Journal of Affective Disorders 99 (2007) 91–99www.elsevier.com/locate/jad

Research report

The neurobiology and clinical significance of depersonalizationin mood and anxiety disorders: A critical reappraisal

Marco Mula ⁎, Stefano Pini, Giovanni B. Cassano

Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies,Section of Psychiatry, University of Pisa, Via Roma, 67-56100 Pisa, Italy

Received 5 July 2006; received in revised form 22 August 2006; accepted 22 August 2006Available online 25 September 2006

Abstract

Depersonalization and derealization occur on a continuum of situations, from healthy individuals to a severely debilitatingdisorder where the symptoms can persist chronically. Since 1960s, different neurobiological models have been hypothesized andthey have been associated with the temporal lobes. Recent advances in the functioning of the limbic system and the application ofGeschwind's concept of disconnection in the cortico-limbic networks, pointed the role of the amygdala and its connections withmedial prefrontal cortex and anterior cingulate cortex, the same structures that are strictly interlinked with the neurobiology ofemotions and affective disorders.

In this paper, we hypothesize that depersonalization may represent a clinical index of disease severity, poorer response totreatment and high level of comorbidity, in mood and anxiety disorders, discussing the neurobiology of depersonalization and theavailable clinical evidence.© 2006 Elsevier B.V. All rights reserved.

Keywords: Depersonalization; Derealization; Amygdala; Bipolar disorder; Major depression; Panic disorder

1. Introduction

Depersonalization (DP) is defined as an experience inwhich the individuals feel a sense of unreality anddetachment from themselves. Symptoms often includedreamy state and a sense of detachment. There may be asensation of being an outside observer of one's mentalprocesses, one's body, or parts of one's body. Varioustypes of sensory anesthesia, lack of affective response,and a sensation of lacking control of one's actions,including speech are often present. These experiencesare not delusional in nature since the sufferer retains

⁎ Corresponding author. Tel.: +39 050 993559; fax: +39 050 21581.E-mail address: marcomula@yahoo.it (M. Mula).

0165-0327/$ - see front matter © 2006 Elsevier B.V. All rights reserved.doi:10.1016/j.jad.2006.08.025

insight that these are subjective phenomena rather thanobjective reality. DP is often associated with derealiza-tion in which the external environment also appearsunfamiliar. The term derealization was coined during theearly 20th century, but, in this paper, unless specificallyindicated, DP will be used as the generic term for bothaspects, as there is no conclusive evidence thatderealization is an independent phenomenon (Sierraand Berrios, 2001).

DP occurs on a continuum of situations, from healthyindividuals (lasting only a few moments), often underconditions of stress, fatigue, or drug use, to a number ofneuropsychiatric conditions such as epilepsy, migraine,anxiety disorders (especially panic disorder), majordepression and schizophrenia. DP may also present as a

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severely debilitating disorder where the symptoms canpersist chronically and unremittingly for decades. DPdisorder is classified with four essential criteria as one ofthe dissociative disorders in the DSM-IV (AmericanPsychiatric Association, 1994) (Table 1).

Although the interest in the phenomenology andepidemiology of the dissociative disorders has flourishedover the last decades with the accumulation of a largeliterature, most of the studies have several limitations: theutilization of different methods in the assessment, datacollection and diagnostic criteria. Transient symptoms ofDP in the general population are common with a lifetimeprevalence rate ranging between 26% and 74% (Hunter etal., 2004). Community surveys using standardizeddiagnostic interviews reveal rates of 1.6%–1.9% for 1-month prevalence in two UK samples (Bebbington et al.,1981, 1997) and 2.4% in a Canadian study (Ross et al.,1991). Prevalence rates in clinical samples of specificpsychiatric disorders vary between 30% of subjects withpost-traumatic stress disorder (Davidson et al., 1990),60% of inpatients with unipolar depression (Noyes andKletti, 1977) and 80% in patients with panic disorder.Interestingly, a Japanese study (Mizobe et al., 1992)reported a relatively low prevalence in patients with panicdisorder (ranging between 9% and 25%) that may be dueto methodological differences or truly national or ethnicvariations in dissociative symptoms.

In this paper we hypothesize that DP may representan index of severity in mood and anxiety disordersdiscussing the neurobiology of DP and the availableclinical evidence.

2. The neurobiology of depersonalization

The neurobiology of DP seems to be partlyinterlinked with that of affective disorders, overlapping

Table 1DSM-IV diagnostic criteria for depersonalization disorder

A. Persistent or recurrent experiences of feeling detached from, and asif one is an outside observer of, one's mental processes or body (e.g.feeling like one is in a dream).

B. During the depersonalization experience, reality testing remainsintact.

C. The depersonalization causes clinically significant distress orimpairment in social, occupational, or other important areas offunctioning.

E. The depersonalization experience does not occur exclusively duringthe course of another mental disorder, such as schizophrenia, panicdisorder, acute stress disorder, or another dissociative disorder, andis not due to the direct physiological effects of substance (e.g. a drugof abuse), a medication or a general medical condition (e.g. temporallobe epilepsy).

in several aspects and differentiating in others. Thus, twomain models are relevant for the understanding of thebiological basis of DP: the neurobiology of emotionalprocessing and the view that DP may represent avestigial brain-response to life-threatening situations(Roth and Argyle, 1988).

