2001 - Symptomatic and Syndromal Anxiety and Depression - Ninan, Berger

8/13/2019 2001 - Symptomatic and Syndromal Anxiety and Depression - Ninan, Berger

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2001 WILEY-LISS, INC.

DEPRESSIONANDANXIETY14:7985 (2001)

SYMPTOMATIC AND SYNDROMAL ANXIETYAND DEPRESSION

Philip T. Ninan, M.D., and Joseph Berger, M.D.

The diagnosis of anxiety disorders and major depression can be reliably madebased on signs and symptoms. However there are significant limitations to thecurrent system of classification including overlapping criteria, high co-morbidity, and the issue of subthreshold syndromes. The literature on treat-ment response documents that selective serotonin reuptake inhibitors areeffective in the treatment of the various anxiety disorders, including whencomorbid major depression is present. The literature also suggests that tricyclic

antidepressant medications have superior benefits over selective serotoninreuptake inhibitors in major depression. Examination of the functional

anatomy of the fear and reward systems may shed light on the underlying pro-cesses in the anxiety and depressive disorders. Such an approach points out theimportance of addressing avoidance behaviors, which may be more responsive tocognitive behavioral treatments than pharmacological agents. Depression

and Anxiety 14:7985, 2001. 2001 Wiley-Liss, Inc.

Key words:anxiety; depression; functional anatomy; treatment

INTRODUCTIONWith the publication of third and subsequent edi-tions of the Diagnostic and Statistical Manuel, the di-agnostic nomenclature in psychiatry in the U.S. shiftedto one based on phenomenology [APA 1980, 1987,1994]. Signs and symptoms (often with time a factor)

became the predominant criteria for diagnoses withthe additional requirement of a threshold for dysfunc-tion/distress. Anxiety and mood disorders were carvedout into several categories with precise criteria. Theresulting improvement in diagnostic reliability becamethe basis for an explosion of clinical studies and ad-vancements in evidence-based clinical management[Depression Guideline Panel, 1993].

There are significant problems with the current classi-fication system, however, that are potential impedimentsto the advancement of clinical practice. Reliability doesnot necessarily equate with validity. Core components ofan illness may not get the appropriate emphasis if theycannot be reliably measured. Diagnostic labels are cat-egorical, implying to the uninitiated, clear boundarieswithout overlap, and coincidental co-morbidity. The re-ality is that clinical diagnoses have overlapping presenta-tions and are potentially heterogeneous with multipleetiopathological pathways. This heterogeneity may alsobe the basis of significant variance in treatment response.

SYMPTOMATIC OVERLAPSymptomatic overlap is present to a prominent de-

gree among diagnostic categories, particularly in the

anxiety and depressive syndromes. Thus anxiety as asymptom emotional, cognitive, somatic and behav-ioral is the norm rather than the exception in majordepressive disorder (MDD). Thus, the majority of pa-tients with MDD experienced anxiety at an emotional,cognitive, and somatic level, as well as 29% who expe-rienced panic attacks [Fawcett and Kravitz, 1983].

Similarly, anxiety disorders have dysphoria as a com-mon symptom. It is hard for individuals preoccupiedwith intense anxiety to focus much on the experienceof pleasure.

Symptomatic overlap also creates confusion becausethe number and severity of symptoms is a measure ofthe severity of illness. However, in clinical medicine,symptomatic severity is only a proxy for illness severity.Thus, the degree of pain experienced in angina does notcorrelate well with the degree of occlusion of coronaryvasculature or cardiac ischemia. Functional impairment(e.g., exertional dyspnea) might be a better measure ofillness severity, but in psychiatry impairment it is oftenmodified by psychosocial and economic factors. Thus,assessment of illness severity requires the measure ofseveral domains and not simply symptoms.

Department of Psychiatry and Behavioral Sciences, Emory

University, School of Medicine, Atlanta, Georgia

*Correspondence to: Dr. Philip T. Ninan, 1841 Clifton Road, Room

401, Atlanta, GA 30329. E-mail: [email protected]

Received for publication 10 April 2000; Accepted 10 May 2001


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80 Ninan and Berger

This confusion is aggravated by the standard ratingscales used in clinical studies. A high correlation existsbetween symptoms of anxiety and depression measuredin the Hamilton Anxiety Scale (HAM-A) and theHamilton Depression Scale (HAM-D). Studies thatevaluated buspirone for the treatment of generalized

anxiety disorder (GAD) and MDD found that bothpopulations showed high correlation between anxietyand depressive symptoms [Copp et al., 1990].

