Introduction

The experience of feeling detached from one's own thoughts, body, or surroundings, as if observing oneself from outside or living in a dream, has been described across cultures and historical periods (Sierra & Berrios, 2001). For most individuals, such experiences are transient, lasting moments triggered by fatigue, stress, or sensory deprivation. However, for a significant minority, these episodes become persistent or recurrent, causing substantial distress and functional impairment (Simeon, 2004). This clinical condition is known as depersonalization-derealization disorder (DPDR).

Despite its prevalence, comparable to that of obsessive-compulsive disorder and greater than that of schizophrenia, DPDR remains one of the most neglected disorders in psychiatric research and clinical practice (Sierra & David, 2011). Patients often suffer for years before receiving an accurate diagnosis, frequently being misdiagnosed with anxiety disorders, depression, or even psychosis (Baker et al., 2003). The maintenance of reality testing during episodes (patients know their perceptions are unreal) paradoxically contributes to this diagnostic neglect, as patients may be dismissed as "not seriously ill" (Medford, 2012).

The past two decades have witnessed renewed interest in DPDR, driven by advances in neuroimaging, the development of validated assessment instruments such as the Cambridge Depersonalization Scale (Sierra & Berrios, 2000), and growing awareness of the disorder's distinct neurobiological signature (Phillips & Sierra, 2003). This review aims to synthesize current knowledge across multiple domains: phenomenological characterization, diagnostic criteria, epidemiology, etiological factors, neurobiological mechanisms, and treatment approaches. By integrating findings from clinical, psychological, and neuroscientific research, the researcher presents an updated framework for understanding DPDR as a disorder of self-awareness and emotional processing (Sierra & David, 2011; Walter & Michal, 2024).

Literature Review

The existing literature on depersonalization-derealization disorder (DPDR) presents a multifaceted picture, with key contributions spanning phenomenology, epidemiology, neurobiology, and treatment, though significant gaps remain. Phenomenologically, the disorder is characterized by persistent or recurrent feelings of detachment from one's self or surroundings, a state described as "thinking without feeling," while reality testing remains intact (Sierra & Berrios, 2000, 2001; Phillips et al., 2001; Medford, 2012; American Psychiatric Association, 2022). Epidemiologically, it is a significant public health concern, affecting 1-2% of the general population with an onset in adolescence, yet it remains underrecognized, frequently misdiagnosed as anxiety or depression (Hunter et al., 2004; Baker et al., 2003; Simeon et al., 2003; Yang et al., 2023; Lee et al., 2021). Etiologically, robust associations exist with childhood interpersonal trauma, including emotional abuse and neglect (Simeon et al., 2001; Shevlin & Elklit, 2023; Spinhoven & Penninx, 2022), a finding that interacts with personality factors like absorption (Simeon et al., 2002; Lyssenko et al., 2018).

The most compelling neurobiological model is the fronto-limbic inhibitory mechanism, supported by functional neuroimaging studies showing prefrontal hyperactivation coupled with limbic hypoactivation in response to emotional stimuli (Phillips et al., 2001; Phillips & Sierra, 2003; Medford et al., 2006; Sierra & David, 2011; Fineberg & Gabbay, 2022; Terpou et al., 2021). This pattern is distinct from hyperarousal PTSD, where the opposite pattern is observed (Lanius et al., 2010; Spiegel, 2025). This neural profile is complemented by objective autonomic blunting and reduced interoceptive accuracy, suggesting a systematic downregulation of emotional and bodily signals (Horn et al., 2020; Sedeno et al., 2014; Saini et al., 2022). Psychologically, the disorder is maintained by a cycle of catastrophic misinterpretation of dissociative experiences, leading to hypervigilance and self-focused attention (Hunter et al., 2003; Guralnik et al., 2000; Walter & Michal, 2024). For treatment, cognitive-behavioral therapy (CBT) is the best-documented psychotherapeutic approach, with a recent feasibility trial showing promise (Hunter et al., 2003, 2025; Llewellyn & Peters, 2022), while evidence for mindfulness-based approaches and Acceptance and Commitment Therapy (ACT) is preliminary (Somer et al., 2013; Ginzburg & Biran, 2023). Conversely, the evidence base for pharmacological interventions is poor, with SSRIs, lamotrigine, and naltrexone showing limited, mixed, or preliminary results and no agent being FDA-approved (Simeon, 2004; Sierra et al., 2003, 2006; Simeon & Knutelska, 2005; Wang et al., 2024; Wilkhoo et al., 2024; Vermetten & Lanius, 2022). Prognostically, the disorder often follows a chronic course, but factors like social support and psychological treatment are associated with better outcomes (Simeon et al., 2003; Baker et al., 2003; Michal et al., 2016; Schmalbach & Petrowski, 2023). Overall, despite advances in neuroimaging that have validated the distinct neurobiological signature of DPDR, critical gaps exist in treatment development, particularly in large-scale, adequately powered randomized controlled trials for both psychotherapeutic and pharmacological interventions.

Methodology and Search Strategy

This review was conducted following the principles of systematic review methodology as outlined by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Page et al., 2021), adapted for a narrative synthesis given the heterogeneous nature of the literature on depersonalization-derealization disorder (DPDR).

Search Strategy

A comprehensive literature search was performed across multiple electronic databases, including PubMed/MEDLINE, PsycINFO, Scopus, and Google Scholar, for publications up to December 2025. The search was not restricted by publication date to ensure inclusion of foundational historical and phenomenological literature, with emphasis on publications from 2000 onwards to capture contemporary neurobiological and clinical advances.