2.1. Depersonalization and the neurobiology of emotions

The neurobiology of emotional processing is still notcompletely clear but converging evidence suggests thatthe amygdala, the anterior cingulated cortex (ACC) andthe medial prefrontal cortex (MPC) are salient structuresof parallel networks that integrate emotional responses.In animals and humans, the amygdala is implicated inprocessing threat and fear stimuli (Adolphs et al., 1994;Buchel et al., 1998; Hamann et al., 1996; LeDoux et al.,1988) and in assigning emotional and cognitivesignificance giving a strong feeling of reality andpersonal relevance (Gloor, 1990). Moreover, neuroima-ging studies also showed activation of the amygdaladuring recall of emotionally charged memories (Cahillet al., 1996) and emotional visual imagery (Shin et al.,1997). Thus, increased amygdala function appears to beclearly linked to phobic disorders (Stein et al., 2002).The central amygdala nucleus seems to play a crucialrole in the generation of autonomic arousal responses tothreat stimuli (LeDoux et al., 1988) and correlates withevoked sympathetic arousal (Buchel et al., 1998; Morriset al., 1997).

The ACC activates during some of the sameemotional states, but also in the emotional assessmentof pain, generation of motivated behavior and attentionalprocesses, suggesting that this region probably repre-sents the main output center for all the autonomicresponses due to amygdala activation in emotionalprocessing. Moreover, recent studies demonstrated thatthe ACC mediates context-driven modulation of bodilyarousal states (Critchley et al., 2003). However, thisprocess has not been completely defined, explaining thecontrasting results of studies investigating the role ofstress hormones in patients with DP disorder, particu-larly the hypothalamic–pituitary–adrenal (HPA) axis(Stanton et al., 2001; Simeon et al., 2001) and thenorepinephrine system (Simeon et al., 2003a,b). Stantonet al. (2001) found that patients with DP disorder havelower basal cortisol levels than subjects with majordepression, supporting the view that DP pathophysiol-ogy, as reflected in the functioning of the HPA axis, isdistinct from depression. Moreover, DP disorder seemsto involve a pattern of HPA axis dysregulation whichdiffers also from PTSD, being the former associated to a

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significant hyposuppression to low-dose dexamethasoneadministration (Simeon et al., 2001). Similarities anddifferences between DP and PTSD have been shown alsoin studies of the norepinephrine system. A pilot study,investigating noradrenergic function in patients with DP,post-traumatic stress disorder and healthy subjects,showed that, although dissociation accompanied byanxiety was associated with a high noradrenergic tone, asobserved in chronic anxiety, there was a markednoradrenergic decline associated with the increasingseverity of dissociation (Simeon et al., 2003a). Norepi-nephrine activity in DP seems to differ also from that ofother anxiety disorders such as panic disorder (Wilk-inson et al., 1998) and obsessive compulsive disorder(Benkelfat et al., 1991) that have shown normal levels atrest. Finally, a study investigated autonomic responseusing the skin conductance response (SCR), in patientswith DP, anxiety disorders and healthy controls (Sierraet al., 2002a). The authors showed that patients with DPdisorder have in common with those with anxietydisorders similarly high anxiety ratings and SCR tonon specific stimuli (a startling noise), suggesting a stateof heightened alertness. However, only DP patientsshowed a marked diminution and delay of response tounpleasant pictures, through a selective inhibitor mech-anism on emotional processing. All these evidencestaken together are in keeping with the hypothesis of anautonomic blunting in DP and suggest a possibleinvolvement of serotoninergic, endogenous opioid andglutamatergic NMDA pathways (Simeon, 2004).

2.2. The sensory–limbic disconnection hypothesis

Sierra and Berrios (1998) postulated an interestingsimilarity between the sensory–limbic disconnectionsyndrome as defined by Geschwind (1965a,b), that iswell characterized in some animal models (Downer,1961), and the neurobiology of DP. According to theirmodel, DP results from the combination of twomechanisms: an inhibitory component mediated byleft-sided MPC hyperactivation that inhibits amygdalaand indirectly the ACC (with a functional sensory–limbic disconnection) and an excitatory componentdriven by uninhibited amygdala circuits controlling bothcholinergic and monoaminergic ascending arousalsystems leading to the activation of the right prefrontalcortex (with a state of vigilant attention) (Fig. 1).

The simultaneous activity of these two opposingmechanisms would lead to a state of hyperattention(modulated by the right hemisphere) associated to a stateof hypoemotionality, where perceptions are reported bythe subject as unreal or detached. This model is focused

on the hyperactivation of MPC with consequentfunctional disconnection of the amygdala. However, itis still unclear whether this model can be applied only toDP. The most replicated findings related to the neuralcircuitry of PTSD include decreased function in theMPC, while data about panic disorder are contradictory(Bremner, 2004). Conversely, PET studies performed inpatients with major depression showed that thehyperactivation of the left MPC is associated with amarked hypofunction of the amygdala bilaterally(Davidson and Sutton, 1995; Drevets et al., 1992). Inthis regard, the case reported by Jimenez-Genchi (2004)is of interest. The author described a patient with DPdisorder who showed a 28% improvement on deper-sonalization scores, after six sessions of repetitivetranscranial magnetic stimulation (rTMS) on the leftMPC. The role of rTMS in modulating inhibitoryneurotransmission, at particular frequencies of stimuli,has been demonstrated by different studies in patientswith neurological and psychiatric disorders (Ziemann,2004; Paus and Barrett, 2004) and this case reinforcesthe hypothesis of a hyperactivation of MPC in DP.Phillips et al. (2001) investigated neural responses toemotionally salient stimuli in DP patients showingreduced neural response in emotion-sensitive regionsand increased responses in regions associated withemotion regulation such as the MPC. All these evidence,taken together, may suggest that the hyperactivation ofthe MPC is essential in DP pathophysiology.