Part of the confusion might be that several overlap-ping terms are used to denote the key states of anxietyand dysphoria. Thus words like nervousness, fear, worry,apprehension, tension, irritability, agitation, and rest-lessness all capture some component of the rubric ofanxiety. Similarly, dysphoria also includes sadness, an-guish, dissatisfaction, rumination, and somatic preoccu-pation. As is evident, many of these terms can be usedinterchangeably in the anxiety and depressive disorders.The difficulty is partly the result of the subjective com-ponent of these experiences, which do not have a linear

relationship with the underlying biological processesthat mediate their entry into conscious awareness.

SYNDROMAL OVERLAPThere are several domains of symptoms subsumed

under anxiety and depressive disorders in the DSM IV.These disorders are largely a collection of symptomsthat clinical medicine would consider as syndromes. InMDD, these domains are emotional (sadness, anhe-donia, and anxiety), cognitive (impaired concentrationand memory, specific cognitions such as guilt, worth-lessness and suicidal ideas), endocrine manifestations(change in sleep and appetite, and diurnal variation), so-

matic expressions (preoccupation with physical symp-toms and health), as well as behavioral manifestations(motor retardation and inertia). Similarly, GAD hasdomains of emotional (anxiety), cognitive (uncontrol-lable worry and poor concentration), somatic (muscletension, autonomic symptoms, and somatic preoccu-pation), and behavioral (irritability and restlessness).

The criteria for GAD and MDD overlap consider-ably in DSM IV terms. GAD requires anxiety as thecore necessary symptom (with cognitive worry achiev-ing prominence in the DSM IV criteria) associatedwith restlessness, fatigue, poor concentration, irrita-bility, muscle tension, and sleep disturbance. Theseassociated symptoms are also part of the criteria for

MDD, which requires sadness and anhedonia as thenecessary core symptoms. However, many patientsare unable to report whether anxiety or sadness is thecore of their experience, which raises questions aboutthe validity of that distinction. Such conceptual con-fusion has implications. Thus, recent genetic studiessuggest that the genetic vulnerability for GAD andMDD is the same [Kendler, 1996]. That may be so,or the unity of genetic factors may be the result of aninability to clinically separate the two conditions withvalidity.

SUBSYNROMAL STATESAt what point do symptoms become a diagnosis?

The term subsyndromal denotes a cluster of symptomsthat fall short of a diagnostic criteria. Subsyndromalstates may still be clinically significant. Mixed anxiety-

depressive disorder has been defined in the DSM IVappendix where the criteria for MDD or an anxietydisorder are not met but significant distress and/or im-pairment exists. In a DSM IV field trial of over 600patients seen in a primary-care medical and outpatientmental health site, Zinbarg et al. [1994] reported thatpatients with a nonspecific pattern of affective symp-toms, who did not meet the definition for a DSM-III-R Axis I disorders, were as common as patients withalready established anxiety and mood disorders. Theseinvestigators also found that the subsyndromal disor-ders were associated with a significant amount of dis-tress and functional impairment, indicating the needfor therapeutic intervention.

Diagnostic categories themselves appear to havesome continuity, and the joints at which they are di-vided need further examination. Thus there is a seem-ing continuity from the depressive personality disorder(DSM IV appendix), adjustment disorder (with de-pressed mood), minor and recurrent brief depressivedisorders (DSM IV appendix), dysthymia, major de-pressive disorder. and melancholia. The discontinuitybetween minor depression, moderate depression(meeting 5 or 6 A criteria in the DSM), and severedepression (meeting 79 A criteria) was the same[Kessler et al., 1997]. There is a similar appearance ofcontinuity among the anxiety disorders from cluster Cpersonality disorders to adjustment disorder with anxi-

ety to full syndromal anxiety disorders.

SYNDROMAL CO-MORBIDITY

Co-morbidity of disorders may occur historically orconcurrently. Anxiety disorders have high co-morbid-ity with depressive disorders. Brawman-Mintzer et al.[1993] in a study of 109 patients with a primary diag-nosis of GAD reported 42% met current or past crite-ria for MDD. Schneier et al. [1992] reported that inthe Epidemiological Catchment Area study, 16.6% ofsubjects with social anxiety disorder had a history ofMDD and 12.5% had dysthymia. Rasmussen andEisen [1992] reported that among 100 subjects with

primary obsessive-compulsive disorder (OCD), 67%met lifetime and 31 % met current criteria for MDD.