The search strategy employed combinations of the following keywords and Medical Subject Headings (MeSH) terms: ("depersonalization" OR "derealization" OR "depersonalization-derealization disorder" OR "dissociative disorders") AND ("neurobiology" OR "neuroimaging" OR "functional MRI" OR "PET" OR "fronto-limbic" OR "amygdala" OR "prefrontal cortex") AND ("etiology" OR "risk factors" OR "trauma" OR "childhood adversity") AND ("treatment" OR "cognitive-behavioral therapy" OR "pharmacotherapy" OR "psychotherapy" OR "neuromodulation") AND ("epidemiology" OR "prevalence" OR "diagnosis" OR "assessment").

Additional articles were identified through hand-searching of reference lists of retrieved articles and relevant review papers. Citation tracking was performed using Web of Science and Google Scholar to identify subsequent studies citing key foundational papers (Sierra & Berrios, 2000; Phillips et al., 2001; Simeon, 2004).

Inclusion and Exclusion Criteria

Studies were included if they met the following criteria: (a) focused on depersonalization-derealization disorder or prominent depersonalization/derealization symptoms in clinical populations; (b) provided original empirical data, systematic reviews, meta-analyses, or comprehensive theoretical frameworks; (c) published in peer-reviewed journals or as academic book chapters; (d) written in English; and (e) addressed one or more of the following domains: phenomenology, diagnostic criteria, epidemiology, etiology, neurobiology, assessment, treatment, or prognosis.

Exclusion criteria included: (a) case reports (unless providing unique clinical or neurobiological insights not available in larger studies); (b) studies focused exclusively on depersonalization as a transient phenomenon in non-clinical populations without relevance to the disorder; (c) non-English publications; (d) dissertations, conference abstracts, and opinion pieces without empirical or comprehensive theoretical content; and (e) studies where depersonalization/derealization was assessed only as a secondary measure without specific focus on the construct.

Study Selection and Data Extraction

Title and abstract screening was conducted by the author to identify potentially relevant articles. Full-text review was then performed for articles meeting initial screening criteria. Data extraction focused on key findings relevant to each review domain: diagnostic phenomenology, epidemiological parameters, etiological and risk factors, neurobiological mechanisms (including functional neuroimaging, structural imaging, autonomic function, and interoceptive measures), assessment instruments, treatment outcomes (psychotherapy, pharmacotherapy, and neuromodulation), and prognostic indicators.

Quality Assessment and Synthesis

Given the narrative nature of this review and the heterogeneity of study designs (including randomized controlled trials, observational studies, case series, and systematic reviews), formal quality scoring was not performed. However, priority was given to findings from large-scale studies, well-controlled neuroimaging investigations, systematic reviews, and meta-analyses where available. For treatment literature, randomized controlled trials were prioritized over open-label studies and case series (Grant & Booth, 2009; Greenhalgh et al., 2018).

Synthesis was conducted using a thematic approach, organizing findings according to the major domains outlined above. Where conflicting evidence existed, this was noted and discussed. The review aimed to provide an integrated framework that bridges phenomenological, neurobiological, and clinical perspectives on DPDR, consistent with the approach recommended for narrative reviews of complex psychiatric conditions (Grant & Booth, 2009; Greenhalgh et al., 2018).

Diagnostic Criteria and Clinical Phenomenology

DSM-5-TR Diagnostic Criteria

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR), the diagnosis of depersonalization-derealization disorder requires the fulfillment of five criteria (American Psychiatric Association, 2022; PsychDB, 2021):

Criterion A: The presence of persistent or recurrent experiences of depersonalization, derealization, or both. Depersonalization is defined as experiences of unreality, detachment, or being an outside observer with respect to one's thoughts, feelings, sensations, body, or actions. This may include perceptual alterations, distorted sense of time, unreal or absent self, and emotional or physical numbing (Sierra & Berrios, 2000). Derealization refers to experiences of unreality or detachment with respect to surroundings, where individuals or objects are experienced as unreal, dreamlike, foggy, lifeless, or visually distorted (American Psychiatric Association, 2022).

Criterion B: During these experiences, reality testing remains intact. The individual maintains awareness that the alterations in perception are not reality-based, a feature that distinguishes DPDR from psychotic disorders (Millman et al., 2022; Heckers et al., 2013). This intact reality testing is a defining feature that patients themselves often emphasize: they know their experiences are not real, yet cannot stop feeling them (Sierra & David, 2011).

Criterion C: The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning (American Psychiatric Association, 2022). Patients frequently report difficulties maintaining relationships due to emotional numbing, occupational impairment due to concentration difficulties, and profound subjective distress about feeling "unreal" (Michal et al., 2016).

Criterion D: The disturbance is not attributable to the physiological effects of a substance (e.g., drug of abuse, medication) or another medical condition (e.g., seizure disorder) (American Psychiatric Association, 2022). This requires careful medical evaluation, as conditions such as temporal lobe epilepsy, brain tumors, and head trauma can produce depersonalization-like symptoms (Simeon, 2004).

Criterion E: The disturbance is not better explained by another mental disorder, such as schizophrenia, panic disorder, major depressive disorder, acute stress disorder, posttraumatic stress disorder, or another dissociative disorder (American Psychiatric Association, 2022; Spiegel & Zimmerman, 2025).

Phenomenological Distinctions

While depersonalization and derealization frequently co-occur, they represent distinct experiential phenomena (Sierra & Berrios, 2001). Depersonalization involves an alteration in one's relationship with oneself, a sense of estrangement from one's own mental processes or body (Medford, 2012). Patients commonly describe feeling like an automaton, observing themselves from outside, or being disconnected from their emotions. As one patient famously described, "I think, but I don't feel my thinking" (Phillips et al., 2001). This detachment extends to bodily sensations: patients may feel as though their limbs are not their own, that their voice sounds foreign, or that they are watching themselves in a movie (Sierra & Berrios, 2000).