The described mechanism is compatible with theevolutionary view of DP as a vestigial brain-response tolife-threatening situations that, in patients with anxietydisorders becomes a response to usually neutral oremotionzally weak situations or even a spontaneousphenomenon.

However, the theoretical framework created by Sierraand Berrios can be easily applied to affective DP but notto other experiences such as somatopsychic andcognitive DP. Especially the first is characterized by afeeling of unreality of the own body or its alteredperception (the hands seem to be bigger or smaller, thelimbs are perceived as disconnected) and in this casesomatosensory areas and their associated regions arelikely to play a role as in patients with neglect orasomatognosia that are usually associated with a lesionin the right parietal cortex (Sierra et al., 2002b).Abnormalities along sequential hierarchical areas, unim-odal and cross-modal, of the visual, somatosensory andauditory processing pathways, as well as in areasresponsible for an integrated body schema, has beensuggested by Simeon et al. (2000) in one of the first PETstudy performed in patients with DP disorder. Therefore,

Fig. 1. A possible neurobiological model of depersonalization. Bold arrows represent disconnected pathways by left prefrontal cortex hyperactivation(modified from Sierra and Berrios, 1998).

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DP phenomena may occur as a result of a disruption in anumber of associative areas that are finally connectedwith the amygdala (Fig. 1).

3. Depersonalization as an index of disease severity

The possibility that DP may represent a feature ofseverity of the disease is suggested by epidemiologicalstudies showing higher rates of these phenomena ininpatients than outpatients or data from GP registers. Forexample, three studies investigated DP in schizophreniaand all of them reported rates of 6.9% in outpatients andmedical practitioner's registers, rising to 36% in samplesof inpatients (Noyes andKletti, 1977; Sedman andKenna,1963; Watts, 1985). Although these studies may beobjectionable because of the different methods employedin assessing DP symptoms (two of them were based onclinical observation and one on a 56-item questionnaire),differences on rates of DP between inpatients and out-patients has been subsequently replicated by other authorsfor other psychiatric disorders. For example, patients withunipolar depression showed rates varying from 4% in aGP register (Strickland et al., 2002) to 28% in outpatientclinics (Sedman and Reed, 1963) and 60% amonginpatients (Noyes and Kletti, 1977). The observationthat DP is more prevalent in hospitalized patients may

suggest that it is associated with a more severe psychiatricdisorder. However, all these studies are cross-sectionaland prospective studies, evaluating the time course of DP,would be appropriate to understandwhether these patientsreally have a poorer prognosis with a higher tendencytoward chronicity.

3.1. Anxiety disorders

That there might be a strong association between DPand anxiety disorders is well known in literature, and itwas often considered as a nonspecific response toanxiety, for example as headlined by Roth (1960) withthe “phobic anxiety–depersonalization syndrome”.However, formal studies explicitly investigating thisassociation are very limited.

In panic disorder, a prevalence of DP ranging between7.8% and 82.6% has been reported. Panic disorder hasbeen hypothesized to be a heterogeneous entity withdistinct subgroups and it is plausible to speculate thatspecific clinical features may characterize panic disorderwith DP. Cassano et al. (1989) investigated DP symptomsin 150 patients with panic disorder showing that thosewithDPwere usually younger, with an earlier age of onsetof the disease, higher prevalence of avoidance behaviorand more severe agoraphobic spectrum phobias (Table 2).

Table 2Clinical features of different psychiatric disorders associated with thepresence of depersonalization

Disorder Clinical featuresassociated with DP

References

Panicdisorder

• Early age at onset Cassano et al., 1989• High prevalence ofavoidance behaviour

Ball et al., 1997

• Rapid development ofphobic avoidance

Segui et al., 2000

• Severe agoraphobicspectrum phobias

Marquez et al., 2001

• High rates ofcomorbidity (depressionand personality disorder)

Katerndahl, 2000;Persson and Nordlund, 1985

Unipolardepression

• Long depressive phase Ackner et al., 1960• Poor response to drugtreatment

Sedman and Reed, 1963

• Poor response to ECT Noyes and Kletti, 1977• Poor response to sleepdeprivation therapy

Gill and Lambourn, 1979;Nuller, 1982;Shelton and Loosen, 1993;Strickland et al., 2002

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These results have been subsequently replicated by otherauthors (Ball et al., 1997; Segui et al., 2000; Marquezet al., 2001)who also found thatDP correlatedwith higherrates of comorbidity, especially with depression andpersonality disorders (Ball et al., 1997) andMarquez et al.(2001), in particular, highlighted the occurrence ofDP as amarker of severity and a poor prognostic sign. Asecondary analysis of survey data from a community-based study on 97 patients with panic disorder reportedthat DP was a key element in the development of phobicavoidance and its rapidity of development (Katerndahl,2000). In fact, the close association between DP andagoraphobia was previously suggested by another studythat compared patients with agoraphobia and socialphobia; the authors showed that agoraphobics had higherratings on DP, although target phobia and global ratingwere of equal severity in the two syndromes (Persson andNordlund, 1985). Moreover, Noyes et al. (1992),investigating distinguishing features in generalized anx-iety disorder and panic disorder in 112 patients, showedthat the latter was more commonly associated with DPand agoraphobia.

The literature on social phobia and DP suggests acloser link between these two clinical phenomena thanhas been acknowledged. In a recent study of 117 patientswith DP disorder, Simeon et al. (2003a) found that 30%met diagnostic criteria for social phobia and 23% foravoidant personality disorder. Michal et al. (2005) founda connection between DP and social fears in a sample of116 psychotherapy in-patients using the CambridgeDepersonalization Scale and the Social InteractionAnxiety Scale. Historically, Paul Schilder considered avery close relation between social neuroses and DP(Schilder, 1938). Although he observed the phenomenonfrom a psychoanalytical point of view, he probablygrasped the clinical evidence of an association betweentwo experiences, namely DP and avoidance behavior.However, there are no studies evaluating the influence ofDP in the time course of the disease and the response totreatment.

