depression the predisposing influence of stress .pdf

8/14/2019 depression the predisposing influence of stress .pdf

1/50


2/50


3/50


4/50


5/50


6/50


7/50


8/50


9/50


10/50


11/50


12/50


13/50


14/50


15/50


16/50


17/50


18/50


19/50


20/50


21/50


22/50


23/50


24/50


25/50

CommentaryI'Anisman & Zacharko: D epression and stress

The neurochemical concomitants of depression and stress.

A & Z note that depression has been associated with anorepinephrine deficiency, a serotonin deficiency, and de-ficiencies in other central neurotransmitters such as acetyl-choline and dopamine. Similarly, uncontrollable acute stresshas been found to lead to deficiencies in norepinephrine,dopamine (in some regions of the brain), and serotonin, but toincreases in the levels of acetylcholine.This proposed physiological basis for the stress-depressionrelationship raises several problems. First, some biochemicaltheories of schizophrenia (for example, Snyder 1974) are basedon the neurochemical concomitants of increased levels ofnorepinephrine and dopamine. Thus, schizophrenia anddepression are contrasting behaviors. It would be difficult(neurochemically) for both to occur at the same time in thesame individual. However, diagnoses of schizoaffective disor-ders imply an inability to distinguish between the two majorsyndromes of schizophrenia and psychotic depression. Fur-thermore, surveys of untreated psychotic depressed patientsoften report a high incidence of typically schizophrenic symp-toms (for example, Rennie 1942). However, leaving this prob-lem aside, if life-stress events are found to precede bothdepression and schizophrenia (Beck & Worthen 1972; Jacobs,Prusoff, & Paykel 1974), how do we explain the stress-schizophrenia association neurochemically?

Finally, the neurochemical concomitants of stress that arenecessary for the stress-neurotransm itter-depression associa-tion to be supported are found only for acute uncontrollablestress. At this stage of research, can it be dem onstrated that thestresses found to precede depression are acute and uncontrol-lable? For example, experience of early separation is found tobe frequent in depressed patients. Is early separation an acuteuncontrollable stress? Possibly yes. Could the reason thatdouble-bind communications may precede schizophrenia butnot depression be that double-bind messages are chronicstresses rather than acute stresses?

Stress a s a distal variable. Stress is an easy variable tomeasure at a distal level of analysis. That is to say, we cansubject a laboratory organism to an objectively defined stress,such as electric shock of a given duration and intensity. We canquantify the recent life-event stresses with a scale. But theintensity of a stress is clearly subject to individual perceptionsand evaluation. The death of a spouse is not 100 points of stressfor all widows and widowers. To measure the subjective levelof stress (a proximal variable) is more difficult, but it would bemore meaningful.

At this proximal level of analysis, the intensity of the stressand the type of stress as well as a knowledge of the type ofindividual, are critical. The stress of a promotion, for example,will be different in intensity and type for a person low inself-confidence than for a person high in self-confidence.

As long as research into stress stays at a distal level ofanalysis, it is likely that its incorporation into propositions willremain less than fully informative.

Schizophrenia, not depression, as a result ofdepleted brain norepinephrine

Stephen T MasonDepartment o f Physiology, The U niversity, Sheffield S10 2TN , England

Anisman and Zacharko (A & Z) suggest that stress maychallenge brain norepinephrine (NE) systems to the point thatthey fail, causing what Ritter, Pelzer, & Ritter (1978) haveelsewhere termed a "functional lesion." The question then iswhat sort of mental pathology would result. A & Z suggest that"depression may be a result of brain NE depletion." I haveelsewhere suggested that a more likely result is a subset of someof the symptoms seen in schizophrenia (Mason 1979a; 1981).

One way to decide what mental pathology would occur afterloss of brain NE function is to examine the behavio ral effects ofNE depletion caused in experimental animals by the neurotox-in 6-hydroxydopamine (6-OHDA). Rats injected bilaterally inthe dorsal NE bundle with 4 fig of 6-OHDA dissolved in 2 /ulof saline-ascorbate solution show depletions of more than 95%in the NE content of the cortex, hippocampus, and other

forebrain areas (see Mason & Iversen 1979). These animals,when examined behaviorally, show unimpaired learning ofmany simple tasks (Mason 1979b) but are resistant to extinction(Mason & Iversen 1975) so that they continue responding inthe face of contrary environmental influences. Such NE-depleted rats are only impaired in learning complex tasks, suchas a multiple choice-point maze (Leconte & H ennevin 1981) orvisual-discrimination tasks and their reversals (Mason & Iver-sen 1977). Similar alterations in complex cognitive processingwithout global learning deficit have also been seen in primatesfollowing alpha-receptor blockade with aceperone (Ridley,Haystead, Baker, & Crow 1981).

One analysis which accounts for these behavioral deficitssuggests that NE depleted rats are deficient in filtering outirrelevant environmental stimuli. This is the attentional model(Mason 1980) based on the notions of a Broadbent selectiveattention fi lter (Broadbent 1958) and its detailed application torodent discrimination behavior (Mackintosh 1965; Sutherland1964). Rather than attempt to review here the extensiveevidence implicating NE in selective attention, I refer thereader to Mason (1980; 1981) for a rigorous treatment.

A pathology of attentional processes has often beensuggested in the history of theory of schizophrenia. Kraepelin(1923) noted that patients let their thoughts wander withoutvoluntary control in the most varied directions" and showed"an irresistible attraction of the attention to casual externalimpressions." Failure to filter out irrelevant stimuli leadsschizophrenics to show overinclusive thinking and an inabilityto preserve the conceptual boundaries which normally act toexclude distantly related material (Cameron, 1938a; 1938b;1939a; 1939b). On object-sorting tasks schizophrenics includemore attributes of the objects than normals (Payne & Friedlan-der 1962; Payne, Ancevich, & Laverty 1963).

NE-depleted rats are more distractable by external stimulithan normals (Roberts, Price, & Fibiger 1976; Mason &Fibiger 1978a), and this parallels similar reports on enhanceddistractability in human schizophrenic patients (Chapman1956; Salzinger, Portnoy, & Feldman 1966).

NE systems project to many sensory relay stations and play adirect role in reducing transmission along these pathways.Thus, NE projections to, and alteration in transmission across,the lateral geniculate nucleus in the visual system (Nakai &Takaori 1974), the dorsal cochlear nucleus in the auditorysystem (Chikamori, Sasa, Fujimoto, Takaori, & Matsuoka 1980)

and the trigeminal nucleus in the somatosensory system (Sasa& Takaori 1973) have been reported, as well as changes inolfactory (Sobrian & Cornwell-Jones 1977) and pain processing(Segal & Sandberg 1977). This raises the possibility that thehallucinations of schizophrenics may be due to the penetrationinto sensory systems of random noise which would normallyhave been filtered out by NE systems.

The resistance to extinction seen in rats after forebrain NEdepletion (Mason & Iversen 1975) parallels the behavioralinflexibility of schizophrenic patients and is truly a cardinalfeature of the NE-depleted rat (as shown by Thornton, Goudie,& Bithell 1975; Tremmel, Morris, & Gebhart 1977; Owens,Boader, & Gray 1977; Plaznik & Kostowski 1980; and Ashford& Jones 1976). This generally consists of continued respondingwhen reward is withdrawn (but see Mason & Fibiger 1978b;1979). While the analogy with schizophrenia is clear, suchinappropriate overresponding would not be thought to be asign of depression.

THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5 113


26/50

Commentary /Anisman & Zacharko: Depression and stress

Space prevents a more inclusive exposition of the parallelsbetween human schizophrenia and the behavior of NE-depleted rodents, but reference may be made to Mason (1979a;1981). Despite the many dangers of extrapolating from animalto human behavior, it does not appear that NE depletion givesrise to a "depressed" rat. Lest the motor depression, failure ofgrooming, rearing, and, forward motion seen in early reports of6-OHDA treatment (Everts, Uretsky, Iversen, & Iversen 1970)be invoked, let it be stated that these effects are now acknowl-edged to be due to dopamine, not NE, loss (Smith, Cooper, &Breese 1973).

Surely, it has been argued, the fact that classical antidepres-sants, such as the tricyclics, block NE reuptake and henceincrease th e availability of NE in the synapse indicates that thebasic pathology in depression is a deficit in NE function.Recent work has suggested that additional effects of thesedrugs may correlate more closely with the time course ofclinical action. Thus, a downward regulation of postsynapticbeta receptors has emerged as a common effect of manyantidepressants (see review by Maas & Huang 1980). The ne teffect of the opposed processes of a block of NE inactivation byreuptake an d fewer NE receptors postsynaptically is lesstransmission through the NE system. This has been shownelectrophysiologically by Huang (1979) and Huang & Maas(1980) for the final effect on the postsynaptic activity ofhippocampal cells; the behavioral effect has been demonstratedin Sue Iversen's laboratory by Wilner & Montgomery (1980) fora behavior known to be under the control of the final outputfrom NE systems, the rate of runway extinction.

