Dissociative identity disorder

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Dissociative identity disorder
Other names	Multiple personality disorder, split personality
An artist's interpretation of one person with multiple "dissociated personality states"
Specialty	Psychiatry
Symptoms	At least two distinct and relatively enduring personality states, trouble remembering certain events
Complications	Suicide, self harm
Duration	Long-term
Causes	Childhood trauma, therapy induced
Diagnostic method	Based on clinical criteria
Differential diagnosis	Major depressive disorder, bipolar disorder, PTSD, psychotic disorder, personality disorder, conversion disorder
Treatment	Supportive care, counselling
Frequency	~2% of people

Dissociative identity disorder (DID), previously known as multiple personality disorder, is a mental disorder characterized by at least two distinct and relatively enduring personality states. This is accompanied by memory gaps beyond what would be explained by ordinary forgetfulness. These states alternately show in a person's behavior; presentations, however, are variable. Other problems which often occur in people with DID include borderline personality disorder (BPD), posttraumatic stress disorder (PTSD), depression, substance use disorders, self-harm, or anxiety.

Some professionals believe the cause to be childhood trauma. In about 90% of cases, there is a history of abuse in childhood, while other cases are linked to experiences of war or health problems during childhood. Genetic factors are also believed to play a role. An alternative hypothesis is that it is a by-product of techniques employed by some therapists, especially those using hypnosis. The diagnosis should not be made if the person's condition is better accounted for by substance abuse, seizures, imaginative play in children, or religious practices.

Treatment generally involves supportive care and counselling. The condition usually persists without treatment. It is believed to affect about 2% of the general population and 3% of those admitted to hospitals with mental health problems in Europe and North America. DID is diagnosed about six times more often in females than males. The number of cases increased significantly in the latter half of the 20th century, along with the number of identities claimed by those affected.

DID is controversial within both psychiatry and the legal system. In court cases, it has been used as a rarely successful form of the insanity defense. It is unclear whether increased rates of the disorder are due to better recognition or to sociocultural factors such as media portrayals. A large proportion of diagnoses are associated with a small number of clinicians, which is consistent with the hypothesis that DID may be therapist-induced. The typical presenting symptoms in different regions of the world may also vary depending on how the disorder is depicted by the media.

Definitions

Dissociation, the term that underlies the dissociative disorders including DID, lacks a precise, empirical, and generally agreed upon definition. A large number of diverse experiences have been termed dissociative, ranging from normal failures in attention to the breakdowns in memory processes characterized by the dissociative disorders. Thus it is unknown if there is a common root underlying all dissociative experiences, or if the range of mild to severe symptoms is a result of different etiologies and biological structures. Other terms used in the literature, including personality, personality state, identity, ego state and amnesia, also have no agreed upon definitions. Multiple competing models exist that incorporate some non-dissociative symptoms while excluding dissociative ones. The most widely used model of dissociation conceptualizes DID as at one extreme of a continuum of dissociation, with flow at the other end, though this model is being challenged.

Some terms have been proposed regarding dissociation. Psychiatrist Paulette Gillig draws a distinction between an "ego state" (behaviors and experiences possessing permeable boundaries with other such states but united by a common sense of self) and the term "alters" (each of which may have a separate autobiographical memory, independent initiative and a sense of ownership over individual behavior) commonly used in discussions of DID. Ellert Nijenhuis and colleagues suggest a distinction between personalities responsible for day-to-day functioning (associated with blunted physiological responses and reduced emotional reactivity, referred to as the "apparently normal part of the personality" or ANP) and those emerging in survival situations (involving fight-or-flight responses, vivid traumatic memories and strong, painful emotions, the "emotional part of the personality" or EP). "Structural dissociation of the personality" is used by Otto van der Hart and colleagues to distinguish dissociation they attribute to traumatic or pathological causes, which in turn is divided into primary, secondary and tertiary dissociation. According to this hypothesis, primary dissociation involves one ANP and one EP, while secondary dissociation involves one ANP and at least two EPs and tertiary dissociation, which is unique to DID, is described as having at least two ANP and at least two EP. Others have suggested dissociation can be separated into two distinct forms, detachment and compartmentalization, the latter of which, involving a failure to control normally controllable processes or actions, is most evident in DID. Efforts to psychometrically distinguish between normal and pathological dissociation have been made, but they have not been universally accepted.

Signs and symptoms

According to the fifth Diagnostic and Statistical Manual of Mental Disorders (DSM-V), DID symptoms include "the presence of two or more distinct personality states" accompanied by the inability to recall personal information, beyond what is expected through normal forgetfulness. Other DSM-V symptoms include a loss of identity as related to individual distinct personality states, and loss referring to time, sense of self and consciousness. In each individual, the clinical presentation varies and the level of functioning can change from severely impaired to adequate. The symptoms of dissociative amnesia are subsumed under the DID diagnosis but can be diagnosed separately. Individuals with DID may experience distress from both the symptoms of DID (intrusive thoughts or emotions) and the consequences of the accompanying symptoms (dissociation rendering them unable to remember specific information). The majority of patients with DID report childhood sexual or physical abuse, though the accuracy of these reports is controversial. Identities may be unaware of each other and compartmentalize knowledge and memories, resulting in chaotic personal lives. Individuals with DID may be reluctant to discuss symptoms due to associations with abuse, shame, and fear. DID patients may also frequently and intensely experience time disturbances.

Around half of people with DID have fewer than 10 identities and most have fewer than 100; as many as 4,500 have been reported. The average number of identities has increased over the past few decades, from two or three to now an average of approximately 16. However, it is unclear whether this is due to an actual increase in identities, or simply that the psychiatric community has become more accepting of a high number of compartmentalized memory components. The primary identity, which often has the patient's given name, tends to be "passive, dependent, guilty and depressed" with other personalities being more active, aggressive or hostile, and often containing a current time line that lacks childhood memory. Most identities are of ordinary people, though historical, fictional, mythical, celebrity and animal identities have been reported.

Comorbid disorders

The psychiatric history frequently contains multiple previous diagnoses of various disorders and treatment failures. The most common presenting complaint of DID is depression, with headaches being a common neurological symptom. Comorbid disorders can include substance abuse, eating disorders, anxiety, post traumatic stress disorder (PTSD), and personality disorders. A significant percentage of those diagnosed with DID have histories of borderline personality disorder and bipolar disorder. Further, data supports a high level of psychotic symptoms in individuals with DID, and that both individuals diagnosed with schizophrenia and those diagnosed with DID have histories of trauma. Other disorders that have been found to be comorbid with DID are somatization disorders, major depressive disorder, as well as history of a past suicide attempt, in comparison to those without a DID diagnosis. Individuals diagnosed with DID demonstrate the highest hypnotizability of any clinical population. The large number of symptoms presented by individuals diagnosed with DID has led some clinicians to suggest that, rather than being a separate disorder, diagnosis of DID is actually an indication of the severity of the other disorders diagnosed in the patient.