In post-traumatic stress disorder the role of DP is moreintuitive. Bremner et al. (1993) investigated dissociativedisorders in 55 Vietnam combat veterans showing thatthose with high levels of dissociative symptoms weremore likely to develop a post-traumatic stress disorder.The same findings have been replicated in Swedish sur-vivors of the M/S Estonia disaster (Eriksson and Lundin,1996). Interestingly, Michaels et al. (1999) assesseddissociative symptoms within a few hours from a non-neurological injury in 140 subjects admitted to a level Itrauma center. Patients with higher DP rates were threetimes more likely to develop a post-traumatic stress

disorder independently from baseline status, severity ofthe injury and the degree of physical recovery, pointingthe role of peritraumatic DP on the occurrence of post-traumatic stress symptoms. However, there are no studiesevaluating whether the extent of peritraumatic dissocia-tion, especially DP, correlates with severity of the diseaseand a tendency towards chronicity.

3.2. Mood disorders

Data on correlates of DP in mood disorders arescanty (Ackner, 1954; Mayer-Gross, 1935; Sedman andReed, 1963) and the issue of DP as a possible prognosticsign has not been explicitly addressed. The latestpublished study is the one by Nuller in 1982, whospecifically evaluated the relationship between DP andmajor depression and observed a possible associationwith a longer duration of the depressive phase andresistance to antidepressant drug therapy (Table 2). Inmood disorders, DP may be the result of differentmechanisms. Strong disruptions and alterations of moodcan, in themselves, disturb the stability of the selfenough to induce DP. Mayer-Gross (1935) reported that50% of individuals with DP described the onset of theirsymptoms during the course of an episode of depressionand in these cases the main focus of the concern for thesufferer is the sense of detachment and emotionalnumbing which result from the depression. In thissituation it is rather evident that the presence of DP may

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indicate a more severe depression and this is furthersuggested by other studies about the responsiveness toECT and sleep deprivation therapy. In a survey of seniorBritish psychiatrists, Gill and Lambourn (1979) showedthat ECT was of little value in patients with mooddisorders and severe DP, observation subsequently con-firmed by other authors (Ackner et al., 1960). Moreover,Shelton and Loosen (1993), examining the effect of totalsleep deprivation in combination with nortriptyline in 20patients with major depressive disorder, showed that theabsence of DP was associated with response to sleepdeprivation.

On the other hand, we are confident that DP may alsoreflect the presence of subthreshold panic spectrumsymptoms, especially in patients with bipolar disorder.Thus, unipolar and bipolar depression have relatively highlevels of comorbid anxiety and the pattern of comorbiditybetween bipolar and panic disorder has been hypothesizedto reflect a sort of syndromal subtype of mixed anxiety–affective disorder (Perugi et al., 1999; Freeman et al.,2002). Goodwin and Hoven (2002) examined theprevalence, psychiatric comorbidity, panic symptomatol-ogy and physical morbidity associated with the co-occurrence of bipolar disorder and panic attacks in thegeneral population. They showed that individuals withbipolar–panic comorbidity had significantly higher meannumber of panic symptoms, compared with those withpanic who did not have bipolar disorder, and specifically,derealizationwas actually referredmore frequently by thiscategory of patients. Bipolar–panic comorbidity isassociated with poorer response to treatment, earlieronset of the bipolar disorder, elevated rates of comorbidpsychopathology, greater levels of depression, moresuicidal ideation and increased familial risk of affectivedisorders (Goodwin and Jamison, 1990; Pini et al., 1997;Goodwin and Hoven, 2002; Frank et al., 2002).

Finally, the lack of studies about mania andDP shouldbe noted. Previous authors suggested that patients withbipolar disorder and evidence of organic brain lesions(mainly derived from EEG data) exhibit an atypical formof affective disorder with a significant amount ofsupplementary signs such as DP (Vovin et al., 1978).Thus, in the context of mania, the occurrence of DP orperiods of detachment may represent signs of temporallobe dysfunction (Sokolski and Denson, 2003), suggest-ing the need of special therapeutic approaches. However,further research is warranted about this subject.

4. Psychopharmacology of depersonalization

Treatment recommendations and guidelines for DPdisorder have not been established and no studies

specifically investigated the role of pharmacotherapy inameliorating DP symptoms in mood and anxietydisorders. Medication options that have been reportedare mainly based on case reports and few controlledclinical trials have been published so far.

Most of the current literature is focused on seroto-ninergic neurotransmission but, despite anecdotalreports, there is no proven effective treatment for DP.Simeon et al. (2004) investigated the efficacy offluoxetine in a randomized, double-blind placebocontrolled trial of 54 patients with DP disorder.Intention-to-treat analysis revealed that fluoxetine wasnot superior to placebo for DP symptoms assessed usingthe Dissociative Experience Scale. Di Michele andBolino (2004) reported a remarkable improvement in DPsymptoms in a young patient with schizophrenia treatedwith citalopram and olanzapine speculating about apossible pharmacodynamic potentiation between the twodrugs. Almost all the serotonin reuptake inhibitors suchas fluoxetine (Simeon et al., 2004; Ratliff and Kerski,1995; Abbas et al., 1995; Fichtner et al., 1992),paroxetine (Strohle et al., 2000) and citalopram (DiMichele and Bolino, 2004; Sachdev, 2002) have beentried with no supporting evidence for a real role of thesedrugs in DP. In previous literature, tricyclics have alsobeen tested especially desipramine (Noyes et al., 1987)and clomipramine (Simeon et al., 1998) but in a limitednumber of patients.