In this view depression results from an overactivity of NEsystems. On the selective-attention model of NE function thiswould be exactly what might be expected from such anoveractivity of NE systems. The patient is actively filtering outmost environmental stimuli, including those which by previousassociation with reward have acquired secondary reinforcingvalue. Thus, a decrease in well-being will occur as a result of

"secondary-conditioned anhedonia" - that is, a failure of thepleasurable stimuli of life to get through.A & Z suggest that mild stress may increase NE function -

and that perhaps this would be a suitable stimulus to precipi-tate depression; but more severe or inescapable acute stress,which depletes NE causing a "functional lesion," would seemon the above data more likely to give us a schizophrenic, rathe rthan a depressed, patient.

Coping, depression, and neurotransmitters

William T. McKinney, Jr.Department of Psychiatry, University of Wisconsin Medical School, Madison,Wis. 53706

In their target article, Anisman and Zacharko (A & Z) attemptto review the stress-depression literature in humans, thelearned-helplessness controversies, the neurochemical con-comitants of depression in humans, and the neurochemicalconcomitants of stress in animals. As they state in theirabstract, they are proposing that stress, especially uncontrolla-ble stress, increases the demand on coping mechanisms andspecifically leads to depletion of norepinephrine and serotoninand that these changes may be the mechanism whereby stressprovokes depression in humans. Each of these represents largeand complex research areas, and it would be impossible in onearticle comprehensively to review any one of them, let alone allof them. A & Z's attempt is to bridge research areas. I considerthis a worthy goal and a particularly important one with

illnesses as complex as depressive illnesses. The task of bridg-ing these areas is particularly difficult because of the shiftingfoundations available for the bridg es. Each of the basic areas isstill in considerable flux. It is, therefore, not surprising thatthere are omissions, and I will mention only those I consider

major. There are some strong points which I will also highlight.There is by now considerable evidence linking certain kinds

of life events and depression in humans. The studies are notentirely consistent and there are some methodological prob-lems, but the trend is clear. Obviously this does not mean thatall persons experiencing such events will develop clinicaldepression or that all patients with depression have a history ofsuch events. Also, it is not a matter of "stress" in a generalsense, and hence the use of this word in the title is unfortunate.Certain classes of events, i.e., separation or exit-type eventsare particularly high-risk events. A & Z do acknowledge this inthe target article. These aversive events probably act toprecipitate depression in vulnerable individuals. Vulnerabilitycan be defined on a number of grounds including genetic,developmental, neurobiological, and environmental. We needmuch more data to further define the relative contributions ofeach of these factors (and others) in determining vulnerability.

There is an unfortunate tendency in some quarters to viewmajor depressions as largely unrelated to environmental orinterpersonal events. Dogmatic assertions are made that thereis no connection between (for example) separation and depres-sion. Such statements are made in the context of genetic andneurobiological theories of affective disorders, and of the factthat most people, when subjected to aversive life events,develop grief reactions but not clinical depression. The latter istrue but does not mean that certain life events cannot be majorprecipitating events when interacting with vulnerability fac-tors. One such factor may be the inability to cope, i.e., thefeeling of helplessness. Another may be a genetic predisposition,but I will not focus on this aspect in this commentary.

To supplement A & Z's article, one could ask what makespeople unable to cope. Theoretically, if people could cope thesubsequent neurochemical changes and resultant depressionwould not occur. In rare instances, the event itself may be sooverwhelming that coping is impossible for anyone, (e.g.,widespread slaughter). However, in most instances, feelings

of helplessness and hopelessness in the face of "stress" aredevelopmental in origin. I use "developmental" here in apsychodynamic sense. It is not a negative criticism of A & Z'sarticle to say that this wasn't covered, because that was not itsstated purpose. However, to understand more fully the"stress-failure-to-cope-neurobiology-depression" linkages,one should also understand some psychodynamics. Tooversimplify, feelings of inability to control events andfeelings of helplessness in the face of stress arise from failure todevelop adequate ego identity or self-esteem in the process ofdevelopment, i.e., an adequate appreciation of one's self andconfidence in one's ability to cope. Without this, one is morevulnerable to certain stressors.

One of A & Z's important points is that depressions shouldno longer be classified in terms of the presence or absence ofenvironmental precipitants. I agree. In integrating theorieswhich we and others have presented elsewhere, depression(s)can be viewed as the final common pathway(s) involvinginteractions among many different kinds of variables. In thiscontext, the contribution of life events is independent of thekind of depression. They do or do not occur in any kind ofdepression. A heavily "endogenomorphic" depression can (orcannot) be precipitated by aversive events as much as a milder"neurotic" one. An emerging body of literature, some of whichis reviewed in A & Z's article, is beginning to identify in animalmodels neurochemical sequelae of certain stresses that mayalso serve as important substrates in depression.

There is nothing new in the part of this paper that deals withthe neurochemical concomitants of depression. This is by farthe weakest section of the paper, but, on the other hand, it isnot intended as the paper's major contribution. This article,like too many other reviews, focuses excessively on norepineph-rine and serotonin and gives only lip service to other neuro-transmitter systems. For example, newer developments in the

114 THE BEHAVIORAL AND BRAIN SCIENCES (1982) 5


27/50

Commentary/Anisman & Zacharko: Depression and stress

field, such as sleep studies, neurophysiological data, neuroen-docriiK- challenge tests, and circadian rhythm studies, are noteven mentioned. The concept that 5-HT depletion may notdirectly cause depression but may be a predisposing factor forthe illness is credited to van Praag and deHaan (1980). Prangeet al. (1974) were major contributors to the developmen t of this"permissive hypothesis."

The most interesting aspects of A & Z's paper concern theneurochemical concomitants of stress. A & Z highlight thevariable of uncontrollability and show how a variety of animalstudies suggest that uncontrollable stress in animals can de-plete NE, 5-HT, and DA and increase ACh. However, A & Zfrequently fail to make clear which species of animal is beingdiscussed. Interestingly, these effects are age-related, beingmore pronounced in older animals. Likewise, the fact thatprior experience with uncontrollable stress can sensitizeneuroehemical systems to subsequent stress provides cor-roborative evidence for our clinical experience and data withdepressed patients.

Behavioral coping mechanisms in humans can fail if thestress is severe enough, but they will fail more frequently forpersonality-developmental reasons at stress levels which don'taffect o thers . N eurobiological changes seen in depression couldbe viewed as derivative or secondary phenomena in thiscontext. This does not mean that they are unimportant assubstrates, but it does mean that their etiologic significance isthat of mediating mechanisms. In other situations it is likelythat the status of the neurotransmitter systems at the time thestress is encountered may influence one's ability to cope ratherthan the lack of coping driving the neurotransmitter systems.In other words, the arrows can go both ways. The status ofneurotransmitter systems may, in turn, be determined by acombination of genetic and developmental events. We do notyet comprehend, and certainly do not have adequate data,about these various theoretical possibilities. From a therapeu-tic standpoint, the implication is that both pharmacotherapy (orelectroconvulsive therapy) combined with some kind ofpsychotherapy focused on personality/developmental/interpersonal coping strategies is critical. It is interesting towonder how much of the differential neurochemical reactivityto different kinds of stress could be altered by attention to howthe person behaviorally/cognitively/intrapsychically deals withstress. Adaptive failures can occur for behavioral or neurochem-ical reasons and could potentially be reversed by either means.

We all need to continue to struggle with the development ofconceptual models that will help integrate multiple levels ofexplanation for illnesses as serious as depressions and serve as abasis for future research. Closed-system or deterministic ex-planations are no longer sufficient to explain such a complex setof illnesses.

Stress as activation

Robert Murison and Holger UrsinInstitute of Physiological Psychology, University of Bergen, 5000 Bergen,Norway

Anisman and Zacharko (A & Z) have provided us with a usefuland long overdue review of the putative relationship betweenchanges in brain chemistry and clinical depression, and alsowith a comprehensive summary of the animal literature on theneurochemical effects of aversive stimulation. In bringingthese two areas together, they have also emphasized theimportance of the subject's previous history and experiences asfactors which may determine the response to later aversivesituations. This seems to us to be a praiseworthy extension of abasic psychosomatic concept into the field of neurochemistry.

With regard to the definition and use of the term "stress,"however, A & Z seem to have added to the general confusionrather than resolving the issue. In their definition, they state

that "stress will be considered the behavioral and physiologicalresponse to actual or impending stimuli." Throughout the bodyof the paper, however, the term is clearly used to refer to thestimulus situation rather than to the response elicited. Thisinconsistency is particularly surprising in view of the authors'stated awareness of the problems of definition.

A & Z write that they know of no adequate definition ofstress. A major problem here is that the word has acquirednegative attributions, which are also implicit in the way theseauthors use the concept. The assumption that stress is bad foryou, an assumption which is implied in modern work-environment legislation, leads inevitably to several paradoxicalsituations. Most, if not all, individuals seek stress in some way,whether it be by climbing mountains or by visiting amusementparks. More constructive discussion might be encouraged bydisposing of the word altogether.