Borderline personality disorder

The DSM-IV-TR states that acts of self-mutilation, impulsivity, and rapid changes in interpersonal relationships "may warrant a concurrent diagnosis of borderline personality disorder." Steven Lynn and colleagues have suggested that the significant overlap between BPD and DID may be a contributing factor to the development of therapy induced DID, in that the suggestion of hidden alters by therapists who propose a diagnosis of DID provides an explanation to patients for the behavioral instability, self-mutilation, unpredictable mood changes and actions they experience. In 1993 a group of researchers reviewed both DID and borderline personality disorder (BPD), concluding that DID was an epiphenomenon of BPD, with no tests or clinical description capable of distinguishing between the two. Their conclusions about the empirical proof of DID were echoed by a second group, who still believed the diagnosis existed, but while the knowledge to date did not justify DID as a separate diagnosis, it also did not disprove its existence. Reviews of medical records and psychological tests indicated that the majority of DID patients could be diagnosed with BPD instead, though about a third could not, suggesting that DID does exist but may be over-diagnosed. Between 50 and 66% of patients also meet the criteria for BPD, and nearly 75% of patients with BPD also meet the criteria for DID, with considerable overlap between the two conditions in terms of personality traits, cognitive and day-to-day functioning, and ratings by clinicians. Both groups also report higher rates of physical and sexual abuse than the general population, and patients with BPD also score highly on measures of dissociation. Even using strict diagnostic criteria, it can be difficult to distinguish between dissociative disorders and BPD (as well as bipolar disorder and schizophrenia), though the presence of comorbid anxiety disorders may help.

Causes

The cause of DID is unknown and widely debated, with debate occurring between supporters of different hypotheses: that DID is a reaction to trauma; that DID is produced by inappropriate psychotherapeutic techniques that cause a patient to enact the role of a patient with DID; and newer hypotheses involving memory processing that allows for the possibility that trauma-induced dissociation can occur after childhood in DID, as it does in PTSD. It has been suggested that all the trauma-based and stress-related disorders be placed in one category that would include both DID and PTSD. Disturbed and altered sleep has also been suggested as having a role in dissociative disorders in general and specifically in DID, alterations in environments also largely affecting the DID patient.

Research is needed to determine the prevalence of the disorder in those who have never been in therapy, and the prevalence rates across cultures. These central issues relating to the epidemiology of DID remain largely unaddressed despite several decades of research. The debates over the causes of DID also extend to disagreements over how the disorder is assessed and treated.

Developmental trauma

People diagnosed with DID often report that they have experienced severe physical and sexual abuse, especially during early to mid-childhood (although the accuracy of these reports has been disputed), and others report an early loss, serious medical illness or other traumatic event. They also report more historical psychological trauma than those diagnosed with any other mental illness. Severe sexual, physical, or psychological trauma in childhood has been proposed as an explanation for its development; awareness, memories and emotions of harmful actions or events caused by the trauma are removed from consciousness, and alternate personalities or subpersonalities form with differing memories, emotions and behavior. DID is attributed to extremes of stress or disorders of attachment. What may be expressed as post-traumatic stress disorder (PTSD) in adults may become DID when occurring in children, possibly due to their greater use of imagination as a form of coping. Possibly due to developmental changes and a more coherent sense of self past the age of six, the experience of extreme trauma may result in different, though also complex, dissociative symptoms and identity disturbances. A specific relationship between childhood abuse, disorganized attachment, and lack of social support are thought to be a necessary component of DID. Other suggested explanations include insufficient childhood nurturing combined with the innate ability of children in general to dissociate memories or experiences from consciousness.

Delinking early trauma from the etiology of dissociation has been explicitly rejected by those supporting the early trauma model. However, a 2012 review article supports the hypothesis that current or recent trauma may affect an individual's assessment of the more distant past, changing the experience of the past and resulting in dissociative states. Giesbrecht et al. have suggested there is no actual empirical evidence linking early trauma to dissociation, and instead suggest that problems with neuropsychological functioning, such as increased distractibility in response to certain emotions and contexts, account for dissociative features. A middle position hypothesizes that trauma, in some situations, alters neuronal mechanisms related to memory. Evidence is increasing that dissociative disorders are related both to a trauma history and to "specific neural mechanisms". It has also been suggested that there may be a genuine but more modest link between trauma and DID, with early trauma causing increased fantasy-proneness, which may in turn render individuals more vulnerable to socio-cognitive influences surrounding the development of DID. Another suggestion made by Hart indicates that there are triggers in the brain that can be the catalyst for different self-states, and that victims of trauma are more susceptible to these triggers than non-victims of trauma; these triggers are said to be related to DID.

The suggestion that DID was the result of childhood trauma increased the appeal of the diagnosis among health care providers, patients and the public as it validated the idea that child abuse had lifelong, serious effects. There is very little experimental evidence supporting the trauma-dissociation hypothesis, and no research showing that dissociation consistently links to long-term memory disruption.

Therapist-induced

The prevailing post-traumatic model of dissociation and dissociative disorders is contested. It has been hypothesized that symptoms of DID may be created by therapists using techniques to "recover" memories (such as the use of hypnosis to "access" alter identities, facilitate age regression or retrieve memories) on suggestible individuals. Referred to as the "sociocognitive model" (SCM), it proposes that DID is due to a person consciously or unconsciously behaving in certain ways promoted by cultural stereotypes, with unwitting therapists providing cues through improper therapeutic techniques. This behavior is enhanced by media portrayals of DID.

Proponents of the SCM note that the bizarre dissociative symptoms are rarely present before intensive therapy by specialists in the treatment of DID who, through the process of eliciting, conversing with and identifying alters, shape, or possibly create the diagnosis. While proponents note that DID is accompanied by genuine suffering and the distressing symptoms, and can be diagnosed reliably using the DSM criteria, they are skeptical of the traumatic etiology suggested by proponents. The characteristics of people diagnosed with DID (hypnotizability, suggestibility, frequent fantasization and mental absorption) contributed to these concerns and those regarding the validity of recovered memories of trauma. Skeptics note that a small subset of doctors are responsible for diagnosing the majority of individuals with DID. Psychologist Nicholas Spanos and others have suggested that in addition to therapy caused cases, DID may be the result of role-playing rather than alternative identities, though others disagree, pointing to a lack of incentive to manufacture or maintain separate identities and point to the claimed histories of abuse. Other arguments that therapy can cause DID, include the lack of children diagnosed with DID, the sudden spike in rates of diagnosis after 1980 (although DID was not a diagnosis until DSM-IV, published in 1994), the absence of evidence of increased rates of child abuse, the appearance of the disorder almost exclusively in individuals undergoing psychotherapy, particularly involving hypnosis, the presences of bizarre alternate identities (such as those claiming to be animals or mythological creatures) and an increase in the number of alternate identities over time (as well as an initial increase in their number as psychotherapy begins in DID-oriented therapy.) These various cultural and therapeutic causes occur within a context of pre-existing psychopathology, notably borderline personality disorder, which is commonly comorbid with DID. In addition, presentations can vary across cultures, such as Indian patients who only switch alters after a period of sleep — which is commonly how DID is presented by the media within that country.