Sierra et al. (2003) tested the efficacy of lamotrigine ina double-blind, placebo-controlled, crossover 12 weekstrial in 9 patients with DP disorder. The supporting evi-dence was related to possible glutamate hyperactivity inthe neurobiology of DP. The authors concluded thatlamotrigine alone was not significantly superior to place-bo and cannot be considered as a sole medication in thetreatment of DP.

Recent studies on the role of opioid antagonists inDP are definitely intriguing. The endogenous opioidsystem is well known to mediate stress-inducedanalgesia (Madden et al., 1977) and, for example inpost-traumatic stress disorder, the analgesic responsecan be blocked by pre-treatment with the opioidantagonist naloxone (Pitman et al., 1990). The κ-opioidsystem is also implicated in dissociation. Actuallyenadoline (a κ-opioid agonist) has been shown toinduce a DP syndrome in healthy subjects withperceptual disturbances and a sense of detachment(Walsh et al., 2001). High doses of opioid antagonistshave been successfully tried in dissociative symptomsin patients with borderline personality disorder (Bohuset al., 1999), post-traumatic stress disorder (Glover,1993) and DP disorder with chronic depersonalization

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(Nuller et al., 2001). Simeon and Knutelska (2005)recently published an open trial of naltrexone in 14patients with DP disorder. There was an average 30%reduction of symptoms as measured by the Clinician-Administered Dissociative States Scale, the CambridgeDepersonalization Scale and the DP subscale of theDissociative Experiences Scale.

In summary, very little is known about successfulpharmacological treatments of DP disorder and DPsymptoms in mood and anxiety disorders. A possiblerole for the serotonin reuptake inhibitors has emerged inrecent years but probably higher doses should be moredeeply investigated. Opioid antagonists seem promisingagents but selective κ-opioid antagonists, which may bemore targeted on DP symptoms, have not beendeveloped yet for use in humans.

5. Conclusions

Current literature points that DP experiences arefrequent and the association with life-threatening eventsmay suggest that they are part of a normal response totrauma and stress. However, DP seems bound up withdepression and anxiety and all studies give the impres-sion that its presence does not represent a generalindicator of distress but a marker of severity of a poorprognostic group. In anxiety disorders this is ratherevident especially in panic disorder where the presenceof DP is strictly interlinked with that of agoraphobia, ahigh prevalence of comorbidity, treatment resistance anda tendency towards chronicity (Table 2). In post-trau-matic stress disorder, DP, as a symptom of peritraumaticdissociation, plays a key role in the subsequentdevelopment of the disorder but its effect on the timecourse of the disease, its severity and response to treat-ment are still unknown. In mood disorders the literatureis limited and this issue has not been specificallyaddressed. However, in unipolar depression the pres-ence of DP seems to be associated with a longer andmore severe depressive phase and a poor response totreatment. Therefore, DP may represent a clinicalmarker of severity in mood and anxiety disorders andthe rational is supported by neurobiological under-pinnings that identify a strong disruption of specificcortico-limbic networks, involving the amygdala inparticular, resulting in an autonomic blunting.

Further research is needed, examining the role of DPin large-scale studies of patients with mood and anxietydisorders, using a standardized assessment of DP symp-toms as well as an examination of clinical subgroups.This data is relevant for prognosis and treatmentchoices.

References

Abbas, S., Chandra, P.S., Srivastava, M., 1995. The use of fluoxetineand buspirone for treatment-refractory depersonalization disorder.J. Clin. Psychiatry 56, 484.

Ackner, B., 1954. Depersonalization. I. Aetiology and phenomenol-ogy; II. Clinical syndromes. J. Ment. Sci. 100 (I, II), 838–872.

Ackner, B., Grant, O.A.,Maxwell, A.E., 1960. The prognostic significanceof depersonalization in depressive illnesses treated with electrocon-vulsive therapy. J. Neurol. Neurosurg. Psychiatry 23, 242–246.

Adolphs, R., Tranel, D., Damasio, H., Damasio, A., 1994. Impairedrecognition of emotion in facial expressions following bilateraldamage to the human amygdala. Nature 372, 669–672.

American Psychiatric Association, 1994. Diagnostic and StatisticalManual of Mental Disorders, 4th ed. American PsychiatricAssociation, Washington, DC.

Ball, S., Robinson, A., Shekhar, A., Walsh, K., 1997. Dissociativesymptoms in panic disorder. J. Nerv. Ment. Dis. 185, 755–760.

Bebbington, P.E., Hurry, J., Tennant, C., Sturt, E., Wing, J.K., 1981.Epidemiology of mental disorders in Camberwell. Psychol. Med.11, 561–579.

Bebbington, P.E., Marsden, L., Brewin, C.R., 1997. The need forpsychiatric treatment in the general population: the Camberwellneeds for care survey. Psychol. Med. 27, 821–834.

Benkelfat, C., Mefford, I.N., Masters, C.F., Nordahl, T.E., King, A.C.,Cohen, R.M., Murphy, D.L., 1991. Plasma catecholamines andtheir metabolites in obsessive–compulsive disorder. PsychiatryRes. 37, 321–331.

Bohus, M.J., Landwehrmeyer, G.B., Stiglmayr, C.E., Limberger, M.F.,Bohme, R., Schmahl, C.G., 1999. Naltrexone in the treatment ofdissociative symptoms in patients with borderline personalitydisorder: an open-label trial. J. Clin. Psychiatry 60, 598–603.