Stress as described by Selye (1936) is a nonspecific responseof the organism to diverse novel or threatening stimuli. Thisclassical definition demands a nervous substra te which receivesinputs from all peripheral sensory systems and from centralprocesses. The general-activation theory of Moruzzi andMagoun (1949) describes just such a system. The brain stemreticular formation receives inputs from peripheral and centralsources and produces EEG activation as well as muscular,autonomic, and behavioural changes. From our point of view,the response aspect of the term "stress" may be replaced by th econcept of general activation. Similarly, the stimulus aspects ofstress may be described as any stimulus that produces generalactivation in the organism. In general, activation is the re-sponse to any stimulus that has properties of novelty, threat orconflict, or homeostatic imbalance. Whenever the actual valuediffers from the set value of any variable controlled by thecentral nervous system, activation will occur (see Ursin 1978for an expansion of this argument).

The general-activation concept has fallen into some disre-pute because of the lack of correlation between differentpsychophysiological indices commonly u sed. This lack of corre-lation between classical psychophysiological indices shouldhardly be surprising in view of the fact that most are duallyinnervated, by the sympathetic and parasympathetic nervoussystems. However, the endocrine system is also involved inactivation, and the relatively recent development of inexpen-sive and reliable assay techniques for various hormones maypresent us with a new opportunity in this area.

It follows simply from general-activation theory that thestress response is general and nonspecific, and that there is awide choice of somatic and endocrine indices that could beused as a measure of "stress." The simplest operational defini-tion of stress, therefo re, is that it is the process which producesa change in your own favorite physiological parameter. How-ever, confusion will be avoided if it is realized that, whichever

measure is chosen on practical and theoretical grounds, it isonly one of many possible indicators, and not necessarily themost interesting from the pathogenic point of view. Thisprocess will also affect brain neurochemistry, and it is thesechanges which A & Z refer to as the stress response. Theproblem , however, is to be able to describe precisely when thisprocess is healthy and when psychological or physiologicaldamage may occur.

The physiological response (activation) provides the animalwith the motivation or drive to cope with its environmentappropriately. The stress response is therefore as important tothe individual's well-being as is the ability to perceive pain,although in acute situations it might be associated with a strongnegative affect. At the same time, data from sensory-deprivation studies and the common phenomenon ofsensation-seeking behaviours indicate the rpere positive as-pects of the stress response. Th ere are, however, such things asstress-induced diseases, and many psychosomaticists wouldargue that there are few disorders which are not precipitated



28/50


by the stress response, or affected by earlier stressful experi-ences. Stress-induced disease will occur when the activation issustained, i.e., when activation-dampening mechanisms fail tocome into play. We believe that sustained activation is also theimportant variable for the A & Z model of depression, and wealso agree with them that coping is one way to avoid thepathological effects of stressful situations. The question is whycoping should protect the individual.

Coping may be operationally defined in terms of the sub-ject's endocrine response (activation) to repeated exposure tothe stress stimulus. It is important, therefore, that the indi-vidual not only master the situation, but that he also perceivehis own mastery. When animals or humans have learned thatthey have mastered the situation, they exhibit a decline in theirendocrine response to subsequent exposure, this decline beingnot necessarily correlated with improved performance(Coover, Ursin, & Levine 1973; Berger, Starzec, & Mason1981: Ursin 1978). On the other hand, if an animal learns thatthere is no way to control aversive stimulation, subsequentexposures lead to sensitization of the adrenocortical response,not only to the aversive stimulus but also to novel environ-ments (Levine, Madden, Conner, Moskal, & Anderson 1973).This may have consequences for the somatic effects of laterstress stimuli (Murison & Isaksen 1980).

As an alternative to coping, the human subject may employpsychological defense mechanisms. Whereas coping occursover several trials, defense mechanisms operate at first expo-sure to the stress stimulus and involve perceptual distortion ofthe situation. Whereas coping leads to stable performance withminimal activation, the operation of psychological defenses hasits own hazards in terms of reliability and safety. High scoreson defense tests (Kragh 1960) are pred ictive of poor and unsafeperformance in parachutists (Ursin, Baade, & Levine 1978) anddivers (Vaernes 1981). High scores on the Kragh test alsocorrelate with the cortisol factor in the subjects' endocrineactivation response to stress stimuli (Ellertsen, Johnsen, &Ursin 1978). Other studies have suggested a relationshipbetween cortisol and depression (Carrol, Curtis, & Mendels1976). There is therefore some evidence for a connectionbetween psychological defense and depression via the cortisolresponse. H owever, th e widespread use of one-hormone/one-symptom studies should make us proceed with caution.

The sustained-activation hypothesis for psychosomatic dis-ease (Ursin 1980) and the model for depression described by A& Z are clear in their predictions of no pathology when thestress stimulus either is short-lasting or can be coped with.Danger occurs when the aversive situation is chronic and nocoping occurs. The symptoms displayed will be a function ofthe predominant factor in the individual's activation pattern.If the predominant factor in the individual's activationresponse is catecholamine as measured in urine, one mightexpect the main effect to be on the cardiovascular system. If,on the other hand, the main factor is that of NE (norepineph-rine) utilization in the brain, one might expect the main effectto be one of clinical depression. The important point is that thecommon process for depression and psychosomatic diseases issustained activation, and it is this process which needs to be de-scribed and used instead of the misleading and unclear "stres s."

Documenting the association of stress (orstressors) with depressive illness

Richard NeugebauerGertrude H. Sergievsky Center Faculty of Medicine, Columbia University;Epidemiology of Brain Disorders Department, New York State PsychiatricInstitute, New York N.Y. 10032

Investigators concerned with physiological (and, specifically,neurochemical) consequences of stress, with psychosocial risk

factors for illness, and with the biology of psychiatric disord ers,often make merely token gestures toward a synthesis ofresearch findings from these three fields. Confronted with thewealth of publications in each area, this course is only p rudent.Consequently, Anisman and Zacharko's (A & Z's) attempt tolink stress with depressive illness by means of catecholaminehypotheses of depression is laudable for its courage and is amost welcome stimulus to debate and future research. Unfor-tunately, the authors' daring is not always matched by theirrigor. Their exposition suffers, at times, from ambiguous andinconsistent terminology and from incompletely elaboratedcausal sequences. In addition, they never satisfactorily arguethat stress is strongly implicated as a risk factor for clinical depression.

The causal sequence proposed by A & Z begins with stressand concludes with depression. But what is "stress"? A & Z'sdefinition advises us that "stress" represents "the behavioraland physiological response to actual or impending aversivestimuli, ' whereas "stressors" refer to "personal life changes."In other words, "stressors" constitute phenomena occurringoutside the organism; "stresses" constitute internal organismicchanges. While this distinction seems serviceable enough, it ispromptly ignored in the text proper. Thus, retrospectivelife-event studies in which depressed patients and nonde-pressed controls are interviewed regarding stressful occurrencesin the period preceding the onset of the illness or the date ofinterview are said to assess "stress history" in the two groups ofsubjects. No. They measure "stressor history." A similarmisnomer appears in the remarks on prospective studies.Implicitly equating stressors with stress while explicitly distin-guishing between them misrepresents the true causalmechanisms examined in these studies and thereby obscurestheir potential contribution to an understanding of the psy-chosocial origins of psychiatric illness. In general, these nonex-perimental investigations look for an association between re-cent routine life events and depression. Let's assume for themoment that their findings of a direct association are valid.Then, if A & Z elect to enlist these studies in the service oftheir argument, they must first address the question of howstressors, such as life events, are related to stress. Do stressorsproduce stress always, usually, or only sometimes? If onlysometimes, the authors' model, to be compelling, shouldinclude personality or social characteristics that attenuate oraugment the ability of given stressors to provoke stress.

A & Z aim at a behavioral and neurochemical model thatexplains the demonstrated association between stress (or stres-sors) and depressive illness. Readers are left in grave doubt,however, as to where, when, and by whom this relationshiphas been demonstrated. A & Z assemble some supportivecitations, only to demolish them with considerable acumen.Four types of studies are noted: (1) reports on the incidence ofaffective states in th e aftermath of catastrophic occurrences; (2)studies of exposure to stressful life events among depressedpatients and nondepressed controls, with data on patientexposure obtained after illness onset; (3) prospective studies ofillness experience among previously depressed patients ex-periencing varying levels of stress (really stressors); (4) experi-mental work involving the administration of minor contrivedstressors in an effort to simulate depression. No sooner arethese studies summoned than they are dismissed for concep-tual or methodological shortcomings. The value of the first andfourth types of studies is properly challenged because theyprovide only meagre information on the possible impact ofmundane stressors experienced in normal nonlaboratory set-tings. The validity of retrospective studies is sensibly ques-tioned because of the inadequacies and possible distortions inlife-event recall; a caution about prospective investigations isalso introduced. Given these shortcomings, A & Z fail to clarifywhy their synthesis and model-building efforts have beenlaunched at this time. Invoking a familiar arithmetic, they



29/50

Commentary IAnisman & Zacharko: Depression and stress

suggest that the replication of a positive association acrossnumerous studies, however imperfect, sums to a persuasivefinding. But it is well to remem ber that the consistency of suchresults may represent merely extended repetition of the sameerrors of design or measurement.