The therapy-caused cases of DID, it is argued, are strongly linked to false memory syndrome, a concept and term coined by members of the False Memory Syndrome Foundation in reaction to memories of abuse they allege were recovered by a range of controversial therapies whose effectiveness is unproven. Such a memory could be used to make a false allegation of child sexual abuse. There is little agreement between those who see therapy as a cause and trauma as a cause. Supporters of therapy as a cause of DID suggest that a small number of clinicians diagnosing a disproportionate number of cases would provide evidence for their position though it has also been claimed that higher rates of diagnosis in specific countries like the United States may be due to greater awareness of DID. Lower rates in other countries may be due to an artificially low recognition of the diagnosis. However, false memory syndrome per se is not regarded by mental health experts as a valid diagnosis, and has been described as "a non-psychological term originated by a private foundation whose stated purpose is to support accused parents", and critics argue that the concept has no empirical support, and furthermore describe the False Memory Syndrome Foundation as an advocacy group that has distorted and misrepresented research into memory.

Children

DID is rarely diagnosed in children, despite the average age of appearance of the first alter being three years. This fact is cited as a reason to doubt the validity of DID, and proponents of both etiologies believe that the discovery of DID in a child that had never undergone treatment would critically undermine the SCM. Conversely, if children are found to only develop DID after undergoing treatment it would challenge the traumagenic model. As of 2011, approximately 250 cases of DID in children have been identified, though the data does not offer unequivocal support for either theory. While children have been diagnosed with DID before therapy, several were presented to clinicians by parents who were themselves diagnosed with DID; others were influenced by the appearance of DID in popular culture or due to a diagnosis of psychosis due to hearing voices—a symptom also found in DID. No studies have looked for children with DID in the general population, and the single study that attempted to look for children with DID not already in therapy did so by examining siblings of those already in therapy for DID. An analysis of diagnosis of children reported in scientific publications, 44 case studies of single patients were found to be evenly distributed (i.e., each case study was reported by a different author) but in articles regarding groups of patients, four researchers were responsible for the majority of the reports.

The initial theoretical description of DID was that dissociative symptoms were a means of coping with extreme stress (particularly childhood sexual and physical abuse), but this belief has been challenged by the data of multiple research studies. Proponents of the traumagenic hypothesis claim the high correlation of child sexual and physical abuse reported by adults with DID corroborates the link between trauma and DID. However, the DID-maltreatment link has been questioned for several reasons. The studies reporting the links often rely on self-report rather than independent corroborations, and these results may be worsened by selection and referral bias. Most studies of trauma and dissociation are cross-sectional rather than longitudinal, which means researchers can not attribute causation, and studies avoiding recall bias have failed to corroborate such a causal link. In addition, studies rarely control for the many disorders comorbid with DID, or family maladjustment (which is itself highly correlated with DID). The popular association of DID with childhood abuse is relatively recent, occurring only after the publication of Sybil in 1973. Most previous examples of "multiples" such as Chris Costner Sizemore, whose life was depicted in the book and film The Three Faces of Eve, disclosed no history of child abuse.

Diagnosis

The fourth, revised edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) diagnoses DID according to the diagnostic criteria found in section 300.14 (dissociative disorders). It has also been found difficult to diagnose the disorder in the first place, due to there not being a universal agreement of the definition of dissociation. The criteria require that an adult be recurrently controlled by two or more discrete identities or personality states, accompanied by memory lapses for important information that is not caused by alcohol, drugs or medications and other medical conditions such as complex partial seizures. While otherwise similar, the diagnostic criteria for children also specifies symptoms must not be confused with imaginative play. Diagnosis is normally performed by a clinically trained mental health professional such as a psychiatrist or psychologist through clinical evaluation, interviews with family and friends, and consideration of other ancillary material. Specially designed interviews (such as the SCID-D) and personality assessment tools may be used in the evaluation as well. Since most of the symptoms depend on self-report and are not concrete and observable, there is a degree of subjectivity in making the diagnosis. People are often disinclined to seek treatment, especially since their symptoms may not be taken seriously; thus dissociative disorders have been referred to as "diseases of hiddenness".

The diagnosis has been criticized by supporters of therapy as a cause or the sociocognitive hypothesis as they believe it is a culture-bound and often health care induced condition. The social cues involved in diagnosis may be instrumental in shaping patient behavior or attribution, such that symptoms within one context may be linked to DID, while in another time or place the diagnosis could have been something other than DID. Other researchers disagree and argue that the existence of the condition and its inclusion in the DSM is supported by multiple lines of reliable evidence, with diagnostic criteria allowing it to be clearly discriminated from conditions it is often mistaken for (schizophrenia, borderline personality disorder, and seizure disorder). That a large proportion of cases are diagnosed by specific health care providers, and that symptoms have been created in nonclinical research subjects given appropriate cueing has been suggested as evidence that a small number of clinicians who specialize in DID are responsible for the creation of alters through therapy. The condition may be under-diagnosed due to skepticism and lack of awareness from mental health professionals, made difficult due to the lack of specific and reliable criteria for diagnosing DID as well as a lack of prevalence rates due to the failure to examine systematically selected and representative populations.

Screening

Perhaps due to their perceived rarity, the dissociative disorders (including DID) were not initially included in the Structured Clinical Interview for DSM-IV (SCID), which is designed to make psychiatric diagnoses more rigorous and reliable. Instead, shortly after the publication of the initial SCID a freestanding protocol for dissociative disorders (SCID-D) was published. This interview takes about 30 to 90 minutes depending on the subject's experiences. An alternative diagnostic instrument, the Dissociative Disorders Interview Schedule, also exists but the SCID-D is generally considered superior. The Dissociative Disorders Interview Schedule (DDIS) is a highly structured interview that discriminates among various DSM-IV diagnoses. The DDIS can usually be administered in 30–45 minutes.

Other questionnaires include the Dissociative Experiences Scale (DES), Perceptual Alterations Scale, Questionnaire on Experiences of Dissociation, Dissociation Questionnaire, and the Mini-SCIDD. All are strongly intercorrelated and except the Mini-SCIDD, all incorporate absorption, a normal part of personality involving narrowing or broadening of attention. The DES is a simple, quick, and validated questionnaire that has been widely used to screen for dissociative symptoms, with variations for children and adolescents. Tests such as the DES provide a quick method of screening subjects so that the more time-consuming structured clinical interview can be used in the group with high DES scores. Depending on where the cutoff is set, people who would subsequently be diagnosed can be missed. An early recommended cutoff was 15–20. The reliability of the DES in non-clinical samples has been questioned.