Among patients with MDD, there is a similar highrepresentation of co-morbidity with anxiety disorders.Schatzberg et al. [1990] reported that 58% of their pa-tients with a current diagnosis of MDD had a historyof an anxiety disorder and 49% met current criteria foranxiety disorder. Similarly, the National Co-morbiditySurvey reported 58% of individuals with a lifetime epi-sode of major depression also met criteria for an anxi-ety disorder [Kessler et al., 1996]. The anxiety disorder


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Theoretical Review Article: Anxiety and Depression 81

developed first in 68% of individuals with major de-pression developing, on average, 11 years later. Thisperiod was shorter for GAD and panic disorder (aver-age 1.5 years) and over a decade each for PTSD,Simple, Social, and Agoraphobia [Kessler et al., 1996].This is consistent with data from the Epidemiological

Catchment Area study, which found 47.2% of patientswith lifetime MDD also had an anx iety disorder[Regier et al., 1998]. The anxiety disorder came first in55% of individuals and MDD in 18%. The averagenumber of years between the phobic disorders and theonset of MDD was around a decade but around an yearfor panic disorder and OCD. Thus anxiety and depres-sive disorders are highly co-morbid syndromes.

Such co-morbidity is not uncommon among com-plex disorders in clinical medicine. An analogy can bemade to hypertension and coronary artery disease,which might be a model for demonstrating the rela-tionship between the anxiety disorders and MDD.Thus, blood pressure is universal, which is equivalent

of tension at an emotional level. Above a certainthreshold, they are both pathologic, i.e., hypertensionand anxiety disorders. The threshold for defining pa-thology is open to debate because of a seeming con-tinuum with normality. There are different forms ofhypertension, just as there are several anxiety disor-ders. The etiopathogenesis for both hypertension andanxiety disorders involve genetic and environmentalfactors. Most importantly, hypertension is a risk factorfor the development of coronary artery disease. Simi-larly, anxiety disorders may be considered a risk factorfor the development of major depression.

The previous literature on the relationship of anxi-ety and depression was complicated by the DSM III,

which gave MDD a higher hierarchy over anxiety dis-orders like GAD. DSM IIIR and IV on the other handencouraged diagnosing co-morbid conditions. Thus, itis unclear how much of the data from the pre l987 lit-erature can be explained more by undiagnosed anxietyrather than depression. It is also interesting to specu-late that atypical depression may include patientswith MDD and a co-morbid anxiety disorder, sinceatypical depression is characterized by high levels ofanxiety including panic attacks, rejection sensitivity,and reverse vegetative symptoms. The pharmacologicaltreatment response of atypical depression showed pref-erential benefit from MAO inhibitors compared withtricyclic antidepressants and may also be responsive to

SSRIs.The distinction between those patients who have full

syndromal co-morbid anxiety disorder and MDD andthose with only a single disorder has not been ad-equately addressed in the literature. A large proportionof studies performed by the pharmaceutical industryfor regulatory purposes did not use structured inter-views to examine co-morbidity even though they wereexclusion criteria. Thus many of the pivotal and otherstudies performed without a stringent diagnostic em-phasis are of little value in examining these issues. Im-

portant questions are the following. Is full syndromalco-morbidity merely a marker for greater severity or isthe MDD present in patients with an anxiety disorderdifferent from those patients MDD without suchcomorbidity? Are there treatment implications to thisdistinction?

RESPONSE TO TREATMENTAll medications effective in treating MDD are his-

torically called antidepressants. The label is probablyinappropriate since antidepressants are effective intreating disorders other than depression. Severalgroups of medications are effective in treating anxietydisorders, including sedative-hypnotics such as thebenzodiazepines, azapirones such as buspirone, andmost antidepressants.

Potent serotonin reuptake inhibitors (SRIs) are ef-fective in the treatment of anxiety disorders, often to asuperior level than medications that are largely potent

norepinephrine reuptake inhibitors (NRIs). This supe-riority of SRIs is best documented in OCD where theonly class of medications effective are the SRIs. Studieswith clomipramine (a non-selective SRI) and selectiveSRIs (SSRIs) such as fluvoxamine, fluoxetine, ser-traline, and paroxetine all document benefit over pla-cebo [Greist et al., 1995]. NRIs such as desipraminefail to show significant benefit [Goodman et al., 1990].In social phobia, SSRIs like paroxetine, sertraline, andfluvoxamine have documented efficacy [Stein et al.,1998], while TCAs are not very effective [Simpson etal., 1998]. In PTSD, SSRIs such as sertraline are moreeffective than placebo [Brady et al., 2000]. A recentmeta-analysis of the PTSD literature reported superior

effect sizes for SSRIs compared with other pharmaco-logical treatments including the TCAs [Penava et al.,1996/1997]. In panic disorder, though TCAs havedocumented efficacy over placebo, the efficacy ofSSRIs are reportedly superior to TCAs [Boyer, 1995].The efficacy of SSRIs in GAD is less well documented,though the efficacy of venlafaxine in GAD is established[Sheehan 1999]. There are a few studies documentingthe efficacy of TCAs in GAD [Kahn et al., 1986].