While A & Z dwell on problems of validity in retrospectivestudies, the reliability of life-event checklists is a psychometri-cally prior question and deserves some discussion. At leastfourteen reliability studies of life-event inventories have beenconducted (Brown & Birley 1968; Casey, Masuda, & Holmes1967; Horowitz, Schaefer, Hiroto, et al. 1977; Hudgens,Robins, & Delong 1970; Jenkin s, H urst , & Rose 1979;McDonald, Pugh, Gunderson, & Rahe 1972; Rahe, Romo,Bennett, & Siltanen 1974; Schless & Mendels 1978; Steele,Hend erson, & Duncan-Jones 1980; Thurlow 1971; Yager,Grant, Sweetwood, & Gerst 1981), with five using depressedpsychiatric patients as subjects. The median reliability level forthese studies was.43; only one result was above.60. (Amongthe nine other studies, only three reported levels above .70; themedian level for the remainder was around .40.) This very lowreliability of stressor measurement, combined with the consis-tently positive findings of a link between stressors and illnessepisodes in retrospective studies, suggests that this link is anillusion produced by recall artifacts or some other source ofbias. At the very least, these reliability investigations preclude,at present, any simple presumption that stressors increase therisk of depressive illness.

Prospective studies involving recall of quite recent events,using event interviews conducted prior to an illness episode,overcome many of the methodological hazards that plagueretrospective investigations. Unfortunately, few prospectivestudies have been conducted to date. A & Z cite the work ofPaykel and Tanner (1976) in support of the association ofstressors and depressive illness. However, the results ofanother prospective study with Bipolar I patients producedlargely negative results (Hall, Dunner, Zeller, & Fieve 1977).

In the absence of a persuasively argued and documentedcase for an association between stress (or stressors) and risk ofdepressive illness, readers may wish to postpone judgment onthe merits of the intriguing neurochemical and behavioralmodel proffered by these authors. As the sage John Seldenremarked not long ago, "The reason of a thing is not to beenquired after, till you are sure the thing itself is so. Wecommonly are at what's the reason of it? before we are sure ofthe thing" (Reynolds 1892, p. 161).

Stress, learning, and neurochemistry inaffective disorder

Katherine M. Noll and John M. Davis'Psychology Department, Bmhurst College, Elmhurst, III. 60126 and Research Department, Illinois State Psychiatric Institute, Chicago, III.60612

Before the advent of somatic treatments for depression andmania in the 1940s and 1950s, the vast majority of theoreticalapproaches to the etiology of the affective disorders involvedthe individual's psychological reaction to various kinds ofstressors. The success of somatic treatments, however, led to thepostulation of biological factors in these disorders. The simul-taneous elucidation of the catecholamine hypothesis of depres-sion by Bun ney and Davis (1965) and by Sch ildkraut (1965) wasfollowed by the indoleamine hypothesis (Lapin & Oxenkrug1969), and later by substantial evidence for the involvement ofACh (Janowsky, El-Yousef, Davis, & Sekerke 1972). As im-plied by Anisman and Zacharko (A & Z), these approaches havebeen seen as being in conflict with each other, and the recentcontributions of the behavioral and cognitive theorists (Abram-son, Seligman, & Teasdale 1978; Beck, Rush, Shaw, & E me ry

1979; Ferster 1973; Lewinsohn, Youngren, & Grosscup 1979)might appear to have further mudd ied th e picture. A & Z havenot mentioned one attempt to integrate some of the apparen tlycontradictory evidence, the "permissive" hypothesis of Prange,Wilson, Lynn, Alltop, & Stikeleather (1974), which postulatedthat depression and mania arose from fluctuations in functionalcatecholamine utilization superimposed on a chronic deficit inserotonergic function. Nevertheless, their attempt to coordi-nate a number of lines of reasoning and evidence and to showthat biochemical and psychological events can be interrelatedranks with the contribution of Depue and Monroe (1978;Depue, 1979) as a landmark. They have made a good ar-gument for the possibility that experience can effectneurochemistry. However, they have ignored the reciprocaleffect that altered neurochemistry may have on the individual'sperception of his experience, a sometimes circular interactionwhich makes cause and effect difficult to untangle. They havealso failed to comment on how neurochemical alterations mightinteract with each other, and how these might be related toother symptoms and symptom patterns seen in depression; norhave they co mm ented on the issue of differential diagnosiswithin the affective disorders. We would like to propose someways in which some of these effects might take place.

Behavioral (and, to some extent cognitive) theories ofdepression have been based on the individual's experience ofrewarding (pleasurable) or punishing (aversive) events. Elec-trode studies of animal brain have suggested that brain stimula-tion which has positive or negative reinforcing properties(suggesting that it is experienced as pleasurable or aversive)can be localized to anatomically distinct brain regions (Olds &Olds 1962) and is subserved by particular excitatory andinhibitory neurotransmitters (Aprison, Hingtgen, & McBride1975; Carlton 1963; Crow 1971; Poschel & Ninteman 1971;Stein 1974), the same transmitters which have been discussedin relation to depression. The relationships between the pa-rameters of reinforcement and these neurotransmitters mightbe summarized as diagrammed in Figure 1.

This pattern of relationships suggests that there are biochem-ical equilibria which could affect the individual's perception of"motivating" events. These equilibria - between excitatory andinhibitory inputs on the one hand and between the relative"saliences" of reward and punishment on the other - mightwell be disturbed by stress-induced transmitter alterationssuch as those which A & Z have described. In addition,preexisting imbalances - such as those which might be left overfrom earlier experienc es or produ ced by genetic influences -could also alter the individual's affective perception of en-vironmental events. Examples that suggest these preexistingimbalances even in currently euthymic individuals are Sitaram,Nurnberger, Gershon, & Gillin's (1980) finding of cholinergicsupersensitivity in depressed and formerly depressed patients,

and the finding by several researchers that many patients whohave recovered from depression still show abnormally lowlevels of 5-HT metabolites in CSF (Coppen, Prange, Why-brow, & Nogura 1972; van Praag 1977).

Reward Punishment

o *S

S S

1 1

Catecholamines

Serotonin

Acetylcholine

Serotonin

Figu re 1 (Noll and Davis). Neu rotran smitt er relationships inthe brain motivational systems.



30/50


Reward Punishment Reward Punishment

S

W

CAs

5-HT

ACh t

5-HT

CA s l

5-HT

ACh

5-HT

CAs |

5-HT

AChf

5-HT

2

Unipolar I Unipolar II

Reward Punishment

o

Unipolar III

Figure 2 (Noll and Davis). Three patterns of alteredneurotransmitter functioning in unipolar affective disorders,t = Functionally elevated; j = Functionally reduced; = Functionally unchanged.

This also shows how changes in the functional activity ofthese neurotransmitters could lead to symptoms that in somecases differ between patients and in some cases are puzzlinglysimilar. For example, either depletion of catecholamines or anexcess of ACh would lead to aversive events' becoming moresalient to the individual than pleasurable events, while at thesame time other functions controlled by these transmitters

would show differences; a reduction in 5-HT in the absence ofchanges in the others might produce an individual generallymore emo tionally respons ive (or labile, to use the clinical term)under normal circumstances and much more affected bystress-induced alterations in catecholamines or ACh. Altera-tions in various behaviors related to transmitter changes havebeen reported in the literature; for example, catecholaminesappear to affect activity level (Seiden 1976), eating behavior(Booth 1968; Ungerstedt 1971), and sexual behavior (Brown,Brown, Kofman, & Quarrington 1978), among other things.Serotonin affects arousal (Hollister, Breese, Kuhn, Cooper, &Schanberg 1976), sleep (Koella 1974), and pain sensitivity(Lints & Harvey 1969; Lytle, Messing, Fisher & Phebus,1975); ACh is significantly involved in memory (Davis, Mohs,& Tinkle nberg 1979; Davis, Mo hs, Tinkle nberg , Pfefferbaum,Hollister, & Kopell 1978; Sitaram, Weingartner, & Gillin1978), dreaming (Sitaram et al. 1980), and behavioral suppres-

c

aoy

H

ib

oy

c

Reward

C A s |

5-HTi

Punishment

ACh

5-HTi

Reward Punishment

o

Io

CAsf

5-HTj

ACh

5-HTi

Mania Depression

Fig ure 3 (Noll and Davis). Patte rns of altered tr ansm itterfunctioning in Bipolar I affective disorder (the "PermissiveHypothesis"). | = Functionally elevated; I = Functionallyreduced; = Functionally unchang ed.

x

aoy

n

b

oy

Reward

CAs |

5 -HTi

Punishment

ACh t

5-HTi

Hypomania

x

aoy

n

b

o

y

Reward

CAs i

5-HTi

Punishment

ACh t

5 - H Ti

Depression

Figu re 4 (Noll and Davis). Patte rns of altered trans mitterfunctioning in Bipolar II affective disorder. \ = Functionallyelevated; | = Fu nctionally reduced; = Functionally un-changed.

sion (Carlton 1963). Cholinergic agonists produce crying spellsin affective patients (Janowsky & Davis 1979). Chang es in thesebehaviors and functions in patients might be expected toparallel the particular neurochemical changes that underliethese patients' depression and could even be used diagnosti-cally. The particular patterns of transmitter alterations, andtheir relation to various diagnostic subgroups, are proposed inFigures 2, 3, and 4.

