuquerque. She is also assistant professorin the department of psychiatry and associatedirector of religious studies at the Universityof New Mexico, Albuquerque.



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