Differential diagnoses

People with DID are diagnosed with five to seven comorbid disorders on average—much higher than other mental illnesses.

Due to overlapping symptoms, the differential diagnosis includes schizophrenia, normal and rapid-cycling bipolar disorder, epilepsy, borderline personality disorder, and autism spectrum disorder. Delusions or auditory hallucinations can be mistaken for speech by other personalities. Persistence and consistency of identities and behavior, amnesia, measures of dissociation or hypnotizability and reports from family members or other associates indicating a history of such changes can help distinguish DID from other conditions. A diagnosis of DID takes precedence over any other dissociative disorders. Distinguishing DID from malingering is a concern when financial or legal gains are an issue, and factitious disorder may also be considered if the person has a history of help or attention seeking. Individuals who state that their symptoms are due to external spirits or entities entering their bodies are generally diagnosed with dissociative disorder not otherwise specified rather than DID due to the lack of identities or personality states. Most individuals who enter an emergency department and are unaware of their names are generally in a psychotic state. Although auditory hallucinations are common in DID, complex visual hallucinations may also occur. Those with DID generally have adequate reality testing; they may have positive Schneiderian symptoms of schizophrenia but lack the negative symptoms. They perceive any voices heard as coming from inside their heads (patients with schizophrenia experience them as external). In addition, individuals with psychosis are much less susceptible to hypnosis than those with DID. Difficulties in differential diagnosis are increased in children.

DID must be distinguished from, or determined if comorbid with, a variety of disorders including mood disorders, psychosis, anxiety disorders, PTSD, personality disorders, cognitive disorders, neurological disorders, epilepsy, somatoform disorder, factitious disorder, malingering, other dissociative disorders, and trance states. An additional aspect of the controversy of diagnosis is that there are many forms of dissociation and memory lapses, which can be common in both stressful and nonstressful situations and can be attributed to much less controversial diagnoses. Individuals faking or mimicking DID due to factitious disorder will typically exaggerate symptoms (particularly when observed), lie, blame bad behavior on symptoms and often show little distress regarding their apparent diagnosis. In contrast, genuine people with DID typically exhibit confusion, distress and shame regarding their symptoms and history.

A relationship between DID and borderline personality disorder has been posited, with various clinicians noting overlap between symptoms and behaviors and it has been suggested that some cases of DID may arise "from a substrate of borderline traits". Reviews of DID patients and their medical records concluded that the majority of those diagnosed with DID would also meet the criteria for either borderline personality disorder or more generally borderline personality.

The DSM-5 elaborates on cultural background as an influence for some presentations of DID.

Many features of dissociative identity disorder can be influenced by the individual's cultural background. Individuals with this disorder may present with prominent medically unexplained neurological symptoms, such as non-epileptic seizures, paralyses, or sensory loss, in cultural settings where such symptoms are common. Similarly, in settings where normative possession is common (e.g., rural areas in the developing world, among certain religious groups in the United States and Europe), the fragmented identities may take the form of possessing spirits, deities, demons, animals, or mythical figures. Acculturation or prolonged intercultural contact may shape the characteristics of other identities(e.g., identities in India may speak English exclusively and wear Western clothes). Possession-form dissociative identity disorder can be distinguished from culturally accepted possession states in that the former is involuntary, distressing, uncontrollable, and often recurrent or persistent; involves conflict between the individual and his or her surrounding family, social, or work milieu; and is manifested at times and in places that violate the norms of the culture or religion.

History in the DSM

The DSM-II used the term Hysterical Neurosis, Dissociative Type. It described the possible occurrence of alterations in the patient's state of consciousness or identity, and included the symptoms of "amnesia, somnambulism, fugue, and multiple personality". The DSM-III grouped the diagnosis with the other four major dissociative disorders using the term "multiple personality disorder". The DSM-IV made more changes to DID than any other dissociative disorder, and renamed it DID. The name was changed for two reasons. First, the change emphasizes the main problem is not a multitude of personalities, but rather a lack of a single, unified identity and an emphasis on "the identities as centers of information processing". Second, the term "personality" is used to refer to "characteristic patterns of thoughts, feelings, moods and behaviors of the whole individual", while for a patient with DID, the switches between identities and behavior patterns is the personality. It is for this reason the DSM-IV-TR referred to "distinct identities or personality states" instead of personalities. The diagnostic criteria also changed to indicate that while the patient may name and personalize alters, they lack an independent, objective existence. The changes also included the addition of amnesia as a symptom, which was not included in the DSM-III-R because despite being a core symptom of the condition, patients may experience "amnesia for the amnesia" and fail to report it. Amnesia was replaced when it became clear that the risk of false negative diagnoses was low because amnesia was central to DID.

The ICD-10 places the diagnosis in the category of "dissociative disorders", within the subcategory of "other dissociative (conversion) disorders", but continues to list the condition as multiple personality disorder.

The DSM-IV-TR criteria for DID have been criticized for failing to capture the clinical complexity of DID, lacking usefulness in diagnosing individuals with DID (for instance, by focusing on the two least frequent and most subtle symptoms of DID) producing a high rate of false negatives and an excessive number of DDNOS diagnoses, for excluding possession (seen as a cross-cultural form of DID), and for including only two "core" symptoms of DID (amnesia and self-alteration) while failing to discuss hallucinations, trance-like states, somatoform, depersonalization, and derealization symptoms. Arguments have been made for allowing diagnosis through the presence of some, but not all of the characteristics of DID rather than the current exclusive focus on the two least common and noticeable features. The DSM-IV-TR criteria have also been criticized for being tautological, using imprecise and undefined language and for the use of instruments that give a false sense of validity and empirical certainty to the diagnosis.

The DSM-5 updated the definition of DID in 2013, summarizing the changes as:

Several changes to the criteria for dissociative identity disorder have been made in DSM-5. First, Criterion A has been expanded to include certain possession-form phenomena and functional neurological symptoms to account for more diverse presentations of the disorder. Second, Criterion A now specifically states that transitions in identity may be observable by others or self-reported. Third, according to Criterion B, individuals with dissociative identity disorder may have recurrent gaps in recall for everyday events, not just for traumatic experiences. Other text modifications clarify the nature and course of identity disruptions.