Derealization, by contrast, involves an alteration in the perceived reality of the external world (Sierra & David, 2011). Patients describe their environment as two-dimensional, foggy, or as if viewed through a veil or behind glass (Lambert et al., 2001). Time may seem to slow down or speed up, and familiar places may feel strange or unfamiliar (American Psychiatric Association, 2022). Objects may appear distorted in size or shape, and colors may seem muted or excessively vivid (Sierra & Berrios, 2000).

A particularly important feature of DPDR is emotional numbing (de-affectualization), the sense that emotions are experienced incompletely or not at all (Medford, 2012). Patients may report knowing that they should feel love, fear, or sadness but experiencing only a hollow cognitive appreciation of these emotions rather than the subjective feeling states themselves (Phillips et al., 2001). Sierra and David (2011) characterized this as "thinking without feeling," a phrase that captures the core phenomenological disturbance.

Differential Diagnosis

DPDR must be distinguished from several other conditions, as accurate differentiation is essential for appropriate treatment selection and prognostic counseling. The key distinguishing features are summarized in Table 1 below.

Table 1: Differential Diagnosis of Depersonalization-Derealization Disorder

Source: Adapted from American Psychiatric Association (2022); PsychDB (2021); Simeon (2004); Spiegel & Zimmerman (2025).

In panic disorder, depersonalization may occur acutely during panic attacks but resolves between episodes (Simeon, 2004). However, some patients with panic disorder develop persistent depersonalization that meets criteria for DPDR, suggesting a potential etiological relationship (Baker et al., 2003).

In major depressive disorder, feelings of unreality may emerge but are typically secondary to mood symptoms and resolve with effective antidepressant treatment (Simeon et al., 2003). The dissociative subtype of posttraumatic stress disorder (PTSD) includes depersonalization and derealization as core features, but these occur in the context of full PTSD criteria and in response to trauma-related triggers (Spiegel, 2025; Lanius et al., 2010).

Schizophrenia spectrum disorders may involve depersonalization-like experiences, but the presence of delusional conviction regarding the unreality of self or world (or, conversely, bizarre delusions about the self) and the absence of intact reality testing distinguish these conditions from DPDR (Heckers et al., 2013). Patients with DPDR maintain insight that their experiences are not real, whereas patients with psychotic disorders may lack this insight (American Psychiatric Association, 2022; Millman et al., 2022).

Epidemiology

Prevalence

Transient depersonalization and derealization experiences are remarkably common in the general population, with estimates suggesting that 25-75% of individuals have experienced at least one such episode in their lifetime (Hunter et al., 2004). However, the prevalence of full-threshold DPDR is substantially lower. Systematic reviews indicate that DPDR affects approximately 1-2% of the general population (Yang et al., 2023). This prevalence rate is comparable to that of obsessive-compulsive disorder and exceeds that of schizophrenia, underscoring the clinical significance of the condition (Hunter et al., 2004; Lee et al., 2021).

A systematic review by Yang and colleagues (2023) synthesized data from multiple epidemiological studies and confirmed these prevalence estimates, while noting substantial methodological heterogeneity across studies. The authors found that point prevalence estimates ranged from 0.8% to 2.8% depending on the assessment instrument used and the population sampled. Schäfer and Harfst (2022) similarly reported that dissociative disorders, including DPDR, are more common in community samples than previously recognized, with rates approaching those of mood and anxiety disorders. The disorder appears to occur equally in men and women, distinguishing it from several other dissociative and anxiety disorders that show female predominance (Simeon et al., 2003; Michal et al., 2016).

Age of Onset

DPDR typically emerges during adolescence or early adulthood (Baker et al., 2003). The mean age of onset is 16 years, with the majority of cases diagnosed before age 20 (Simeon et al., 2003). Onset in early or middle childhood is well-documented but may be underrecognized due to children's limited capacity to articulate these complex experiences (Simeon, 2004). Onset after age 25 is relatively uncommon, accounting for only about 5% of cases, and onset after age 40 is rare (Baker et al., 2003; Michal et al., 2016).

Course and Comorbidity

The course of DPDR is variable (Simeon, 2004). Some individuals experience episodic symptoms that remit spontaneously or with treatment, while others develop a chronic, unremitting course (Michal et al., 2016). Longitudinal studies suggest that for many patients, the disorder follows a persistent trajectory lasting years or decades without intervention (Simeon et al., 2003; Baker et al., 2003). A retrospective study of 117 cases found that the mean duration of illness at presentation was approximately 16 years, highlighting the chronicity of untreated DPDR (Simeon et al., 2003). Schmalbach and Petrowski (2023) found in a 10-year follow-up study that depersonalization symptoms showed moderate stability over time, with approximately 40% of patients continuing to meet diagnostic criteria at follow-up.

Comorbidity is the rule rather than the exception in DPDR (Baker et al., 2003). According to clinical studies, up to 72% of individuals with DPDR meet criteria for at least one additional psychiatric disorder (Simeon et al., 2003). Anxiety disorders (particularly panic disorder and social anxiety disorder) and major depressive disorder are the most common comorbid conditions (Michal et al., 2016). This high comorbidity rate has complicated efforts to establish the independent validity of DPDR, though accumulating evidence supports its status as a distinct diagnostic entity (Sierra & David, 2011; Yang et al., 2023).

A longitudinal study from the Gutenberg Health Study found that depersonalization symptoms predicted a worse course of depression, suggesting that DPDR may represent an adverse prognostic factor in comorbid conditions (Michal et al., 2024). This finding underscores the clinical importance of identifying and treating DPDR even when it occurs alongside other psychiatric disorders.

Etiology and Risk Factors

Trauma and Early Life Adversity

The most robustly established etiological factor in DPDR is exposure to severe stress, particularly during childhood (Simeon et al., 2001). Multiple studies have documented elevated rates of childhood interpersonal trauma among individuals with DPDR. A seminal study by Simeon and colleagues (2001) found that patients with depersonalization disorder reported significantly higher rates of childhood emotional abuse, physical abuse, and neglect compared to healthy controls. Specifically, 89% of patients reported some form of childhood trauma, compared to 23% of controls (Simeon et al., 2001).