Thus , in all depressed groups, patients would be experienc-ing an excess of aversive experience over pleasurable experi-ence, and thus would probably experience a great deal of stresseven if there were not a large number of stressful eventshappening to them. Furthermore, these individuals would(correctly) perceive that these changes in their experiencewere internal, global, and stable, the characteristics of thelearned-helplessness-generating cognitions proposed by Ab-ramson et al. (1978). Their reward-maintained behaviors wouldextinguish (as noted by Fers ter 1973 ; and Lew insohn et al.1979). Patients in the Bipolar II group, whose transmitter

profile is postulated to be the most abnormal, have beenobserved by Dunner, Gershon, & Goodwin (1976) to have thehighest probability of attempting suicide; this may be the sameapparently unipolar, low-5-HIAA group observed by Asberg,Traskman, & Thoren (1976) to have a higher risk of attemptedand completed suicide than other depressed patients.

This paradigm shows how preexisting changes in nervous-system chemistry might lead to a patient's experiencing ofexcessive levels of stress even in the ab sence of clearly stressfulenvironmental events; combined with stress-induced furtheralterations in transmitters such as those proposed by A & Z,symptoms would be expected to grow progressively worse, andthis is in fact what is frequently observed.

A & Z have mentioned several possibilities for how anindividual might be genetically predisposed to theseneurohumoral disruptions, but have been vague as to whatspecific enzymes might be involved, or how these changesmight produce the transmitter alterations. One possibility is achange in the calcium- and magnesium-dependent contractileprotein responsible for the exocytosis of vesicles containingcertain of the neurotransmitters. While NE, DA, and ACh arereleased by this calcium-dependent process (Berl, Puszkin, &Nicklas 1973), 5-HT and GABA are not (Katz, Chase, & Kopin1969); and GABA and 5-HT have been found to be deficient indepressed patients (Gold, Bowers, Roth, & Sweeney, 1980).This might be the site of action of lithium ion; Birch (1973)observed that lithium binds to many calcium and magnesiumbinding sites in various enzymes, and has varying effects ontheir function. Another likely candidate is the enzyme cholineacetyltransferase (choline acetylase), the activity of which is therate-limiting step in the produc tion of AC h. An individual whohad more of this enzyme available (perhaps by inheriting moregene segments containing the DNA sequence for the enzyme)might show more elevated cholinergic function in response to



31/50


stress (and on the other side of the coin, might also have abetter memory). Treatments that brought the activity of thisenzyme into the normal range might produce a subjectivememory deficit for that individual, concomitant with recovery- and in fact many successful treatments for depression areaccompanied by memory complaints by the patient. A finalinteresting possibility is presented by the evidence that

neurons which will become part of the autonomic nervoussystem go through a period - parts of which last significantlybeyond birth - during which the neuron can become eithernoradrenergic or cholinergic, and a variety of factors affectwhich neurotransmitter the cell will in fact "choose" (Bunge,Johnson, & Ross 1978). If this is true of the neurons that lateraffect the cholinergic-adrenergic balance proposed here, and ifthis period lasts into childhood in humans (and there isevidence of considerable neuronal plasticity in humans duringthe first several years of life), this might also be one of the waysin which childhood stress could produce adult predisposition todepression.

Stress: Chicken or egg?Ted L. RosenthalDepartment of Psychiatry, University of Tennessee College of Medicine andMemphis Mental Health Institute, Memphis, Tenn. 38105

Anisman and Zacharko (A & Z) present a good review of thegrowing knowledge and remaining ambiguities concerning therelations between stress and depression. Let me say at theoutset that some major role for neurochemical (see Akiskal1979) and genetic (e.g., Akiskal, Rosenthal, Haykal,.Lemmi,Rosenthal, & Scott-Strauss 1980; Rosenthal, Akiskal, Scott-Strauss, Rosenthal, & David 1981) determination now appearsbeyond dispute in both the full syndromal and subsyndromalforms of affective disease. Likewise, the role of stress as at least

a modulator and perhaps a cause of depression keeps gainingplausibility. Given such substantial agreement with A & Z'skey views, I shall confine further comment to issues leftunraised, and I shall examine them from the standpoint of aworking clinician (with a few technical citations given to thescientific literature ).

In our experience at the University of Tennessee Depart-ment of Psychiatry's Stress Management Clinic, extant life-event scales do not allow sufficiently for the role of personalperceptions and values in assigning subjective weights to a(potential) stressor. For this reason, we are collaborating withProfessor Albert Bandura to develop self-efficacy scales thatcan better index common sources of stress as subjectivelyweighted by the patient. Our reasoning is based on sociallearning theory (Bandura 1981; Rosenthal, in press) plus

considerable clinical exposure, and it leads me to raise threematters from that vantage point which are ignored in A & Z'sdiscussion.

First, the effective impact of a stressor will hinge heavily onhow well or poorly the patient deploys attention. For instance,endorphins may enter into somatosensory (and perhaps alsovisual and auditory) attentional mechanisms (see Davis,Buchsbaum, & Bunney, in press), likewise, clinically, whenunder duress and time pressures, patients typically surrenderthe leisure interests and other distracting activities, which theymisperceive as "low-priority." These life events serve essentialbuffer functions and, when deleted, can hasten the develop-ment of an exacerbation cycle which may result in an affectiveepisode, in cardiovascular strain, in gastrointestinal illness, etc.(For a discussion of attention, distraction, and depression seeRosenthal 1980.)

Second, once the person's attention becomes "stuck" onstressful cues, a pattern of self-referent brooding, worrying,and negative self-evaluation is often observed clinically.

Whether one emphasizes - as do A & Z - potential neurochem-ical determinants or the burdens on cognitive-phenomen-ological events (see Bandura 1981), such ruminations arethe source of much human misery and may create orinvite depletion of brain chemicals as well as altering theperson's vulnerability to developing affective or physical ill-ness. Hence, therapeutics that combine pharmacological inter-

ventions and guidance to change cognitive and life-style pat-terns will often surpass either approach used alone. Forinstance, despite thymoleptics, depressed persons usuallyneed much clinical persuasion to resume social and recre-ational activities that have lain fallow.

Third, an aspect of subjective stress nowhere discussed by A& Z involves perfectionism. In social-learning term s, thisentails having set "acceptable" standards for oneself (andothers) that are so high that the distribution of "acceptable"performances becomes thin. In a statistical sense , as comparedto normative achievements of peers, the person's "failures" areclumped high, and there is a low-amplitude wide skew in the"success" direction. Even upon recovery from an acute affec-tive episode (or reduction in objectively high ex ternal stress) itis no mean clinical feat to teach,' urge, model, and nag the

patient to adopt personal performance standards that are morerealistically in line with human fallibility. If this is not done, "B+"and "A" performances may remain subjective failures andhence stressors for the patien t. (See Rosenthal & B andura 1978for a discussion of cognitive standards for self-regulation.)

In early and preliminary data, derived from the self-reportdevices we are refining (in collaboration with Professor Ban-dura at Standord), we have been struck by the empiricalconcordance among the following: (1) diminution of leisureactivities and interests (especially in physical exercise), (2)inability to resist complying with others' "urgent" demands, (3)inability to take breaks or slow down, lest one "waste" time , (4)inability to relax (without the aid of alcohol or drugs) after along, hard day and (5) inability to concentrate attention on justone high-priority task without worrying about others not yetbegun or checking on how much time has elapsed on the task(nominally) at hand.

Is chronic stress better than acute stress?

Douglas K. RushPsychologisches Institut II, University DOsseldort 4 DQsseldort, WestGermany

In the first and second parts of their article, Anisman andZarchako (A & Z) present evidence that (1) stress is a predispos-ing factor in the development of at least some cases ofdepressive illness and (2) depression is characterized by dys-

function of neurotransmitter systems. In developing an inte-grated position relating stress, depression, and neurotransmit-ter dysfunction in humans, A & Z in a third section examinestudies of stress-induced neurochemical changes in animals.Their review indicates that acute uncontrollable stress (e.g.,one hour of cold swimming or footshock) often results inmaladaptive behavior, such as failure to escape from shock,whereas chronic stress (e.g., several hours of stress in a singlesession or several days of one-hour sessions) does not have thiseffect. Likewise, acute-stress treatment has been shown toresult in depletions of NE, DA, and 5-HT and an increase inACh, whereas changes in the levels of neuro transm itters are nolonger observed following chronic treatment. Rather, an in-crease in synthesis and a reduction of reuptake occurs, changeswhich apparently act to normalize both escape/avoidance be-havior and the levels of transmitters available at the synapse.