Controversy

DID is among the most controversial of the dissociative disorders and among the most controversial disorders found in the DSM-IV-TR. The primary dispute is between those who believe DID is caused by traumatic stresses forcing the mind to split into multiple identities, each with a separate set of memories, and the belief that the symptoms of DID are produced artificially by certain psychotherapeutic practices or patients playing a role they believe appropriate for a person with DID. The debate between the two positions is characterized by intense disagreement. Research into this hypothesis has been characterized by poor methodology. Psychiatrist Joel Paris notes that the idea that a personality is capable of splitting into independent alters is an unproven assertion that is at odds with research in cognitive psychology.

Some believe that DID is caused by health care, i.e. symptoms of DID are created by therapists themselves via hypnosis. This belief also implies that those with DID are more susceptible to manipulation by hypnosis and suggestion than others. The iatrogenic model also sometimes states that treatment for DID is harmful. According to Brand, Loewenstein and Spiegel, "[t]he claims that DID treatment is harmful are based on anecdotal cases, opinion pieces, reports of damage that are not substantiated in the scientific literature, misrepresentations of the data, and misunderstandings about DID treatment and the phenomenology of DID”. Their claim is evinced by the fact that only 5%–10% of people receiving treatment worsen in their symptoms.

Psychiatrists August Piper and Harold Merskey have challenged the trauma hypothesis, arguing that correlation does not imply causation—the fact that people with DID report childhood trauma does not mean trauma causes DID—and point to the rareness of the diagnosis before 1980 as well as a failure to find DID as an outcome in longitudinal studies of traumatized children. They assert that DID cannot be accurately diagnosed because of vague and unclear diagnostic criteria in the DSM and undefined concepts such as "personality state" and "identities", and question the evidence for childhood abuse beyond self-reports, the lack of definition of what would indicate a threshold of abuse sufficient to induce DID and the extremely small number of cases of children diagnosed with DID despite an average age of appearance of the first alter of three years. Psychiatrist Colin Ross disagrees with Piper and Merskey's conclusion that DID cannot be accurately diagnosed, pointing to internal consistency between different structured dissociative disorder interviews (including the Dissociative Experiences Scale, Dissociative Disorders Interview Schedule and Structured Clinical Interview for Dissociative Disorders) that are in the internal validity range of widely accepted mental illnesses such as schizophrenia and major depressive disorder. In his opinion, Piper and Merskey are setting the standard of proof higher than they are for other diagnoses. He also asserts that Piper and Merskey have cherry-picked data and not incorporated all relevant scientific literature available, such as independent corroborating evidence of trauma.

Pathophysiology

Despite research on DID including structural and functional magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, event-related potential, and electroencephalography, no convergent neuroimaging findings have been identified regarding DID, making it difficult to hypothesize a biological basis for DID. In addition, many of the studies that do exist were performed from an explicitly trauma-based position, and did not consider the possibility of therapy as a cause of DID. There is no research to date regarding the neuroimaging and introduction of false memories in DID patients, though there is evidence of changes in visual parameters and support for amnesia between alters. DID patients also appear to show deficiencies in tests of conscious control of attention and memorization (which also showed signs of compartmentalization for implicit memory between alters but no such compartmentalization for verbal memory) and increased and persistent vigilance and startle responses to sound. DID patients may also demonstrate altered neuroanatomy. Experimental tests of memory suggest that patients with DID may have improved memory for certain tasks, which has been used to criticize the hypothesis that DID is a means of forgetting or suppressing memory. Patients also show experimental evidence of being more fantasy-prone, which in turn is related to a tendency to over-report false memories of painful events.

Treatment

There is a general lack of consensus in the diagnosis and treatment of DID and research on treatment effectiveness focuses mainly on clinical approaches described in case studies. General treatment guidelines exist that suggest a phased, eclectic approach with more concrete guidance and agreement on early stages but no systematic, empirically-supported approach exists and later stages of treatment are not well described and have no consensus. Even highly experienced therapists have few patients that achieve a unified identity. Common treatment methods include an eclectic mix of psychotherapy techniques, including cognitive behavioral therapy (CBT), insight-oriented therapy, dialectical behavioral therapy (DBT), hypnotherapy and eye movement desensitization and reprocessing (EMDR). Medications can be used for comorbid disorders or targeted symptom relief. Some behavior therapists initially use behavioral treatments such as only responding to a single identity, and then use more traditional therapy once a consistent response is established. Brief treatment due to managed care may be difficult, as individuals diagnosed with DID may have unusual difficulties in trusting a therapist and take a prolonged period to form a comfortable therapeutic alliance. Regular contact (weekly or biweekly) is more common, and treatment generally lasts years—not weeks or months. Sleep hygiene has been suggested as a treatment option, but has not been tested. In general there are very few clinical trials on the treatment of DID, none of which were randomized controlled trials.

Therapy for DID is generally phase oriented. Different alters may appear based on their greater ability to deal with specific situational stresses or threats. While some patients may initially present with a large number of alters, this number may reduce during treatment—though it is considered important for the therapist to become familiar with at least the more prominent personality states as the "host" personality may not be the "true" identity of the patient. Specific alters may react negatively to therapy, fearing the therapist's goal is to eliminate the alter (particularly those associated with illegal or violent activities). A more realistic and appropriate goal of treatment is to integrate adaptive responses to abuse, injury or other threats into the overall personality structure. There is debate over issues such as whether exposure therapy (reliving traumatic memories, also known as abreaction), engagement with alters and physical contact during therapy are appropriate and there are clinical opinions both for and against each option with little high-quality evidence for any position.

Brandt et al., noting the lack of empirical studies of treatment effectiveness, conducted a survey of 36 clinicians expert in treating dissociative disorder (DD) who recommended a three-stage treatment. They agreed that skill building in the first stage is important so the patient can learn to handle high risk, potentially dangerous behavior, as well as emotional regulation, interpersonal effectiveness and other practical behaviors. In addition, they recommended "trauma-based cognitive therapy" to reduce cognitive distortions related to trauma; they also recommended that the therapist deal with the dissociated identities early in treatment. In the middle stage, they recommended graded exposure techniques, along with appropriate interventions as needed. The treatment in the last stage was more individualized; few with DD [sic] became integrated into one identity.

The International Society for the Study of Trauma and Dissociation has published guidelines to phase-oriented treatment in adults as well as children and adolescents that are widely used in the field of DID treatment. The first phase of therapy focuses on symptoms and relieving the distressing aspects of the condition, ensuring the safety of the individual, improving the patient's capacity to form and maintain healthy relationships, and improving general daily life functioning. Comorbid disorders such as substance abuse and eating disorders are addressed in this phase of treatment. The second phase focuses on stepwise exposure to traumatic memories and prevention of re-dissociation. The final phase focuses on reconnecting the identities of disparate alters into a single functioning identity with all its memories and experiences intact.