The specific types of trauma most strongly associated with DPDR include emotional abuse and neglect, witnessing domestic violence, and having a severely impaired or mentally ill parent (Simeon et al., 2001; Simeon, 2004). Shevlin and Elklit (2023) conducted a meta-analytic review confirming that childhood interpersonal trauma, particularly emotional abuse and neglect, shows a robust association with dissociative experiences across clinical and non-clinical populations. Notably, the relationship between trauma and depersonalization may operate through a psychological "dampening" mechanism: chronic exposure to overwhelming stress may lead individuals to develop a habitual pattern of emotional detachment as a protective strategy, which becomes generalized and persists even in the absence of ongoing threat (Walter & Michal, 2024). Spinhoven and Penninx (2022) found in a longitudinal cohort study that childhood maltreatment predicted the development of depersonalization symptoms over time, with the effect partially mediated by emotion regulation difficulties.

Personality factors also appear to moderate the relationship between trauma and DPDR (Simeon et al., 2002). Individuals with higher levels of absorption (a tendency to become immersed in internal experiences) and hypnotizability may be more vulnerable to developing depersonalization in response to trauma (Simeon et al., 2002). This finding is consistent with the broader literature linking dissociation to hypnotic susceptibility (Lyssenko et al., 2018).

Stress and Precipitating Factors

While childhood trauma represents a distal risk factor, acute stressors often precipitate the onset or exacerbation of DPDR symptoms (Baker et al., 2003). Common precipitants include severe life stress, panic attacks (which may trigger depersonalization that then becomes persistent), substance use (particularly cannabis, hallucinogens, or MDMA), and physical illness (Simeon, 2004). The disorder may also emerge following head injury or neurological illness, though such cases must be distinguished from organic conditions that directly cause depersonalization-like symptoms (Simeon, 2004).

In a large case series of 204 patients, Baker and colleagues (2003) found that the most common precipitating factors were severe stress (41% of cases), a panic attack (28%), and substance use (15%). Interestingly, many patients could identify a specific triggering event, while others described a gradual, insidious onset without a clear precipitant (Baker et al., 2003).

Psychological Models

Several psychological models have been proposed to explain the maintenance of DPDR symptoms (Hunter et al., 2003). The cognitive-behavioral model developed by Hunter and colleagues (2003) proposes that depersonalization arises from a catastrophic misinterpretation of normally transient dissociative experiences. According to this model, individuals who experience depersonalization in response to stress (a normative phenomenon) may respond with anxiety and hypervigilance, which paradoxically intensifies and perpetuates the symptoms (Hunter et al., 2003). This creates a self-maintaining cycle: depersonalization ? anxiety about the experience ? increased self-focused attention ? amplification of symptoms ? further anxiety (Hunter et al., 2003).

Guralnik and colleagues (2000) examined cognitive processes in depersonalization and found evidence of selective attention to internal states and difficulties with cognitive reappraisal. These cognitive biases may contribute to the persistence of symptoms by preventing patients from disengaging from dissociative experiences (Guralnik et al., 2000).

The emotion regulation framework offers a complementary perspective (Walter & Michal, 2024). Walter and Michal (2024) argue that DPDR can be understood as an extreme, maladaptive form of the emotion regulation strategy of detachment or cognitive distancing. While such strategies are adaptive when used flexibly, their chronic and inflexible application leads to the pervasive emotional numbing characteristic of the disorder (Ochsner & Gross, 2005; Walter & Michal, 2024).

Neurobiology of Depersonalization-Derealization Disorder

Functional Neuroimaging Findings

Neuroimaging studies have consistently identified patterns of functional abnormality in DPDR that distinguish it from both healthy controls and other psychiatric disorders (Phillips et al., 2001; Sierra & David, 2011). The most replicated finding is a fronto-limbic imbalance characterized by prefrontal hyperactivation coupled with limbic (particularly amygdala) hypoactivation in response to emotional stimuli (Phillips & Sierra, 2003; Medford et al., 2006; Fineberg & Gabbay, 2022).

Phillips and colleagues (2001) were among the first to demonstrate this pattern using positron emission tomography (PET). In their study, patients with depersonalization disorder showed increased activation in prefrontal cortical regions (particularly right dorsolateral and ventrolateral prefrontal cortex) and decreased activation in limbic regions (including the amygdala and insula) when viewing emotionally aversive stimuli compared to healthy controls (Phillips et al., 2001). This pattern suggests an "executive override" mechanism whereby prefrontal regions actively suppress emotional responses at the limbic level (Phillips & Sierra, 2003).

Sierra and David (2011) synthesized these findings into an influential model proposing that depersonalization reflects a selective impairment in the integration of emotional information with self-awareness. According to this model, the prefrontal hyperactivation represents an attempt to cognitively control emotional responses, but this top-down regulation is achieved at the cost of dampening the subjective experience of emotion (Sierra & David, 2011; Medford, 2012).

Medford and colleagues (2006) extended these findings using functional MRI, demonstrating that patients with DPDR show reduced amygdala response to fearful faces despite normal cognitive recognition of emotional expressions. This dissociation between cognitive and affective processing of emotional stimuli is a hallmark of the disorder (Medford et al., 2006). The authors concluded that depersonalization involves a selective disruption of the affective component of emotional processing, while the cognitive component remains intact (Medford, 2012).

Büetiger and colleagues (2020) examined neural correlates of depersonalization in individuals at clinical high-risk for psychosis and those with full-threshold DPDR. They found overlapping patterns of fronto-limbic dysregulation, suggesting that depersonalization may represent a transdiagnostic dimension of experience with common neurobiological underpinnings (Büetiger et al., 2020). This finding is consistent with the high rates of depersonalization across multiple psychiatric disorders (Lyssenko et al., 2018).