Bremner, J.D., 2004. Brain imaging in anxiety disorders. Exp. Rev.Neurotherapeutics 4, 275–284.

Bremner, J.D., Steinberg, M., Southwick, S.M., Johnson, D.R.,Charney, D.S., 1993. Use of the Structured Clinical Interview forDSM-IV Dissociative Disorders for systematic assessment ofdissociative symptoms in posttraumatic stress disorder. Am. J.Psychiatry 150, 1011–1014.

Buchel, C., Morris, J., Dolan, R.J., Friston, K.J., 1998. Brain systemsmediating aversive conditioning: an event-related fMRI study.Neuron. 20, 947–957.

Cahill, L., Haier, R.J., Fallon, J., Alkire, M.T., Tang, C., Keator, D.,Wu, J., McGaugh, J.L., 1996. Amygdala activity at encodingcorrelated with long-term, free recall of emotional information.Proc. Natl. Acad. Sci. U. S. A. 93, 8016–8021.

Cassano,G.B., Petracca,A., Perugi,G., Toni, C., Tundo,A.,Roth,M., 1989.Derealization and panic attacks: a clinical evaluation on 150 patientswith panic disorder/agoraphobia. Compr. Psychiatry 30, 5–12.

Critchley, H.D., Mathias, C.J., Josephs, O., O'Doherty, J., Zanini, S.,Dewar, B.K., Cipolotti, L., Shallice, T., Dolan, R.J., 2003. Humancingulate cortex and autonomic control: converging neuroimagingand clinical evidence. Brain 126, 2139–2152.

Davidson, J.R., Kudler, H.S., Saunders, W.B., Smith, R.D., 1990.Symptom and comorbidity patterns in World War II and Vietnamveterans with posttraumatic stress disorder. Compr. Psychiatry 31,162–170.

Davidson, R.J., Sutton, S.K., 1995. Affective neuroscience: theemergence of a discipline. Curr. Opin. Neurobiol. 5, 217–224.

Di Michele, V., Bolino, F., 2004. Adjunctive citalopram is effective onhallucinations and depersonalization symptoms: a case report. Eur.Psychiatry 19, 185.

98 M. Mula et al. / Journal of Affective Disorders 99 (2007) 91–99

Downer, J.L., 1961. Changes in visual gnostic functions and emotionalbehaviour following unilateral temporal pole damage in the ‘split-brain’ monkey. Nature 191, 50–51.

Drevets,W.C.,Videen, T.O., Price, J.L., Preskorn, S.H.,Carmichael, S.T.,Raichle, M.E., 1992. A functional anatomical study of unipolardepression. J. Neurosci. 12, 3628–3641.

Eriksson, N.G., Lundin, T., 1996. Early traumatic stress reactionsamong Swedish survivors of the M/S Estonia disaster. Br. J.Psychiatry 169, 713–716.

Fichtner, C.G., Horevitz, R.P., Braun, B.G., 1992. Fluoxetine in deper-sonalization disorder. Am. J. Psychiatry 149, 1750–1751.

Frank, E., Cyranowski, J.M., Rucci, P., Shear, M.K., Fagiolini, A.,Thase, M.E., Cassano, G.B., Grochocinski, V.J., Kostelnik, B.,Kupfer, D.J., 2002. Clinical significance of lifetime panic spectrumsymptoms in the treatment of patients with bipolar I disorder. Arch.Gen. Psychiatry 59, 905–911.

Freeman, M.P., Freeman, S.A., McElroy, S.L., 2002. The comorbidityof bipolar and anxiety disorders: prevalence, psychobiology, andtreatment issues. J. Affect. Disord. 68, 1–23.

Geschwind, N., 1965a. Disconnexion syndromes in animals and man:I. Brain 88, 237–294.

Geschwind, N., 1965b. Disconnexion syndromes in animals and man:II. Brain 88, 585–644.

Gill, D., Lambourn, J., 1979. Indications for electric convulsion therapyand its use by senior psychiatrists. Br. Med. J. 6172, 1169–1171.

Gloor, P., 1990. Experiential phenomena of temporal lobe epilepsy.Facts and hypotheses. Brain 113, 1673–1694.

Glover, H., 1993. A preliminary trial of nalmefene for the treatment ofemotional numbing in combat veterans with post-traumatic stressdisorder. Isr. J. Psychiatry Relat. Sci. 30, 255–263.

Goodwin, F.K., Jamison, K.R., 1990.Manic Depressive Illness. OxfordUniversity Press, New York.

Goodwin, R.D., Hoven, C.W., 2002. Bipolar–panic comorbidity in thegeneral population: prevalence and associated morbidity. J. Affect.Disord. 70, 27–33.

Hamann, S.B., Stefanacci, L., Squire, L.R., Adolphs, R., Tranel, D.,Damasio, H., Damasio, A., 1996. Recognizing facial emotion.Nature 379, 497.

Hunter, E.C., Sierra, M., David, A.S., 2004. The epidemiology ofdepersonalisation and derealisation. A systematic review. Soc.Psychiatry Psychiatr. Epidemiol. 39, 9–18.

Jimenez-Genchi, A.M., 2004. Repetitive transcranial magneticstimulation improves depersonalization: a case report. CNS Spectr.9, 375–376.

Katerndahl, D.A., 2000. Predictors of the development of phobicavoidance. J. Clin. Psychiatry 61, 618–623.