A study was conducted with the goal of developing an "expertise-based prognostic model for the treatment of complex posttraumatic stress disorder (PTSD) and dissociative identity disorder (DID)". Researchers constructed a two-stage survey and factor analyses performed on the survey elements found 51 factors common to complex PTSD and DID. The authors concluded from their findings: "The model is supportive of the current phase-oriented treatment model, emphasizing the strengthening of the therapeutic relationship and the patient's resources in the initial stabilization phase. Further research is needed to test the model's statistical and clinical validity."

Prognosis

Little is known about prognosis of untreated DID. It rarely, if ever, goes away without treatment, but symptoms may resolve from time to time or wax and wane spontaneously. Patients with mainly dissociative and posttraumatic symptoms face a better prognosis than those with comorbid disorders or those still in contact with abusers, and the latter groups often face lengthier and more difficult treatment. Suicidal ideation, failed suicide attempts, and self-harm also occur. Duration of treatment can vary depending on patient goals, which can range from merely improving inter-alter communication and cooperation, to reducing inter-alter amnesia, to integration of all alters, but generally takes years.

Epidemiology

There is little systematic data on the prevalence of DID. It occurs more commonly in young adults and declines with age. Reported rates in the community vary from 1% to 3% with higher rates among psychiatric patients. It is 5 to 9 times more common in females than males during young adulthood, though this may be due to selection bias as males who could be diagnosed with DID may end up in the criminal justice system rather than hospitals. In children rates among females and males are approximately the same (5:4). DID diagnoses are extremely rare in children; much of the research on childhood DID occurred in the 1980s and 1990s and does not address ongoing controversies surrounding the diagnosis.

Though the condition has been described in non-English speaking nations and non-Western cultures, these reports all occur in English-language journals authored by international researchers who cite Western scientific literature and are therefore not isolated from Western influences.

Changing prevalence

Rates of diagnosed DID were increasing, reaching a peak of approximately 40,000 cases by the end of the 20th century, up from less than 200 before 1970. Initially DID along with the rest of the dissociative disorders were considered the rarest of psychological conditions, numbering less than 100 by 1944, with only one further case added in the next two decades. In the late 1970s and 80s, the number of diagnoses rose sharply. An estimate from the 1980s places the incidence at 0.01%. Accompanying this rise was an increase in the number of alters, rising from only the primary and one alter personality in most cases, to an average of 13 in the mid-1980s (the increase in both number of cases and number of alters within each case are both factors in professional skepticism regarding the diagnosis). Others explain the increase as being due to the use of inappropriate therapeutic techniques in highly suggestible individuals, though this is itself controversial while proponents of DID claim the increase in incidence is due to increased recognition of and ability to recognize the disorder. Figures from psychiatric populations (inpatients and outpatients) show a wide diversity from different countries.

North America

The DSM does not provide an estimate of incidence for DID and dissociative disorders were excluded from the Epidemiological Catchment Area Project. As a result, there are no national statistics for prevalence and incidence of DID in the United States.

DID is a controversial diagnosis and condition, with much of the literature on DID still being generated and published in North America, to the extent that it was once regarded as a phenomenon confined to that continent though research has appeared discussing the appearance of DID in other countries and cultures. A 1996 review offered three possible causes for the sudden increase in people diagnosed with DID:

1. The result of therapist suggestions to suggestible people, much as Charcot's hysterics acted in accordance with his expectations.
2. Psychiatrists' past failure to recognize dissociation being redressed by new training and knowledge.
3. Dissociative phenomena are actually increasing, but this increase only represents a new form of an old and protean entity: "hysteria".

Paris believes that the first possible cause is the most likely. Etzel Cardena and David Gleaves believe the over-representation of DID in North America is the result of increased awareness and training about the condition which had formerly been missing.

History

Early references

One of ten photogravure portraits of Louis Vivet published in Variations de la personnalité by Henri Bourru and Prosper Ferdinand Burot.

 

The first case of DID was thought to be described by Paracelsus in 1646. In the 19th century, "dédoublement," or double consciousness, the historical precursor to DID, was frequently described as a state of sleepwalking, with scholars hypothesizing that the patients were switching between a normal consciousness and a "somnambulistic state".

An intense interest in spiritualism, parapsychology and hypnosis continued throughout the 19th and early 20th centuries, running in parallel with John Locke's views that there was an association of ideas requiring the coexistence of feelings with awareness of the feelings. Hypnosis, which was pioneered in the late 18th century by Franz Mesmer and Armand-Marie Jacques de Chastenet, Marques de Puységur, challenged Locke's association of ideas. Hypnotists reported what they thought were second personalities emerging during hypnosis and wondered how two minds could coexist.

The plaque on the former house of Pierre Marie Félix Janet (1859–1947), the philosopher and psychologist who first alleged a connection between events in the subject's past life and present mental health, also coining the words "dissociation" and "subconscious."

 

In the 19th century, there were a number of reported cases of multiple personalities which Rieber estimated would be close to 100. Epilepsy was seen as a factor in some cases, and discussion of this connection continues into the present era.

By the late 19th century, there was a general acceptance that emotionally traumatic experiences could cause long-term disorders which might display a variety of symptoms. These conversion disorders were found to occur in even the most resilient individuals, but with profound effect in someone with emotional instability like Louis Vivet (1863–?), who suffered a traumatic experience as a 17-year-old when he encountered a viper. Vivet was the subject of countless medical papers and became the most studied case of dissociation in the 19th century. 

Between 1880 and 1920, various international medical conferences devoted time to sessions on dissociation. It was in this climate that Jean-Martin Charcot introduced his ideas of the impact of nervous shocks as a cause for a variety of neurological conditions. One of Charcot's students, Pierre Janet, took these ideas and went on to develop his own theories of dissociation. One of the first individuals diagnosed with multiple personalities to be scientifically studied was Clara Norton Fowler, under the pseudonym Christine Beauchamp; American neurologist Morton Prince studied Fowler between 1898 and 1904, describing her case study in his 1906 monograph, Dissociation of a Personality.

20th century

In the early 20th century, interest in dissociation and multiple personalities waned for a number of reasons. After Charcot's death in 1893, many of his so-called hysterical patients were exposed as frauds, and Janet's association with Charcot tarnished his theories of dissociation. Sigmund Freud recanted his earlier emphasis on dissociation and childhood trauma.

In 1908, Eugen Bleuler introduced the term "schizophrenia" to represent a revised disease concept for Emil Kraepelin's dementia praecox. Whereas Kraepelin's natural disease entity was anchored in the metaphor of progressive deterioration and mental weakness and defect, Bleuler offered a reinterpretation based on dissociation or "splitting' (Spaltung) and widely broadened the inclusion criteria for the diagnosis. A review of the Index medicus from 1903 through 1978 showed a dramatic decline in the number of reports of multiple personality after the diagnosis of schizophrenia became popular, especially in the United States. The rise of the broad diagnostic category of dementia praecox has also been posited in the disappearance of "hysteria" (the usual diagnostic designation for cases of multiple personalities) by 1910. A number of factors helped create a large climate of skepticism and disbelief; paralleling the increased suspicion of DID was the decline of interest in dissociation as a laboratory and clinical phenomenon.