A problem with such comparisons is that few studieshave been performed as direct comparisons of a SRIagainst an NRI, and historical comparisons are fraughtwith difficulties. Additionally, since NRIs in the U.S.are limited to tricyclic antidepressants, prominent side-

effects might have prevented a trial of adequate dosesin a substantial number of patients. The soon to beavailable selective norepinephrine transport inhibitor,reboxetine, will allow a better test of the efficacy of anorepinephrine transport inhibitor in the differentanxiety disorders. In the meantime, the uniformity ofthe data argues that anxiety disorders (as against anxi-ety symptoms) are more responsive to the pharmaco-logical effect derived from powerful inhibition of theserotonin reuptake mechanism.

Since lifetime major depression occurs in the major-


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ity of patients with an anxiety disorder, a critical ques-tion is the treatment response in patients with co-mor-bid anxiety and depressive disorders. MDD patientswith a lifetime history of an anxiety disorder (mostlypanic disorder and GAD) were less responsive tonortriptyline than those with MDD without a history

of an anxiety disorder [Brown et al., 1993]. Similarly,patients with panic disorder and current co-morbidMDD had a poorer treatment response when treatedlargely with tricyclic antidepressants [Grunhaus et al.,1986]. On the other hand, open trials of an SSRI,fluvoxamine, in 30 patients with MDD with a co-mor-bid anxiety disorder, Sonawalla et al. [1999] found sig-nificant benefit for both depression and anxiety. Thepatients enrolled had current panic disorder, socialphobia, simple phobia, OCD, PTSD, and GAD. Ser-traline, an SSRI, was more effective for both OCD andthe co-morbid MDD than desipramine. [Hoehn-Saricet al., 2000]. Thus, the limited literature suggests thatpatients with both an anxiety disorder and MDD are

responsive to a SSRI but may be less responsive to tri-cyclic antidepressant treatment. Thus, comorbiditymay explain some of the heterogeneity of treatment re-sponse in MDD.

If there is differential efficacy of SRIs over NRIs inthe anxiety disorders, is there evidence of differentialefficacy in MDD? The interpretation of data address-ing this issue is open to debate. The Danish Univer-sity Group studies documented superior efficacy ofclomipramine over SSRIs, paroxetine, and citalopram[DUAG, 1986, 1990]. They argued that clomipra-mines dual NRI and SRI effects mediated its superiorefficacy over the SSRIs. Roose et al. [1994 ] docu-mented nortriptyline, a tricyclic antidepressant, as be-

ing superior to fluoxetine, a SSRI, in elderly patientswith melancholic depression. Differential efficacy of aSRI over NRI would be more difficult to document innon-melancholic MDD with milder intensity of symp-toms as these individuals often have a greater degreeof placebo response. More severely ill or melancholicpatients with MDD are less likely to have a placeboresponse and therefore are better subjects to evaluatedifferential treatment efficacy.

An intriguing possibility is that SSRIs are marketedas antidepressants because industry-sponsored studiesoften fail to assess co-morbidity in patients with MDD.Roughly half the patients with MDD are expected tohave a co-morbid anxiety disorder based on epidemio-

logical data [Kessler, 1996]. The efficacy of SSRIsdemonstrated in clinical trials of patients with MDDmay have been driven partly by their benefits in the co-morbid anxiety disorder. Thus only 5 of 14 studieswith fluoxetine found statistical superiority over pla-cebo in MDD before FDA approval in the U.S. [FDA,1988]. A study of a cohort of patients with MDD with-out a comorbid anxiety disorder compared to a groupwith comorbid anxiety disorder might be enlighteningto evaluate a potential differential response to a SSRIvs. an NRI. Such a study was previously impractical be-

cause of the side effect profile of tricyclic antidepres-sants prevented a substantial number of patients toler-ating the medications or being able to reach high dosesto examine efficacy. With the future availability of pureNRIs like reboxetine with improved tolerance, such astudy may be practical.