Terpou and colleagues (2021) conducted a systematic review of functional neuroimaging studies in dissociation and found consistent evidence for prefrontal hyperactivation and limbic hypoactivation across dissociative disorders, supporting the fronto-limbic inhibition model. Rabellino and colleagues (2023) extended these findings by examining default mode network connectivity in dissociative states, finding altered connectivity between prefrontal regions and limbic structures that correlated with symptom severity.

Autonomic and Interoceptive Abnormalities

The emotional dampening in DPDR is not merely subjective; it manifests objectively in autonomic and interoceptive domains (Horn et al., 2020). A systematic review by Horn and colleagues (2020) examined electrodermal activity (EDA) studies in depersonalization and found consistent evidence of reduced skin conductance responses to emotionally evocative stimuli. Patients show blunted autonomic arousal to unpleasant pictures, sounds, or autobiographical memories compared to controls, despite reporting equivalent cognitive appraisal of stimulus intensity (Horn et al., 2020; Sierra & David, 2011).

This autonomic blunting is accompanied by abnormalities in interoception, the perception of internal bodily states (Saini et al., 2022). Saini and colleagues (2022) proposed that depersonalization involves a systematic downregulation of interoceptive signals, effectively reducing the neural representation of bodily feelings. Using a heartbeat detection paradigm, they found that patients with DPDR showed significantly reduced interoceptive accuracy compared to healthy controls (Saini et al., 2022). This reduction in interoceptive information may explain the characteristic "empty" or "unreal" quality of self-experience in DPDR (Sedeno et al., 2014).

Sedeno and colleagues (2014) examined interoceptive processing in depersonalization using both behavioral and neuroimaging measures. They found that patients showed reduced activation in the insula, a key interoceptive hub, during interoceptive tasks, providing a neural correlate of the interoceptive deficits observed behaviorally (Sedeno et al., 2014).

Interestingly, while patients show reduced autonomic reactivity to emotional stimuli, they may demonstrate heightened baseline physiological arousal (Sierra & David, 2011). Studies have found elevated heart rate and skin conductance levels at rest, suggesting a state of chronic hypervigilance (Horn et al., 2020). The response to startling stimuli is also accelerated, consistent with the clinical observation that patients are in a state of heightened alertness, even as their emotional responses are suppressed (Sierra & David, 2011).

Structural Neuroimaging

Structural neuroimaging studies in DPDR are less numerous than functional studies but have yielded intriguing findings (Bremner, 2010). Some studies have reported alterations in gray matter volume in regions implicated in self-processing and body representation, including the temporoparietal junction, insula, and prefrontal cortex (Sierra & David, 2011). The temporoparietal junction, which plays a critical role in distinguishing self from other and in bodily self-consciousness, has been a particular focus of interest (Eddy, 2016).

Salami and colleagues (2020) conducted a systematic review of brain electrical activity studies in depersonalization and found evidence of altered connectivity in networks involved in self-referential processing and emotion regulation. These findings suggest that DPDR may involve not only regional abnormalities but also disrupted functional connectivity between brain regions (Salami et al., 2020).

Neurobiological Distinction from PTSD

An important validation of DPDR as a distinct neurobiological entity comes from studies comparing the dissociative subtype of PTSD to the hyperarousal subtype (Lanius et al., 2010). In hyperarousal PTSD, fMRI studies show increased amygdala and anterior insula activity with decreased medial prefrontal and rostral anterior cingulate activity, a pattern consistent with emotional dyscontrol and hyperreactivity (Lanius et al., 2010). In the dissociative subtype of PTSD (characterized by prominent depersonalization/derealization), this pattern is reversed: patients show prefrontal hyperactivation and limbic hypoactivation, mirroring the findings in primary DPDR (Lanius et al., 2010; Spiegel, 2025). This reversal suggests that the dissociative subtype represents a distinct neurobiological pathway involving emotion suppression rather than emotion hyperreactivity (Lanius et al., 2010).

Summary of Neurobiological Findings

The neurobiological findings across functional neuroimaging, autonomic physiology, interoception, and structural imaging converge on a consistent picture of DPDR as a disorder of fronto-limbic regulation and emotional processing. Table 2 provides a comprehensive summary of these findings across multiple domains.

Table 2: Summary of Neurobiological Findings in Depersonalization-Derealization Disorder

Assessment and Diagnosis

Clinical Interview

The diagnosis of DPDR is made through clinical interview, guided by DSM-5-TR criteria (American Psychiatric Association, 2022). Key elements include establishing the presence of persistent or recurrent depersonalization or derealization, confirming intact reality testing, ruling out substance-related or medical etiologies, and excluding other mental disorders that might better account for the symptoms (PsychDB, 2021).

A particular challenge in clinical assessment is the tendency of patients to withhold their symptoms due to fear of being labeled "crazy" or difficulty articulating their experiences (Simeon, 2004). Direct, non-judgmental questioning is essential. Useful probes include: "Have you ever felt as if you were outside your body, watching yourself from a distance?" and "Have you ever felt as if the world around you wasn't real, like you were in a dream or behind glass?" (Sierra & Berrios, 2000; Simeon, 2004).

The clinical interview should also assess the temporal course of symptoms (episodic vs. persistent), functional impairment, and the presence of comorbid conditions (Baker et al., 2003; Michal et al., 2016). A thorough trauma history should be obtained, given the strong association between childhood adversity and DPDR (Simeon et al., 2001; Shevlin & Elklit, 2023).