Starting in about 1927, there was a large increase in the number of reported cases of schizophrenia, which was matched by an equally large decrease in the number of multiple personality reports. With the rise of a uniquely American reframing of dementia praecox/schizophrenia as a functional disorder or "reaction" to psychobiological stressors—a theory first put forth by Adolf Meyer in 1906—many trauma-induced conditions associated with dissociation, including "shell shock" or "war neuroses" during World War I, were subsumed under these diagnoses. It was argued in the 1980s that DID patients were often misdiagnosed as suffering from schizophrenia.

The public, however, was exposed to psychological ideas which took their interest. Mary Shelley's Frankenstein, Robert Louis Stevenson's Strange Case of Dr Jekyll and Mr Hyde, and many short stories by Edgar Allan Poe, had a formidable impact.

The Three Faces of Eve

In 1957, with the publication of the bestselling book The Three Faces of Eve by psychiatrists Corbett H. Thigpen and Hervey M. Cleckley, based on a case study of their patient Chris Costner Sizemore, and the subsequent popular movie of the same name, the American public's interest in multiple personality was revived. More cases of dissociative identity disorder were diagnosed in the following years. The cause of the sudden increase of cases is indefinite, but it may be attributed to the increased awareness, which revealed previously undiagnosed cases or new cases may have been induced by the influence of the media on the behavior of individuals and the judgement of therapists. During the 1970s an initially small number of clinicians campaigned to have it considered a legitimate diagnosis.

Between 1968 and 1980, the term that was used for dissociative identity disorder was "Hysterical neurosis, dissociative type." The APA wrote in the second edition of the DSM: "In the dissociative type, alterations may occur in the patient's state of consciousness or in his identity, to produce such symptoms as amnesia, somnambulism, fugue, and multiple personality." The number of cases sharply increased in the late 1970s and throughout the 80s, and the first scholarly monographs on the topic appeared in 1986.

Sybil

In 1974, the highly influential book Sybil was published, and later made into a miniseries in 1976 and again in 2007. Describing what Robert Rieber called "the third most famous of multiple personality cases," it presented a detailed discussion of the problems of treatment of "Sybil Isabel Dorsett," a pseudonym for Shirley Ardell Mason. Though the book and subsequent films helped popularize the diagnosis and trigger an epidemic of the diagnosis, later analysis of the case suggested different interpretations, ranging from Mason's problems having been caused by the therapeutic methods used by her psychiatrist, Cornelia B. Wilbur, or an inadvertent hoax due in part to the lucrative publishing rights, though this conclusion has itself been challenged. Dr. David Spiegel, a Stanford psychiatrist whose father treated Shirley Ardell Mason on occasion, says that his father described Mason as "a brilliant hysteric. He felt that Dr. Wilbur tended to pressure her to exaggerate on the dissociation she already had." As media attention on DID increased, so too did the controversy surrounding the diagnosis.

Re-classifications

With the publication of the DSM-III, which omitted the terms "hysteria" and "neurosis" (and thus the former categories for dissociative disorders), dissociative diagnoses became "orphans" with their own categories with dissociative identity disorder appearing as "multiple personality disorder." In the opinion of McGill University psychiatrist Joel Paris, this inadvertently legitimized them by forcing textbooks, which mimicked the structure of the DSM, to include a separate chapter on them and resulted in an increase in diagnosis of dissociative conditions. Once a rarely occurring spontaneous phenomenon (research in 1944 showed only 76 cases), became "an artifact of bad (or naïve) psychotherapy" as patients capable of dissociating were accidentally encouraged to express their symptoms by "overly fascinated" therapists.

In a 1986 book chapter (later reprinted in another volume), philosopher of science Ian Hacking focused on multiple personality disorder as an example of "making up people" through the untoward effects on individuals of the "dynamic nominalism" in medicine and psychiatry. With the invention of new terms entire new categories of "natural kinds" of people are assumed to be created, and those thus diagnosed respond by re-creating their identity in light of the new cultural, medical, scientific, political and moral expectations. Hacking argued that the process of "making up people" is historically contingent, hence it is not surprising to find the rise, fall, and resurrection of such categories over time. Hacking revisited his concept of "making up people" in an article published in the London Review of Books on 17 August 2006.

"Interpersonality amnesia" was removed as a diagnostic feature from the DSM III in 1987, which may have contributed to the increasing frequency of the diagnosis. There were 200 reported cases of DID as of 1980, and 20,000 from 1980 to 1990. Joan Acocella reports that 40,000 cases were diagnosed from 1985 to 1995. Scientific publications regarding DID peaked in the mid-1990s then rapidly declined.

There were several contributing factors to the rapid decline of reports of multiple personality disorder/dissociative identity disorder. One was the discontinuation in December 1997 of Dissociation: Progress in the Dissociative Disorders, the journal of The International Society for the Study of Multiple Personality and Dissociation. The society and its journal were perceived as uncritical sources of legitimacy for the extraordinary claims of the existence of intergenerational satanic cults responsible for a "hidden holocaust" of Satanic ritual abuse that was linked to the rise of MPD reports. In an effort to distance itself from the increasing skepticism regarding the clinical validity of MPD, the organization dropped "multiple personality" from its official name in 1993, and then in 1997 changed its name again to the International Society for the Study of Trauma and Dissociation. 

In 1994, the fourth edition of the DSM replaced the criteria again and changed the name of the condition from "multiple personality disorder" to the current "dissociative identity disorder" to emphasize the importance of changes to consciousness and identity rather than personality. The inclusion of interpersonality amnesia helped to distinguish DID from dissociative disorder not otherwise specified, but the condition retains an inherent subjectivity due to difficulty in defining terms such as personality, identity, ego-state and even amnesia. The ICD-10 still classifies DID as a "Dissociative [conversion] disorder" and retains the name "multiple personality disorder" with the classification number of F44.81.

21st century

A 2006 study compared scholarly research and publications on DID and dissociative amnesia to other mental health conditions, such as anorexia nervosa, alcohol abuse and schizophrenia from 1984 to 2003. The results were found to be unusually distributed, with a very low level of publications in the 1980s followed by a significant rise that peaked in the mid-1990s and subsequently rapidly declined in the decade following. Compared to 25 other diagnosis, the mid-90's "bubble" of publications regarding DID was unique. In the opinion of the authors of the review, the publication results suggest a period of "fashion" that waned, and that the two diagnoses "[did] not command widespread scientific acceptance."

Society and culture

Robert Louis Stevenson's Strange Case of Dr Jekyll and Mr Hyde is known for its portrayal of a split personality and has become synonymous with multiple personalities in both lay and scientific literature

 

Despite its rareness, DID is portrayed with remarkable frequency in popular culture, appearing in numerous books, films, and television shows. Film examples include Split, Psycho, Fight Club, Sybil, Shutter Island.