FUNCTIONAL ANATOMY OFANXIETY AND DEPRESSION

The current challenges with diagnostic boundariesand assessing treatment response are inherent with apurely clinical approach. Signs and symptoms are sur-face phenomena with potentially multiple overlappingpathways to their expression. If the recent explosion ofknowledge in the neurosciences and molecular biologycan be translated into clinically relevant concepts, thepractice of psychiatry will be considerably enriched. Theresult will be a better understanding of the processes

that underlie conditions like anxiety and depressive dis-orders. A conceptual scaffold of the potential patho-physiology of anxiety and depressive disorders will thusenhance diagnosis and have implications for treatment.The exercise by its nature is reductionistic. Additionally,animal models cannot take into consideration the ex-panded prefrontal cortex in humans with the ability ofcognitive control of emotional experiences.

Brain structure is crucial for understanding patho-physiology as anatomy defines but also limits function.Thus elucidation of the neurocircuitry mediating suchbasic emotions such as anxiety and sadness are a neces-sary step. Emotions are derived from the activity ofmotivational systems and feelings are the subjective

awareness in consciousness of such activations [Lang etal., 1998]. Emotions and feelings add color to experi-ences and allow them to be classified. Just as the retinalreceptors for the three primary colors allow the per-ception of millions of colors through their combina-tion, similarly, motivational systems allow a plethora ofseamless emotional states.

Preclinical studies provide insights into neural cir-cuits that underlie motivational systems from whichemotional and behavioral responses are derived [David-son and Irwin, 1999; Ninan, 1999]. The neural cir-cuitry associated with emotional processing is complexbut overlaps significantly with the classical limbic sys-tem as described by Papez. Two such systems have

been described [Konorski, 1967]. The first is a protec-tive one involving the amygdala and closely linked tofear conditioning, from which anxiety may be derived[Davis et al., 1994]. The second is a preservative onethat is rewarding (hedonic) and responds to appetitivestimulation.

Fear is a normal response to physical threat, whileanxiety can be defined as socially derived or inappro-priate fear. The protective response to aversive threatis an evolutionarily maintained, unconditioned re-sponse, hard-wired in the brain. The fear/anxiety re-


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sponse does not have to be learned and includes defen-sive behaviors, autonomic arousal, hypoalgesia, poten-tiation of somatic reflexes, and activation of the stressaxis through the hypothalamic-pituitary-adrenal axis[LeDoux, 1998]. Davis [1998] proposed an amygdala-based circuit as mediating the fear response with the

anxiety response mediated through the bed nucleus ofthe stria terminalis, part of the extended amygdala. Theoutput of the central nucleus of the amygdala, its mainefferent pathway, can explain the various symptoms ex-perienced in anxiety states [Davis, 1992]. The amygdalais central to registering the emotional significance ofstimuli and the development of emotional memories.Fear conditioning is a model for understanding emo-tional memories, whereby a conditioned stimulus, oncepaired with an unconditioned one, is now able to elicitthe behavior (anxiety, in this instance). The pairing ap-pears to occur because of increases in synaptic strengthin the amygdala as well as the thalamus [McKernan andShinnick-Gallagher 1997].

The cueing of anxiety may involve threat, novelty,social, or performance situations, conditioned associa-tive memories, and other cognitive mechanisms. Opti-mal activity in the anxiety circuits is associated with anormal readiness to respond to situations. Exaggeratedchallenges induce anxiety and resources are mar-shaled to respond. Life threatening challenges result inthe permanent imprinting of the experience in theemotional circuits that encompass the full emotionalmemory of the experience.

The context of the emotional experience are consid-ered associated cues that are stored through the de-clarative (conscious) memory circuits that involve thehippocampus. This allows for associated cues to trigger

the emotional memory of the trauma, bringing it toconscious awareness. Avoidance conditioning allowsfor the individual to avoid associated sensory, cogni-tive, or other stimuli that potentially trigger the returnof the emotional experience of the trauma.

Cueing of anxiety varies in different anxiety dis-orders. Thus, in GAD, anxiety is triggered withoutconnection to contextual cues, making them free-floating and the cognitive pattern is to have pessimis-tic concerns with any issue at hand. In panic attacks,the concern is with imminent death. In social anxietydisorder, the concern is with social embarrassment. InOCD, anxiety is triggered by the intrusive awarenessof senseless and distressing obsessions. PTSD has

components of re-experiencing the trauma, avoidance,and hyperarousal based on the emotional memory of thetrauma. The inability to successfully control cognitivetriggers can result in the intrusive recollections of thetrauma.