Structured Assessment Instruments

The Cambridge Depersonalization Scale (CDS), developed by Sierra and Berrios (2000), is the most widely used and well-validated instrument for assessing depersonalization severity. The CDS assesses both the frequency and duration of depersonalization symptoms across multiple domains, including emotional numbing, bodily alienation, and perceptual alterations (Sierra & Berrios, 2000). The scale consists of 29 items, each rated on both frequency (1-4) and duration (1-4), yielding a total score ranging from 29 to 232 (Sierra & Berrios, 2000). A score of 70 or above is considered clinically significant (Simeon, 2004).

Other useful measures include the Dissociative Experiences Scale (DES), though this scale assesses a broader range of dissociative phenomena and is less specific to DPDR (Lyssenko et al., 2018). The DES has been widely used in epidemiological studies, but its lack of specificity means that elevated scores may reflect other dissociative disorders or even normal dissociative experiences (Lyssenko et al., 2018). The Clinician-Administered Dissociative States Scale (CADSS) provides a structured interview format for assessing current dissociative symptoms and is particularly useful in research settings (Spiegel & Zimmerman, 2025).

Medical and Substance-Related Exclusion

Before establishing a diagnosis of DPDR, clinicians must rule out medical and substance-related etiologies (American Psychiatric Association, 2022). Conditions that can produce depersonalization-like symptoms include seizure disorders (particularly temporal lobe epilepsy), brain tumors, head trauma, migraine, and CNS infections (Simeon, 2004). A neurological evaluation, including EEG and neuroimaging, may be indicated in cases with atypical features or neurological signs (Simeon, 2004).

Substance-induced depersonalization is common, particularly with cannabis, hallucinogens, ketamine, and MDMA, and diagnosis requires that symptoms persist beyond the physiological effects of the substance (American Psychiatric Association, 2022). In clinical practice, it is important to obtain a detailed substance use history, as many patients may not spontaneously report substance use (Simeon, 2004). The diagnosis of DPDR can be made if symptoms persist for a significant period after cessation of substance use (typically weeks to months) and are not better accounted for by substance intoxication or withdrawal (American Psychiatric Association, 2022).

Treatment Approaches

Psychotherapy

Cognitive-behavioral therapy (CBT) represents the best-documented psychological treatment for DPDR (Hunter et al., 2003; Somer et al., 2013). The CBT model, developed by Hunter and colleagues (2003), targets the maintaining cycles of catastrophic misinterpretation, hypervigilance, and avoidance. Key components of treatment include:

• Psychoeducation: Normalizing depersonalization experiences and explaining their mechanism reduces secondary anxiety and catastrophic appraisals (Hunter et al., 2003). Patients are taught that depersonalization is the brain's natural response to stress, not a sign of impending psychosis (Somer et al., 2013).

• Cognitive restructuring: Identifying and challenging misinterpretations (e.g., "This means I'm going crazy") and replacing them with more accurate appraisals (e.g., "This is my brain's way of protecting itself from overwhelming stress") (Hunter et al., 2003). This component draws on standard cognitive therapy techniques adapted for dissociative symptoms (Somer et al., 2013).

• Attention training: Reducing self-focused attention and hypervigilance to internal states (Hunter et al., 2003). Patients are taught to shift attention externally and to disengage from monitoring their internal experiences (Guralnik et al., 2000).

• Grounding techniques: Using sensory anchors (tactile, visual, auditory) to reconnect with present-moment reality (Somer et al., 2013). Common grounding techniques include holding ice cubes, focusing on the sensation of feet on the floor, or describing the immediate environment in detail (Gentile et al., 2014).

• Behavioral activation: Gradually re-engaging with avoided situations (Hunter et al., 2003). Avoidance maintains symptoms by preventing disconfirmation of catastrophic beliefs, so structured exposure to previously avoided situations is an important component (Hunter et al., 2003).

A recent feasibility randomized trial of CBT for DPDR (CBT-f-DDD) by Hunter and colleagues (2025) found promising results, with acceptable recruitment and retention rates and preliminary evidence of symptom improvement. The trial randomized 60 patients to either 12 sessions of CBT or treatment as usual, and found a moderate-to-large effect size in favor of CBT (Hunter et al., 2025). These findings await replication in a fully powered efficacy trial.

Llewellyn and Peters (2022) conducted a systematic review and meta-analysis of CBT for depersonalization, finding moderate effect sizes for CBT compared to control conditions, though they noted the limited number of high-quality trials available. The authors concluded that CBT should be considered a first-line treatment for DPDR based on current evidence (Llewellyn & Peters, 2022).

Mindfulness-based approaches and dialectical behavior therapy (DBT) have also been employed, particularly for patients with prominent emotion regulation difficulties or co-occurring borderline personality disorder (Walter & Michal, 2024). However, controlled trials specific to DPDR are lacking (Somer et al., 2013). A systematic review by Somer and colleagues (2013) concluded that while case reports suggest potential benefit from mindfulness-based interventions, evidence from controlled trials is needed.

Ginzburg and Biran (2023) reported a case series of Acceptance and Commitment Therapy (ACT) for DPDR, finding promising results with reductions in depersonalization symptoms and improvements in psychological flexibility. However, larger controlled studies are required to establish efficacy (Ginzburg & Biran, 2023).

Pharmacotherapy

Pharmacological treatment of DPDR has yielded generally disappointing results, and no medication is currently FDA-approved specifically for this disorder (Wang et al., 2024; Wilkhoo et al., 2024). However, several agents have been investigated. Table 3 provides a comprehensive summary of pharmacological interventions for DPDR.

Table 3: Pharmacological Interventions for Depersonalization-Derealization Disorder

Sources: Simeon (2004); Simeon et al. (2003); Sierra et al. (2003); Sierra et al. (2006); Simeon & Knutelska (2005); Wang et al. (2024); Wilkhoo et al. (2024).