Presumably because of the differential effects of acute andchronic stress on behavior and neurotransmitter levels, A & Zrely on the effects of acute uncontrollable stress to provide an



32/50

CommentaryI'Anisman & Zacharko: Depression and stress

appropriate model for understanding the changes in neuro-transmitter functioning that occur in human depression. Ananimal model based on chronic-stress effects is seen as lessappropriate, although A & Z do suggest that some individualsmay be unable, du e to constitutional, environmental, or expe-riential factors, to compensate for the increased utilization oftransmitters via increased synthesis, etc., and may thus show adepressive reaction when chronically stressed. An emphasis onthe effects of acute stress as a model implies that less stress(acute) is more likely to result in the neurochemical changesleading to depression than is more (chronic) stress. In fact, atthe end of the section on neurochemical concomitants of stress,A & Z suggest that chronic stress may reduce the symptoms ofdepression in the same way that certain tricyclic antidepres-sants do. Should one conclude that chronic stress might be aneffective treatment for depression?

An emphasis on the effects of acute stress as a model is atvariance with the evidence that stressful life events are aprecipitating factor in the development of depression. Suchevidence implies that depression is more likely to occur withincreasing stress - i.e., more likely with chronic than withacute stress. Experimental treatments and their effects in ananimal model should reflect as closely as possible the etiologi-cal factors and symptomatology of the hum an psychopathologybeing modelled. Although presumed behavioral analogues ofthe symptoms of human depression in animals, such as im-paired escape/avoidance, are not always found followingchronic stress (Weiss, Glazer, & Pohorecky 1976 vs. Seligman& Groves 1970), few studies comparing the behavioral effectsof acute and chronic stress have been conducted, and there isno clear consensus as to what forms of stress leading tobehavioral impairment likewise induce changes in neuro-transm itter systems (for a discussion of these issues, see Selig-man, Weiss, Weinraub, & Schulman 1980). In terms ofneurochemical disturbances in human depression, thephysiological effects of chronic stress in animals may provide a

better model than the effects of acute stress.For example, the study of the effects of chronic stress onneurotransmitter function could aid the search for variablespredicting which individuals are predisposed to depression. A& Z suggested that not all humans suffering chronic stress maybe able to compensate for increased utilization of neuro-transmitters, and that those who cannot consequently becomedepressed. If there were a greater emphasis in animal studieson the effects of chronic stress, attention could be focused onthose animal subjects who do not show the compensatorychanges. A search for variables that predicted which subjectsdo not show these adaptive changes might also have someimport for understanding which humans are unable to adaptneurochemically to stressful life events. (Such an approachwould assume, of course, that it is changes in neurotransmitter

levels that are responsible for depression.)In depressed humans, the only direct evidence for changes

in the levels of neurotransmitters comes from post-mortemanalysis of brain tissue. The only consistent result, according toA & Z, is that the level of 5-HT is reduced in depressedsuicides. Most of the evidence indicating dysfunction ofneurotransmitter systems in depressed humans stems from theanalysis of metabolites in cerebrospinal fluid and urine andfrom knowledge of the biochemical effects of antidepressantdrugs. Neither area provides unequivocal evidence for changesin transmitter levels. The failure to find changes in levelsfollowing chronic stress in animals should thus not rule out thepossibility that chronic-stress effects may aid our understand-ing of human d epression.

Two areas of human depression research reviewed by A & Zsuggest that more than changes in levels are involved. The firstconcerns the subpopulations of depressives who differ both in3-methoxy-4-hydroxy-phenylglycol (MHPG) excretion rate and

in which drug treatment has the best therapeutic effect. Thesecond area of research centers on the effects of des-methylimipramine. Based in part on the finding that thisantidepressant may exert its therapeutic effect by reducingNE, both Sulser, Vetulani, and Mobley (1978) and Maas andHuang (1980) have suggested that depression might be theresult of postsynaptic receptor hypersensitivity.

We can no longer rely on the notion that only changes inlevels of neurotransmitters are correlated with or cause depres-sion. Changes can occur in synthesis, reuptake, and degrada-tion rates, in receptor sensitivity, and probably in otherprocesses not yet understood. After having reviewed bothhuman and animal studies, A & Z present an integrated theoryrelating depression, stress, and neurotransmitters. They con-clude that depletion of amines under acute uncontrollablestress and the failure of adaptive compensatory mechanisms tomaintain normal levels under chronic stress conditions maylead to dep ression. Certainly such a viewpoint is an advance inconceptualizing the relationships between stress, neuro-transmitters, and depression. With increasing knowledge of thecomplexity of changes occurring in human depressive illness, afurther extension of the theory proposed by A & Z is war-ranted. A more thorough examination of the neurochemicaleffects of chronic stress in animals may aid this extension.

Problems with a stress-depression model

William P. SaccoDepartment of Psychology, University of South Florida, Tam pa, Fla. 33620

Anisman and Zacharko (A & Z) have presented a comprehen-sive review and integration of findings in the area of stress anddepression with special attention to neurochemical mediators.They have delineated some problems faced by a stress-depression model. However, the shortcomings of a view that

focuses on the role of stress in causing depression warrantfurther attention. Specifically, the utility of such an approach islimited by problems of inconsistent use of terms, lack ofconsensus regarding measurement and quantification, and weakempirical relationships between life events and depression orother pathological states. Though in the abstract stress wouldseem to be related to depression, the relationship appearsextremely complex and mediated by such a large number ofvariables as to render it a construct of limited explanatoryvalue.

A & Z indicate that they are not aware of any adequatedefinition of the term "stress." They define "stress" and"stressor"; yet their use of these and other terms (e.g.,"aversive experiences," "aversive events," "stresses") is oftenfar from distinct, and it is often difficult to discern conceptualand operational differences among terms. Take, for example,their statement that "aversive experiences give rise to be-havioral attemp ts to cope with s tress." Their definition of stressas "the behavioral and physiological response to actual orimpending aversive stimuli" suggests that aversive experienceslead to behavioral attempts to cope with the response to th eaversive stimuli rather than to attempts to cope with theaversive stimuli itself. A & Z's reference to uncontrollablestress is similarly confusing. Do they mean to refer to anuncontrollable response or an uncontrollable aversive event -or are the terms meant to be interchangeable?

"Uncontrollability" is another term that plays an importantrole in A & Z's conceptualization. They imply that uncontrolla-bility is a function of the severity of the aversive insult and thesuccess of behavioral coping mechanisms, terms that resembleLazarus's concepts of primary and secondary appraisal (Lazarus& Launier 1978). But is severity and success at coping deter-mined subjectively by the victim or by more objective means?



33/50

Commentary/Anisman & Zacharko: D epression and stress

According to A & Z, individual differences in response tostresses of equivale nt sev erity would reflect th e adaptability ofthe neurochemical system." The authors also state that cogni-tions of helplessness may b e manifestations of the more centralneurochemical changes they hypothesize. Sufficient evidencesuggests that depressed individuals are likely to differ fromnondepressed ones in their subjective appraisal of severity and

success at coping (e.g., Garb er, Miller, & Seaman 1979;Hammen & Cochran 1981; Hollon & Beck 1979). Thus, it wouldappear that A & Z must demonstrate that differences insubjective appraisals of severity of stressor and success atcoping follow and reflect individual differences in neurochemi-cal responding rather than preexisting differences in cognitivestyle.

Perhaps because of problems in defining terms, stressresearchers have found it difficult to decide how to measure"stressful" life events. Stress researchers still seek to de ter-mine which sample of stressful even ts is most important toexamine and what level of stressfulness is associated with eachevent (Dohrenwend & Dohren wend 1979). Events ranging inseverity from loss of parent to daily hassles (Delongis, Coyne,Dakoff, Folkman, & Lazarus, in press) have been implicated inthe stress-pathology relationship.

Stress models must also contend with th e fact that th eevidence establishing a relationship betw een stressful ev entsand depression or other disorders is weak. Th e followingconclusions underscore this problem: th e general point re-mains that most stressful events are not followed by psychiatri-cally treated depression. Some a re followed by other psychiat-ric disorders . . . or by somatic disorders, bu t many do not leadto any disorder at all" (Paykel 1979, p. 257); it is by no meansclear that research has dem ons trated their [life even ts'] impor-tance either in the etiology of psychiatric disorders or ofphysical illnesses" (Dohrenwend & Dohrenwend 1979, p. 119).In addition, most studies examining life events and depressionsuffer from various methodological flaws, one of the moreimportant being th e failure to use psychiatric or medicalcontrol groups to establish t he specificity of a stress-d epre ssionrelationship (Crook & Eliot 1980; Lloyd 1980a; 1980b).