LeDoux, J.E., Iwata, J., Cicchetti, P., Reis, D.J., 1988. Differentprojections of the central amygdaloid nucleusmediate autonomic andbehavioral correlates of conditioned fear. J. Neurosci. 8, 2517–2529.

Madden IV, J., Akil, H., Patrick, R.L., Barchas, J.D., 1977. Stress-induced parallel changes in central opioid levels and pain responsive-ness in the rat. Nature 265, 358–360.

Marquez, M., Segui, J., Garcia, L., Canet, J., Ortiz, M., 2001. Is panicdisorder with psychosensorial symptoms (depersonalization–derealization) a more severe clinical subtype? J. Nerv. Ment. Dis.189, 332–335.

Mayer-Gross, W., 1935. On depersonalization. Br. J. Med. Psychol.15, 103–126.

Michaels, A.J., Michaels, C.E., Moon, C.H., Smith, J.S., Zimmerman,M.A., Taheri, P.A., Peterson, C., 1999. Posttraumatic stress dis-order after injury: impact on general health outcome and early riskassessment. J. Trauma 47, 460–466.

Michal, M., Kaufhold, J., Grabhorn, R., Krakow, K., Overbeck, G.,Heidenreich, T., 2005. Depersonalization and social anxiety.J. Nerv. Ment. Dis. 193, 629–632.

Mizobe, Y., Yamada, K., Fujii, I., 1992. The sequence of panic symp-toms. Jpn. J. Psychiatry Neurol. 46, 597–601.

Morris, J.S., Friston, K.J., Dolan, R.J., 1997. Neural responses to salientvisual stimuli. Proc. R. Soc. Lond., B Biol. Sci. 264, 769–775.

Noyes Jr, R., Kletti, R., 1977. Depersonalization in response to life-threatening danger. Compr. Psychiatry 18, 375–384.

Noyes Jr., R., Kuperman, S., Olson, S.B., 1987. Desipramine: apossible treatment for depersonalization disorder. Can. J. Psychi-atry 32, 782–784.

Noyes Jr., R., Woodman, C., Garvey, M.J., Cook, B.L., Suelzer, M.,Clancy, J., Anderson, D.J., 1992. Generalized anxiety disorder vs.panic disorder. Distinguishing characteristics and patterns ofcomorbidity. J. Nerv. Ment. Dis. 180, 369–379.

Nuller, Y.L., 1982. Depersonalisation – symptoms, meaning, therapy.Acta Psychiatr. Scand. 66, 451–458.

Nuller, Y.L., Morozova, M.G., Kushnir, O.N., Hamper, N., 2001.Effect of naloxone therapy on depersonalization: a pilot study.J. Psychopharmacol. 15, 93–95.

Paus, T., Barrett, J., 2004. Transcranial magnetic stimulation(TMS) of the human frontal cortex: implications for repetitiveTMS treatment of depression. J. Psychiatry Neurosci. 29,268–279.

Persson, G., Nordlund, C.L., 1985. Agoraphobics and social phobics:differences in background factors, syndrome profiles and thera-peutic response. Acta Psychiatr. Scand. 71, 148–159.

Perugi, G., Toni, C., Akiskal, H.S., 1999. Anxious–bipolar comorbid-ity. Diagnostic and treatment challenges. Psychiatr. Clin. NorthAm. 22, 565–583 (viii).

Phillips, M.L., Medford, N., Senior, C., Bullmore, E.T., Suckling, J.,Brammer, M.J., Andrew, C., Sierra, M., Williams, S.C., David, A.S.,2001. Depersonalization disorder: thinking without feeling. Psychi-atry Res. 108, 145–160.

Pini, S., Cassano, G.B., Simonini, E., Savino, M., Russo, A., Mont-gomery, S.A., 1997. Prevalence of anxiety disorders comorbidity inbipolar depression, unipolar depression and dysthymia. J. Affect.Disord. 42, 145–153.

Pitman, R.K., van der Kolk, B.A., Orr, S.P., Greenberg, M.S., 1990.Naloxone-reversible analgesic response to combat-related stimuli inposttraumatic stress disorder. A pilot study. Arch. Gen. Psychiatry 47,541–544.

Ratliff, N.B., Kerski, D., 1995.Depersonalization treatedwith fluoxetine.Am. J. Psychiatry 152, 1689–1690.

Ross, C.A., Joshi, S., Currie, R., 1991. Dissociative experiences in thegeneral population: a factor analysis. Hosp. Community Psychiatry42, 297–301.

Roth, M., 1960. The phobic anxiety–depersonalization syndrome andsome general aetiological problems in psychiatry. J. Neuropsychi-atry 1, 293–306.

Roth, M., Argyle, N., 1988. Anxiety, panic and phobic disorders: anoverview. J. Psychiatr. Res. 22 (Suppl 1), 33–54.

Sachdev, P., 2002. Citalopram–Clonazepam combination for primarydepersonalization disorder: a case report. Aust. N. Z. J. Psychiatry36, 424–425.

Schilder, P., 1938. The social neurosis. Psychoanal. Rev. 25, 1–19.Sedman, G., Kenna, J.C., 1963. Depersonalization and mood changes

in schizophrenia. Br. J. Psychiatry 109, 669–673.Sedman, G., Reed, G.F., 1963. Depersonalization phenomena in obses-

sional personalities and in depression. Br. J. Psychiatry 109,376–379.

99M. Mula et al. / Journal of Affective Disorders 99 (2007) 91–99

Segui, J., Marquez, M., Garcia, L., Canet, J., Salvador-Carulla, L.,Ortiz, M., 2000. Depersonalization in panic disorder: a clinicalstudy. Compr. Psychiatry 41, 172–178.