Another motivational system is preservative and re-sponds to appetitive stimulation. The result is reward-ing and the potential emotions derived are joy, sexualpassion, and nurturance [Konorski, 1967]. Hedonic re-sponses have been associated with so-called rewardpathways for the brain, including the ventral tegmental

area (VTA), nucleus accumbens, and medial prefrontalcortex [Scheel-Kruger and Willner, 1991; Schultz etal., 1997]. In particular, the VTA/nucleus accumbenscircuit is implicated in reward-driven behavior, e.g.,operant conditioning. Neurochemical studies moststrongly link dopamine to this circuit, but other neu-

rotransmitters are associated with reward, with mount-ing evidence for both serotonin and norepinephrine.Evidence for state-dependent dysregulation of thesecircuits in MDD has been reported and may predicttreatment responsiveness [Mayberg, 1997].

These systems potentially mediate the regulation ofnormal emotion as well as mechanisms underlyingclinical anxiety and depression. Activation of these sys-tems occurs within milliseconds of stimuli, prior toconscious awareness in some circumstances [Whalen,1998]. Activation of these motivational circuits pre-sumably drives subsequent events including consciousawareness of feelings, cognitive responses, and volun-tary behavior, all of which require more complex pro-

cessing. Thus, we feel first, and the feelings drivecognition and behavior.

Prefrontal cortical sites are reciprocally connectedwith the amygdala and other limbic sites, allowing forself-imposed regulation of affect and the modulation ofautonomic and neuroendocrine function. The medialprefrontal cortex controls the shifting of focus betweeninternal and external cues, mood shifts based on thelikelihood of punishment or reward, and the expecta-tions based on past experience [Barkley, 1997]. Thesecapabilities allow for cognitive control of the anxi-ety response, a top-down approach that is potentiallythe basis of benefit derived from cognitive therapy.

Countering the effects of previous fear conditioning

that have resulted in avoidance requires new experi-ences in the same context with more benign outcomesand the new associations may bring about extinction ofthe previous fear response. However, the original im-print and associations still exists, since it can bereawakened with new experiences of similar threat. Intimes of emotional arousal, the control shifts from theprefrontal executive centers to lower limbic cen-ters like the amygdala [Mayberg et al., 1999]. Behav-iors are then guided by patterns that are learned earlieror species typical programmed ones. Thus the nor-mal individual has the capability to choose their re-sponse in a given situation, i.e., cognitive, emotional,or behavioral. Psychopathology is the limitation of that

choice to a narrow repertoire entrained in a specificway based on previous experience without prominentinput from executive centers in the prefrontal cortex.

Distinguishing fear conditioning from avoidanceconditioning is an important clinical issue. Thus, manypatients with panic disorder go on to develop agora-phobia but others do not, even though they mightexperience anticipatory anxiety. Because avoidance be-havior quite often is the critical mediator of dysfunc-tion, the recognition of a mechanism that separates itfrom the other aspects of anxiety is conceptually im-


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portant. The avoidance dimension may also have treat-ment implications since our current pharmacologicalrepertoire might not have an agent that is specificallyhelpful for this domain of symptoms. Improvement inthis domain might be secondary based on factors suchas exposure. The tendency to expose oneself to fearful

stimulation might be dependent on certain behaviortraits, hormonal factors, as well as sociocultural ones.Cognitive behavior therapy that focuses on exposureand response prevention addresses this symptom com-plex directly and might largely explain its superior ben-efit in reducing these symptoms. The particular valueof combination treatment, (pharmacological and CBT)in these patients may be because they are workingthrough different mechanisms.

CONCLUSIONPsychiatric nosology codified in the DSM IV has

achieved a reliable system for classifying clinical presen-

tations into relevant categories. However, their value islimited by the increasing recognition that comorbiditiesoccur frequently, particularly with increasing severity ofillness. This has important treatment implications.There is strong evidence for superiority of SRIs overNRIs in the treatment of the anxiety disorders and sug-gestive evidence for the superior value of NRIs inMDD, particularly with melancholia.

Future advances are contingent on improving ourconceptual understanding of the nature of these ill-nesses. We can begin to develop a conceptual scaffoldbased on the functional anatomy of anxiety and depres-sion and derive a potential pathophysiological mecha-nism that underlies the anxiety and depressive disorders.

Such a model provides the conceptual basis for contem-plating future advances, particularly in treatment.

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