Further evidence damaging to a stress-depression model isprovided by Warheit (1979), who examined th e role of lifeevents, coping resources, and depressive symptoms by inter-viewing a random sample of 517 community residents th reeyears apart. By far th e best predictor of depress ion scores atTime-2 was Tim e-1 depres sion scores. A vailability of copingresources and occurrence of loss-related life events (PaykelInventory: Paykel 1971) we re significantly relate d to depres-sion scores, bu t accounted for a much smaller amount ofvariance. Whereas Time-1 depression scores accounted for44.57% of variance in Time-2 scores (24.95% unique contribu-tion), losses contributed 9.83% (2.86% uniqu e). Warheit 's

findings are not surprising in light of research demon stratingthat clinically depressed states in depression-prone individualsoften recur (e.g., Beck 1976).

In an effort to deal with the weak relationsh ip betw een lifeevents and depression, a host of interrelated personal andenvironmental variables that may media te th e s t r e ss -depression effect have been postulated (e.g., Brown 1979;Paykel 1979). However, despite their heuristic value, th enumber of variables and the complexity of their relationshipsare formidable. Most would agree that easily identified severestressful events such as th e loss of a loved o ne often lead to griefreactions which are symptomatically quite similar to depres-sion (DSM-III, 1980). However, in most cases, even suchpowerful events as object loss do not lead to depression(Clayton, Halikas, & Maurice 1972). Rather, it seems more

plausible to conclude that in most cases various life eventsmerely provide th e context in which d epression-proneindividuals become depressed.

Stress depression and helplessness

Arnold D Sherman and Frederick PettyDepartment of Psychiatry University of Iowa, Iowa City Iowa 52242

In attempting to assess th e relationship between stress anddepression, th e commentator is invariably faced with onemonumental problem - that the effects of stress on neuro-

transmitter systems in the human brain are essentially unde-fined. This problem can be circumvented by relying on stu diesof the neurochemical effects of well-defined stressors in ani-mals. If t he rat brain can be taken as an acceptable model forthe human, one wonders why studies of the effects of chronicstress on rat behavior hav e been om itted from Anisman 6c Zach-arko's (A & Z's) review, especially cons idering th e substantialcontribution that Dr . Anisman s lab has made to this area.

Exposure to aversive stimulation does produce a transientescape deficit in rats which is not eviden t after c hronicexposure to stress. Chronic stress, in the form of 20 days ofalternating shock, food deprivation, swimming in cold water,water depriva tion, tail pinches, be ing shaken, sw itching of cagemates, increased housing density, or isolation (Katz, Roth, &Carroll 1981) also produces only transient behavioral changes.In addition, nonbehavioral stressors (i.e., ether anesthesia)which result in a hypothalmic norepinephrine depletion whichoutlasts th e anesthesia (Vellucci 1977) are without behavioralconsequences. In light of this, one must conclude either thatth e rat is an unacceptable model for studies on stress anddepression or that during some "stressful" situations someother factor is also pres ent, and that this second factor may, infact, be the one related to the precipitation of depression.

Another indication that a second factor, actually related todepression, may be involved can be obtained from literaturereviews. Fo r example, at one point A & Z propose thatsufficiently protracted and uncontrollable stress may result inneurochemical changes which are manifested as affective dis-orders. Later, they note that chronic stress has actions similarto those produced by antidep ressan ts, and thus would elimina tesome depressive sym ptoms. Thu s, unless stress is both the causean d th e cure of depression, a second factor might be present.

Some of the reluctance to admit the possibility of a secondfactor's being present in some stress situations may derive fromthe assumption that "controllable stress" is really not verystressful, while "uncontrollable stress" is. Just the opposite isthe case. More of the classical signs of the general adaptationsyndrome (i.e., gastric lesions, changes in adrenal weight,thymus involution, and elevated 17-hydroxy-corticosteroids)were observed in the 1950s in the animals performing anavoidance task than in their yoked counterparts, who receivedidentical shock that was uncontrollable by them.

We performed a neuroch emical stud y which differentiatesbetween these two factors (Petty & Sherm an 1980b). Animals

were either stressed by being forced to acquire and perform anescape response ("executives") or received an equal amount ofshock in a "yoked" paradigm. Th e "yoked" animals are thusexposed to equivalent shock, but a much reduced level ofstress. In assaying the crude synaptosom al pellets derived fromseveral brain regions for serotonin, two distinct pattern s w ereclear. "Executive" (stressed) animals showed a slight elevationof serotonin similar to that seen after restraint stress (Curzonand Green, 1971). These changes dissipated in 24 hours."Yoked" animals had decreased levels of serotonin in pelletsderived from th e septum and anterior neocortex. These de -creases were returning to normal in five days, bu t were stillsignificantly lower when compared either to unshocked con-trols or to "executives." Since no other neurotransm ittersystems were measured, there is no eviden ce that this effect

was specific to serotonin.This "second factor," neurochemically and behaviorally dif-

ferentiated from "stress," was suggested almost 15 years ago



34/50

CommentaryVAnisman & Zacharko: Depression and stress

(Seligman & M aier 1967). It is the separation of reinforcementfrom behavior leading to "helplessness." This state, althoughdismissed by A & Z as a "hypothetical cognitive change," iseasily defined and measured in animals, who are the source ofal l of the neurochemical data on stress. Animals exposed to"uncontrollable stress" have a long-lasting behavioral deficitwhich can be reversed by chronic treatment with tricyclicantidepressants (Petty & Sherman 1980a), atypical antidepres-sants, or MAO inhibitors, but not major or minor tranquilizersor stimulants. Although one may argue about the cognitiveaspects of helplessness in humans, failing to include thisimportant theory (which has immense predictive utility) in areview involving studies on animals represents a considerableoversight.

Noradrenergic function during stress anddepression: An alternative view

Eric A. StoneMillhauser Laboratories, Department o f Psychiatry New York UniversitySchool of Med icine, New York N. Y 10016

Anisman and Zacharko (A & Z) attempt a major synthesis ofstress and depression based on central neurochemical changesknown to occur after stress. Although they consider a numberof mechanisms involving multiple transmitters, it appears thatthe central aspect of their argument concerns changes in brainnoradrenergic function. Specifically, the depletion of brainnorepinephrine (NE) after acute stress is held to be a sign ofimpaired neurotransmission that contributes to the etiology ofdepression, while adaptive changes of enhanced noradrenergicfunction after chron ic stress are held to be restitu tive processesleading to remission.

We think that a good case can be made for the reverse seriesof changes - i.e., an excessive norad renergic activity after acutestress followed by an adaptive decrease after chronic exposu re.First, in the acute situation, the evidence indicates that thedepletion of brain NE by stress does not lead to a decrease ofNE release but rather to an increase. We have demonstratedthis point in studies with forced running stress in rats involvingmeasures of hypothalamic NE turnov er based on the utilizationof tritiated NE and the decline of endogenous NE aftersynthesis blockade (Stone 1971; 1973). The same effect (in-creased release during depletion) was found by Weiss, Glazer,and Pohorecky (1976) in the hypothalamus, brain stem, andtelencephalon of rats subjected to uncontrollable shock stress.Similar findings were also reported in the rat brain stem duringacute hindlimb ischemia (Stoner & Elson 1971; Stoner & Hunt1976). Second, in the chronic-stress situation our evidencesupports the occurrence of decreased noradrenergic function.

We and others have found that chronic footshock or restraintstress leads to reduced postsynaptic sensitivity to NE in the ratcortex, hypothalamus, and brain stem (Stone 1978; 1979a;U'Prichard & Kvetnansky 1980; Torda, Yamaguchi, Hirata,Kopin, & Axelrod 1981). The chronic situation is made morecomplex because changes indicative of increased presynapticfunction (elevated tyrosine hydroxylase [TH] activity and re-duced reuptake) are known to occur. Our data suggest thatthese changes may be misleading, however. The increase inbrain TH should lead to an increase in the amount of NEreleased by stress. We have not found this to be the case(unpublished experiments). Rats subjected to chronic foot-shock and having a higher brain TH activity do show increasedresting-brain NE release but do not show augmented stress-induced release. If anything, these animals show diminishedNE release in the brain stem and possibly the hypothalamus.The other p resynaptic change, a decrease in reuptake, shouldprolong and enhance the action of NE at receptors. However,this action was not evident in our studies of the cAMP (cyclicAMP) response to NE in brain slices from stressed rats (Stone

1978). We observed no effect of chronic footshock on theconcentration of NE required to elicit a half-maximal cAMPresponse (EC5o) in the cortex or hypothalamus; it is known thata reduced reuptake will markedly shift the NE-cAMP dose-response curve to the left to produce a smaller EC30 (Kalisker,Rutledge, & Perkins 1973).