Shelton, R.C., Loosen, P.T., 1993. Sleep deprivation accelerates theresponse to nortriptyline. Prog. Neuro-Psychopharmacol. Biol.Psychiatry 17, 113–123.

Shin, L.M., Kosslyn, S.M., McNally, R.J., Alpert, N.M., Thompson,W.L., Rauch, S.L., Macklin, M.L., Pitman, R.K., 1997. Visualimagery and perception in posttraumatic stress disorder. A positronemission tomographic investigation. Arch. Gen. Psychiatry 54 (3),233–241.

Sierra, M., Berrios, G.E., 1998. Depersonalization: neurobiologicalperspectives. Biol. Psychiatry 44, 898–908.

Sierra, M., Berrios, G.E., 2001. The phenomenological stability ofdepersonalization: comparing the old with the new. J. Nerv. Ment.Dis. 189, 629–636.

Sierra, M., Senior, C., Dalton, J., McDonough, M., Bond, A., Phillips,M.L., O'Dwyer, A.M., David, A.S., 2002a. Autonomic response indepersonalization disorder. Arch. Gen. Psychiatry 59, 833–838.

Sierra, M., Lopera, F., Lambert, M.V., Phillips, M.L., David, A.S.,2002b. Separating depersonalisation and derealisation: the rele-vance of the “lesion method”. J. Neurol. Neurosurg. Psychiatry 72,530–532.

Sierra, M., Phillips, M.L., Ivin, G., Krystal, J., David, A.S., 2003. Aplacebo-controlled, cross-over trial of lamotrigine in depersonal-ization disorder. J. Psychopharmacol. 17, 103–105.

Simeon, D., 2004. Depersonalisation disorder: a contemporary over-view. CNS Drugs 18, 343–354.

Simeon, D., Knutelska, M., 2005. An open trial of naltrexone in thetreatment of depersonalization disorder. J. Clin. Psychopharmacol.25, 267–270.

Simeon, D., Stein, D.J., Hollander, E., 1998. Treatment of deperson-alization disorder with clomipramine. Biol. Psychiatry 44,302–303.

Simeon, D., Guralnik, O., Hazlett, E.A., Spiegel-Cohen, J., Hollander,E., Buchsbaum, M.S., 2000. Feeling unreal: a PET study ofdepersonalization disorder. Am. J. Psychiatry 157, 1782–1788.

Simeon, D., Guralnik, O., Knutelska, M., Hollander, E., Schmeidler,J., 2001. Hypothalamic–pituitary–adrenal axis dysregulation indepersonalization disorder. Neuropsychopharmacology 25,793–795.

Simeon, D., Guralnik, O., Knutelska, M., Yehuda, R., Schmeidler, J.,2003a. Basal norepinephrine in depersonalization disorder.Psychiatry Res. 121, 93–97.

Simeon, D., Knutelska, M., Nelson, D., Guralnik, O., 2003b. Feelingunreal: a depersonalization disorder update of 117 cases. J. Clin.Psychiatry 64, 990–997.

Simeon, D., Guralnik, O., Schmeidler, J., Knutelska, M., 2004. Fluox-etine therapy in depersonalisation disorder: randomised controlledtrial. Br. J. Psychiatry 185, 31–36.

Sokolski, K.N., Denson, T.F., 2003. Exacerbation of mania secondaryto right temporal lobe astrocytoma in a bipolar patient previouslystabilized on valproate. Cogn. Behav. Neurol. 16, 234–238.

Stanton, B.R., David, A.S., Cleare, A.J., Sierra, M., Lambert, M.V.,Phillips, M.L., Porter, R.J., Gallagher, P., Young, A.H., 2001.Basal activity of the hypothalamic–pituitary–adrenal axis inpatients with depersonalization disorder. Psychiatry Res. 104,85–89.

Stein, M.B., Goldin, P.R., Sarren, J., Zorilla, L.T.E., Brown, G.G.,2002. Increased amygdala activation to angry and contemptuousfaces in generalized social phobia. Arch. Gen. Psychiatry 59,1027–1034.

Strickland, P.L., Deakin, J.F., Percival, C., Dixon, J., Gater, R.A., Goldberg,D.P., 2002. Bio-social origins of depression in the community.Interactions between social adversity, cortisol and serotonin neuro-transmission. Br. J. Psychiatry 180, 168–173.

Strohle, A., Kumpfel, T., Sonntag, A., 2000. Paroxetine for deper-sonalization associated with multiple sclerosis. Am. J. Psychiatry157, 150.

Vovin, Ria, Eryshev, O.F., Khvilivitskii, Tia, 1978. Clinical features ofmanic–depressive psychosis with organic brain defects. Zh.Nevropatol. Psikhiatr. Im. S S Korsakova 78, 397–402.

Walsh, S.L., Strain, E.C., Abreu, M.E., Bigelow, G.E., 2001. Enado-line, a selective kappa opioid agonist: comparisonwith butorphanoland hydromorphone in humans. Psychopharmacology (Berl.) 157,151–162.

Watts, C.A., 1985. A long-term follow-up of schizophrenic patients:1946–1983. J. Clin. Psychiatry 46, 210–216.

Wilkinson, D.J., Thompson, J.M., Lambert, G.W., Jennings, G.L.,Schwarz, R.G., Jefferys, D., Turner, A.G., Esler, M.D., 1998.Sympathetic activity in patients with panic disorder at rest, underlaboratory mental stress, and during panic attacks. Arch. Gen.Psychiatry 55, 511–520.

Ziemann, U., 2004. TMS induced plasticity in human cortex. Rev.Neurosci. 15, 253–266.