Selective serotonin reuptake inhibitors (SSRIs) are often prescribed given the high comorbidity with anxiety and depression (Simeon, 2004), but evidence for their efficacy in treating core depersonalization symptoms is limited (Wang et al., 2024). They may be useful for co-occurring mood or anxiety symptoms but rarely eliminate depersonalization itself (Simeon, 2004). A retrospective study of 117 patients found that only a minority reported meaningful improvement with SSRI monotherapy (Simeon et al., 2003).

Lamotrigine, an anticonvulsant, has shown mixed results (Sierra et al., 2003; Sierra et al., 2006). A small placebo-controlled crossover trial of lamotrigine (200 mg/day) in 10 patients found no significant benefit over placebo (Sierra et al., 2003). However, a retrospective study of 32 patients found that approximately 30% showed moderate to marked improvement when lamotrigine was added to existing medication (Sierra et al., 2006). The evidence remains insufficient to recommend lamotrigine as monotherapy, but it may be considered as an augmentation strategy in refractory cases (Wang et al., 2024).

Naltrexone, an opioid antagonist, has been evaluated in an open trial with some positive findings (Simeon & Knutelska, 2005). In an open-label study of 14 patients, naltrexone (50-150 mg/day) was associated with significant reduction in depersonalization symptoms in approximately half of participants (Simeon & Knutelska, 2005). The rationale for naltrexone comes from the observation that endogenous opioids may mediate dissociative states (Simeon & Knutelska, 2005). However, controlled studies are lacking (Wang et al., 2024).

Clomipramine, a tricyclic antidepressant with anti-obsessional properties, has shown benefit in some case reports but has not been systematically studied (Simeon, 2004). A systematic review by Wang and colleagues (2024) concluded that the quality of evidence for pharmacological interventions in DPDR is generally poor and that no medication can be recommended as first-line treatment at present.

A comprehensive review by Wilkhoo and colleagues (2024) similarly concluded that pharmacological options for DPDR remain limited, with most evidence coming from small open-label studies or case series. The authors called for larger, adequately powered randomized controlled trials of candidate agents including lamotrigine, naltrexone, and glutamatergic agents (Wilkhoo et al., 2024).

Vermetten and Lanius (2022) reviewed pharmacological approaches to dissociative disorders and noted that while SSRIs show limited efficacy, agents targeting the glutamatergic system (such as ketamine and lamotrigine) and the opioid system (naltrexone) warrant further investigation in controlled trials. They emphasized the importance of distinguishing between treatment of core dissociative symptoms versus comorbid mood and anxiety symptoms (Vermetten & Lanius, 2022).

Neuromodulation

Given the emerging understanding of DPDR as a disorder of cortical-limbic regulation, neuromodulation approaches have generated interest (Karris et al., 2017). Repetitive transcranial magnetic stimulation (rTMS) targeting prefrontal regions has been reported in case studies, with some patients showing improvement (Karris et al., 2017). A case report of two patients with chronic DPDR found that a course of rTMS over the right dorsolateral prefrontal cortex was associated with marked symptom reduction that persisted for several months (Karris et al., 2017). However, controlled trials are needed (Wang et al., 2024). Other neuromodulation techniques, including transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS), remain purely experimental in DPDR (Wilkhoo et al., 2024).

Summary of Treatment Approaches

Table 4 provides a comprehensive summary of all treatment modalities for DPDR, integrating psychotherapy, pharmacotherapy, and neuromodulation approaches.

Table 4: Comprehensive Summary of Treatment Approaches for Depersonalization-Derealization Disorder

Sources: Hunter et al. (2003); Somer et al. (2013); Hunter et al. (2025); Simeon (2004); Wang et al. (2024); Wilkhoo et al. (2024); Karris et al. (2017); Ginzburg & Biran (2023); Llewellyn & Peters (2022).

Treatment Considerations for Dissociative Subtype of PTSD

For patients whose depersonalization/derealization occurs in the context of PTSD (dissociative subtype), treatment modifications are recommended (Spiegel, 2025; Lanius et al., 2010). Standard exposure-based therapies may provoke overwhelming dissociation and should be modified to include a stabilization phase, gradual exposure, and explicit attention to dissociative symptoms (Spiegel, 2025). Hypnosis may be useful for containing traumatic memories and restructuring dissociative experiences (Spiegel & Zimmerman, 2025). The treatment guidelines from the International Society for Traumatic Stress Studies (ISTSS) recommend that patients with the dissociative subtype of PTSD receive skills training in affect and dissociation regulation before exposure therapy (Spiegel, 2025).

Van der Hart and Nijenhuis (2021) provided an updated framework for phase-oriented treatment of chronic dissociative disorders, emphasizing the importance of stabilization, trauma processing, and integration phases, with careful attention to pacing and the therapeutic relationship in patients with prominent dissociative symptoms.

Prognosis

The natural history of untreated DPDR is often chronic (Simeon et al., 2003; Baker et al., 2003). Longitudinal studies indicate that many patients experience symptoms for years or decades without spontaneous remission (Simeon et al., 2003). In the case series of 117 patients, the mean duration of illness at presentation was 16 years, and fewer than 20% reported any significant improvement without treatment (Simeon et al., 2003). However, treatment, particularly CBT, appears to offer meaningful improvement for many patients (Hunter et al., 2025; Llewellyn & Peters, 2022). Factors associated with poorer prognosis include early age of onset, presence of comorbid personality pathology, and ongoing exposure to severe stress (Simeon et al., 2002; Simeon, 2004).

The impact of DPDR on quality of life can be substantial (Michal et al., 2016; Michal et al., 2024). Patients often report difficulties in relationships (due to emotional numbing), occupational impairment (due to concentration difficulties and reduced engagement), and significant subjective distress (Michal et al., 2016). A longitudinal study from the Gutenberg Health Study found that depersonalization symptoms predicted a worse course of depression, suggesting that DPDR may represent an adverse prognostic factor in comorbid conditions (Michal et al., 2024). This finding underscores the importance of identifying and treating DPDR even when it co-occurs with other disorders (Michal et al., 2024).