The above findings have led us to conceptualize stress,depression, and central neurochemical changes in the follow-ing way (Stone, 1979b): When animals are first exposed tostress there is an excessive release of catecholamines as well asof other neurotransmitters and hormones. The release of thesesubstances causes a variety of behavioral, emotional, andphysiological reactions. A subset of these responses, involvingchanges in motivation and mood, comprises the phenomenonthat we call depression. It should be noted that in this schemeNE depletion is held to be an index of high release and not, asA & Z propose, a deficit leading to impaired transmission. Asanimals are subjected to repeated stress a number of adaptivechanges occur which reduce the impact of stress. O ne of thesechanges is a reduction in the function of adrenerg ic recep tors.Others may include subsensitivity to endorphins and altera-tions in responsiveness to brain dopamine and serotonin. Asthese receptor changes develop, the animals show feweradverse reactions to stress, and there is a correspondingreduction of depressive symptoms.

We think that our theory has a number of advantages overthe one presented by A & Z. First, our hypothesis offers aunified conceptual framework which fits togeth er many dive rsefindings on stress, adaptation, depression, and antidepressanttherapy. According to our view the various antidepressantagents, all of which are known to induce subsensitivity to NE inthe brain, work by mimicking the biochemical effects ofadaptation to stress at brain NE (and possibly other) receptors.By inducing subsensitivity, these agents may increase resis-tance to emotional stress in patients, and this process mayfacilitate recovery from depression. Antidepressant therapycan therefore b e viewed as a uniqu e form of adaptation to stressin which adaptive changes are produced without actuallysubjecting patients to stress. Second, our theory appears toagree more closely with the physiological actions ofcatecholamines. These substances are extremely potent, theyare generally liberated in emergency situations, and whenreleased excessively or for prolonged periods they are known toproduce deleterious effects. Subsensitivity to catecholamineswould therefore be expected to reduce adverse consequencesof stress. Third, our view, like A & Z's, is in accordance withthe time course of the relationship between stress and dep res-sion and also agrees with the time course of antidepressanttherapy . When th ere is clear evidence of precipitation by stress- e.g., after ob ject loss or loss of function - dep ression isusually an acute reaction which gradually diminishes with

time. Although many cases of depression coexist with chronicstress, this may reflect a failure of adaptive processes ratherthan an etiological effect of the chronicity of the stress.Likewise, antidepressant therapy is generally effective onlyafter several weeks of treatm ent, an interval similar to the timeneeded for adaptation and receptor changes to occur. Finally,our hypothesis is unique in that it predicts the effectiveness ofantidepressants in a nondepressive disorder involving a highdegree of stress - i.e., panic and phobic states such asagoraphobia.

Stress (whatever that is) and depression

Earl UsdinDepartment of Health & Hum an Services, National Institute of Mental Health,Rockville, Md. 20857

The terminology in the Stress field is enough to cause depres-sion. That which we are sure is stress (e.g., personal life



35/50

Response /Anisman & Zacharko: Depression and stress

changes and physical or psychological trauma) is defined in thispaper as "stressors," and that which we are sure is the responseto stress (e.g., the physiological or psychological reactions toaversive insults) is defined here as "stress." If one wereparticularly sensitive, one might also become depressed by thefact that no simple correlation is proposed between changes inlevel of one neurotransmitter or other, but rather there seems

to be the suggestion of some interaction(s) between levels ofseveral neurotransmitters and various depression-relatedphenomena.

It might be hoped that even if there are problems in the"softer" aspects, when we get to the neurochemistry of depres-sion we will hit hard ground. But this just isn't so. Superim-posed on the NE and 5-HT hypotheses are some involving AChand DA; surely peptides would have been included if Anisman& Zacharko (A & Z) had waited but a short time in thepreparation of their review. To confound the CNS results,differences are cited between results obtained from differenttapping sites as well as with or without probenecid pretreat-ment. And should we look at HVA, 5-HIAA, or MHPG (orHMPG)? Ah, but if you decide that CSF studies are just tooconfusing, you may decide that urinary metabolite levels areyour preferred variable. One cited report even concludes thatthere are no differences in urinary metabolites betweendepressed and nondepressed subjects. Of course, the A & Zreview then goes on to cite a paper which shows that urinaryMHPG levels are lower in depressed patients than in controls.But fear not: citations are then given to even later work inwhich no differences could be found, and even to other workindicating that it may require subclassification of depressivepatients to reveal differences.

Not only do different types of stress (again: whatever that is)produce different neurochemical sequelae, but so too (accord-ing to this review) do different lengths of time of stress,different numbers of stress applications (or should I w rite"stressor applications"?), and even differences in time of tissuesampling after stress. And, of course, there is a lack ofconsistency among cited reports. About the only conclusion Ican draw is that we are not yet ready to reach definitiveconclusions on the predisposing influence of stress.

Authors' Response

Stressing our points

Hymie Anisman and Robert M. ZacharkoDepartment of Psychology, Carleton University, Ottawa, Ontario, Canada K1S5 8 6

The purpose of our target article was to sketch amechanism whereby aversive events might increasevulnerability to clinical depression. As indicated byseveral commentators (Akiskal, Dimsdale, Lester,McKinney, Noll & Davis), the symptoms that charac-terize depression vary widely among individuals, and itmight be more appropriate to consider the illness interms of subtypes with some common underlying fea-tures. The pharmacological and biochemical evidencelends support to the contention that differentneurochemical and hormonal factors subserve or areassociated with these different subtypes of depression.In view of the diversity of symptoms which characterizedepression and the potential for complex neurochemical

interactions contributing to symptom profiles, it is notsurprising that disentangling the relationship betweenstressful life events, neurochemical lability, and depres-sion would not be simple. It is even less surprising thatconsiderable disagreement and different focuses ofattention would exist between the views we expressed and

those of several commentators.Despite the shortcomings and inconsistencies in thestress-depression literature there is reason to believethat stressors contribute to depression through theiractions on neurochem ical processes. Although one mightchoose to offer alternatives or elaborations of our work-ing hypothesis (Beck Harrison, Hingtgen Aprison,Stone), it is inappropriate to assume that provisionalworking models cannot be derived on the basis ofavailable data (Usdin). Many of the commentatorsprovided insightful and provocative suggestions thatrequired modifying our working model and that certainlypoint to the need for multidisciplinary research. Wehave directed our response primarily to those issueswhich either appeared most frequently in the commen-taries or appeared to us as most challenging. Limitationsof space and time prevented a detailed discussion ofseveral other issues.

Stress as an elusive concept. The intention of ourdefinition of stress was twofold. First, we wished toindicate that the concept is a vague one and that it isunderstandably difficult to provide a definition to whichsome investigators will not take exception. Second, wewanted to emphasize that stressful experiences shouldbe considered, inter alia, in terms of the organism'sability to cope with those experiences. That an aversive

event can be coped with through behavioral means doesnot ru le out the fact that it is a stressor. An individual cancertainly consider an aversive experience stressfulregardless of wh ether or not control over that stimulus ispossible. Likewise if one chooses to consider stress aphysiological response to aversive stimulation theneither controllable or uncontrollable stressors can beassumed to produce stress, even though these treat-ments may induce quantitatively (and perhaps qualita-tively) different physiological effects. We had hoped thatwe could bypass semantic arguments and get to the gistof the problem, namely, the conditions that provoke orexacerbate clinical depression. If our expectation was notmet, we suppose this might be considered a stressor -hopefully depression will not ensue.

Several commentators (de Catanzaro, Ham ilton, Les-ter, Murison & Ursin, Neugebauer, Rosenthal, Sacco)took exception to our definition of stress and offeredalternatives. De Catanzaro, for example, finds the term"stress" vague, and chooses instead to define "stressors"as "events threatening an organism's health and repro-duction." Murison & Ursin suggest that the simplestoperational definition of stress would be "the processwhich produces a change in your own [the experiment-er's] favorite physiological parameter." Hamiltondifferentiates between stress as an agent and stress as aneffect and suggests that agents be termed stressors and

effects be te rme d strain. The combination of stressor andstrain represents the load on an adaptive system. Saccocorrectly indicates that stress should be considered interms of subjective appraisal of environmental events.



36/50

Response/Anisman & Zacharko: Depression and stress

He also notes that we frequently interchange the termsstress and stressor, while Neugebauer appears to delightin this revelation again (and again). It is certainly essen-tial to define operationally what is meant by stress;however, it appears that Neugebauer had little difficultyin recognizing those occasions in which we

inappropriately used the term stress (or stressor).We were sorry that Usdin found the stress terminol-ogy depressing. He no doubt recalls the "Panel Discus-sion on Stress Theory" in the volume edited by Usdin,Kvetnansky, and Kopin (1980), in which the participantsof the symposium were apparently likewise unable toreach agreement on an appropriate definition. Indeed,the proposal was made there tha t "we be as specific as wecan when we use the word and that the definition ofstress awaits the next Symposium on Catecholaminesand Stress" (p.

Documents

depression the predisposing influence of stress .pdf