Schmalbach and Petrowski (2023) found in a 10-year follow-up study that factors associated with better prognosis included higher levels of social support, lower baseline symptom severity, and engagement in psychological treatment. Conversely, ongoing trauma exposure, substance use, and comorbid personality pathology predicted a more chronic course (Schmalbach & Petrowski, 2023).

Limitations

This review is subject to several important limitations. Methodologically, the narrative synthesis approach involves inherent subjectivity in study selection and interpretation, while the restriction to English-language publications may have excluded relevant research and introduced cultural bias. The broader evidence base for DPDR is characterized by small sample sizes, lack of longitudinal neuroimaging data, significant clinical heterogeneity across patient populations, and considerable variability in diagnostic and assessment instruments across studies. The pharmacological treatment literature is particularly underdeveloped, consisting predominantly of small open-label trials and case reports with no large-scale, replicated placebo-controlled randomized trials available. Neurobiological findings, while compelling, cannot establish causality or specificity, and the dominant fronto-limbic inhibition model remains incomplete regarding neurotransmitter systems, mechanisms underlying bodily alienation and self-disturbances, and the transdiagnostic nature of dissociative phenomena. Additionally, research has focused predominantly on Western populations, pediatric and adolescent studies are scarce, and no validated clinical guidelines or biomarkers currently exist to translate findings into routine practice. These limitations underscore that many questions about DPDR remain unanswered and that clinical recommendations must be applied cautiously.

Future Research

Despite advances over the past two decades, substantial gaps remain in our understanding of DPDR, and no intervention has demonstrated robust efficacy in large-scale controlled trials. Several priorities for future research can be identified.

Neurobiological Mechanisms: While the fronto-limbic inhibition model is well-supported, the precise neural circuitry and neurotransmitter systems involved remain incompletely characterized. Studies combining neuroimaging with pharmacological probes could help identify treatment targets. The role of the glutamate system, given the effects of NMDA antagonists like ketamine in producing depersonalization-like states, warrants further investigation (Vermetten & Lanius, 2022). Future research should also examine the role of the default mode network and salience network in DPDR, building on preliminary findings (Rabellino et al., 2023; Fineberg & Gabbay, 2022).

Treatment Development: The most pressing clinical need is for effective treatments. Large-scale, adequately powered randomized controlled trials of both psychotherapeutic and pharmacological interventions are urgently needed. The development of novel compounds targeting the glutamate system or the opioid system warrants investigation (Wilkhoo et al., 2024; Wang et al., 2024). Comparative effectiveness trials of different psychotherapy approaches (CBT, ACT, mindfulness-based approaches) are also needed (Llewellyn & Peters, 2022; Ginzburg & Biran, 2023).

Subtyping: DPDR is clinically heterogeneous, with latent profile analysis suggesting meaningful subtypes that may differ in etiology, neurobiology, or treatment response (Millman et al., 2022). These subtypes may have different prognostic and treatment implications. Future research should validate these subtypes using neurobiological and treatment outcome data to inform personalized treatment approaches.

Childhood Presentations: DPDR often begins in childhood or early adolescence, yet research on pediatric populations is scarce. Developmentally appropriate assessment instruments and treatments are needed, and early intervention in at-risk children could potentially prevent chronic DPDR (Simeon, 2004). Longitudinal studies from childhood into adulthood could identify early risk factors and windows for intervention.

Predictors of Treatment Response: Identifying which patients respond to which interventions is a key step toward personalized treatment. Baseline neuroimaging measures, symptom profiles, or biomarker assessments might eventually guide treatment selection. Machine learning approaches to predict treatment response from baseline characteristics represent a promising future direction.

Cross-Cultural Research: Systematic studies of DPDR prevalence, phenomenology, and treatment response across cultures are needed, as cultural variations may influence help-seeking behavior and treatment outcomes. The expression of depersonalization symptoms may vary across cultural contexts, and cultural adaptations of CBT and other interventions may be needed.

Integration with Trauma Research: Given the strong link between childhood trauma and DPDR, future research should examine whether interventions targeting trauma-related mechanisms (such as trauma-focused CBT or eye movement desensitization and reprocessing [EMDR]) are effective for DPDR, particularly in patients with the dissociative subtype of PTSD (Van der Hart & Nijenhuis, 2021; Spiegel, 2025).

Conclusion

For clinicians, recognizing DPDR and providing accurate diagnosis offers immediate relief to patients who have often suffered in silence with fears of "going crazy." Many individuals with DPDR endure years of misdiagnosis, unnecessary investigations, and iatrogenic harm simply because the condition is not considered in differential diagnosis. Raising clinical awareness is therefore not an academic exercise but a therapeutic intervention in itself.

For researchers, the disorder presents fascinating questions about the nature of self-awareness, emotional experience, and the brain mechanisms that integrate perception with subjectivity. Understanding how the brain can maintain seemingly intact sensory processing while stripping experience of its subjective "felt" quality touches on fundamental issues in consciousness research.

As neurobiological understanding deepens and treatment trials advance, the prognosis for individuals with DPDR will likely improve. However, progress depends on sustained research funding, greater collaboration between clinical and basic science investigators, and a shift in how dissociative disorders are prioritized relative to other psychiatric conditions. For now, accurate diagnosis and targeted psychotherapy remain the cornerstones of care, but with continued empirical efforts, the future for those living with this distressing condition can be markedly brighter.

Acknowledgement

The author thanks the academic and clinical communities whose published research formed the basis of this review.

Conflict of Interest

The author does not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

Clinical Trial Registration

This research does not involve any clinical trials.

Permission to reproduce material from other sources

Not Applicable

Author Contributions

The sole author was responsible for the conceptualization, methodology, literature review, analysis, writing, and final approval of the manuscript.

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