Psychiatrist Colin A. Ross has stated that based on documents obtained through freedom of information legislation, psychiatrists linked to Project MKULTRA claimed to be able to deliberately induce dissociative identity disorder using a variety of aversive techniques.

Surveys of the attitudes of Canadian and American psychiatrists towards dissociative disorders completed in 1999 and 2001 found considerable skepticism and disagreement regarding the research base of dissociative disorders in general and DID in specific, as well as whether the inclusion of DID in the DSM was appropriate. 

NFL player Herschel Walker published an autobiography in 2008 discussing his life and diagnosis of DID.

Legal issues

Within legal circles, DID has been described as one of the most disputed psychiatric diagnoses and forensic assessments. The number of court cases involving DID has increased substantially since the 1990s and the diagnosis presents a variety of challenges for legal systems. Courts must distinguish individuals who mimic symptoms of DID for legal or social reasons. Within jurisprudence there are three significant problems:

1. Individuals diagnosed with DID may accuse others of abuse, but lack objective evidence and base their accusations solely on regular or recovered memories.
2. There are questions regarding the civil and political rights of alters, particularly which alter can legally represent the person, sign a contract or vote.
3. Finally, individuals diagnosed with DID who are accused of crimes may deny culpability on the grounds that the crime was committed by a different identity-state.

In cases where not guilty by reason of insanity (NGRI) is used as a defence in a court, it is normally accompanied by one of three legal approaches—claiming a specific alter was in control when the crime was committed (and if that alter is considered insane), deciding whether all (or which) alters may be insane, or whether only the dominant personality meets the insanity standard. NGRI is rarely successful for individuals with DID accused of committing crimes while in a dissociated state.

There is no agreement within the legal and mental health fields whether an individual can be acquitted due to a diagnosis of DID. It has been argued that any individual with DID is a single person with a serious mental illness, and therefore exhibits diminished responsibility; this was first recognized in an American court in 1978, in the State of Ohio v. Milligan case. However, public reaction to the result of the case involving William S. "Billy" Milligan was strongly negative, and since that time the few cases claiming insanity have found either that the altered consciousness found in DID is irrelevant or that the actual diagnosis itself was not admissible evidence. The self-reported nature of the symptoms used to reach a diagnosis makes it difficult to determine their credibility, although objective measuring of brain activation and structural patterns are a promising direction for future scientific research into distinguishing malingered from genuine DID in forensic settings. Forensic experts called on to conduct forensic examinations for DID must use a multidisciplinary approach, including multiple screening instruments.

p53

From Wikipedia, the free encyclopedia

TP53
Available structures PDB Ortholog search: PDBe RCSB

List of PDB id codes
Identifiers
Aliases	TP53, BCC7, LFS1, P53, TRP53, tumor protein p53, BMFS5
External IDs	OMIM: 191170 MGI: 98834 HomoloGene: 460 GeneCards: TP53

Gene location (Human) Chr. Chromosome 17 (human) Band 17p13.1 Start 7,661,779 bp End 7,687,550 bp

RNA expression pattern

Tumor protein p53, also known as p53, cellular tumor antigen p53 (UniProt name), phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice). This homolog (originally thought to be, and often spoken of as, a single protein) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene. (Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.) 

The name p53 was given in 1979 describing the apparent molecular mass; SDS-PAGE analysis indicates that it is a 53-kilodalton (kDa) protein. However, the actual mass of the full-length p53 protein (p53α) based on the sum of masses of the amino acid residues is only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is. In addition to the full-length protein, the human TP53 gene encodes at least 15 protein isoforms, ranging in size from 3.5 to 43.7 kDa. All these p53 proteins are called the p53 isoforms. The TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation. TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.

Gene

In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1). The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53. TP53 orthologs have been identified in most mammals for which complete genome data are available. 

In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility; however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer. A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males. A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer. One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer.

Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk and endometrial cancer risk. A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer. Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma.

Structure

A schematic of the known protein domains in p53. (NLS = Nuclear Localization Signal).

 

Crystal structure of four p53 DNA binding domains (as found in the bioactive homo-tetramer) and has seven domains:

1. an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factors. The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes.
2. activation domain 2 (AD2) important for apoptotic activity: residues 43-63.
3. proline rich domain important for the apoptotic activity of p53 by nuclear exportation via MAPK: residues 64-92.
4. central DNA-binding core domain (DBD). Contains one zinc atom and several arginine amino acids: residues 102-292. This region is responsible for binding the p53 co-repressor LMO3.
5. Nuclear Localization Signaling (NLS) domain, residues 316-325.
6. homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for the activity of p53 in vivo.
7. C-terminal involved in downregulation of DNA binding of the central domain: residues 356-393.

A tandem of nine-amino-acid transactivation domains (9aaTAD) was identified in the AD1 and AD2 regions of transcription factor p53. KO mutations and position for p53 interaction with TFIID are listed below: The competence of the p53 transactivation domains 9aaTAD to activate transcription as small peptides was reported.

 

9aaTADs mediate p53 interaction with general coactivators – TAF9, CBP/p300 (all four domains KIX, TAZ1, TAZ2 and IBiD), GCN5 and PC4, regulatory protein MDM2 and replication protein A (RPA).

Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore, OD mutations have a dominant negative effect on the function of p53. 

Wild-type p53 is a labile protein, comprising folded and unstructured regions that function in a synergistic manner.

Function

DNA damage and repair

p53 plays a role in regulation or progression through the cell cycle, apoptosis, and genomic stability by means of several mechanisms:

• It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging.
• It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition—if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.
• It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable.
• It is essential for the senescence response to short telomeres.

p53 pathway: In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.

 

Activated p53 binds DNA and activates expression of several genes including microRNA miR-34a, WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to the G1-S/CDK (CDK4/CDK6, CDK2, and CDK1) complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. 

When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division. Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.

The p21 protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein. 

The p53 and RB1 pathways are linked via p14ARF, raising the possibility that the pathways may regulate each other.

p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning.

Stem cells

Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. 

In human embryonic stem cells (hESCs)s, p53 is maintained at low inactive levels. This is because activation of p53 leads to rapid differentiation of hESCs. Studies have shown that knocking out p53 delays differentiation and that adding p53 causes spontaneous differentiation, showing how p53 promotes differentiation of hESCs and plays a key role in cell cycle as a differentiation regulator. When p53 becomes stabilized and activated in hESCs, it increases p21 to establish a longer G1. This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation. p53 also activates miR-34a and miR-145, which then repress the hESCs pluripotency factors, further instigating differentiation.

In adult stem cells, p53 regulation is important for maintenance of stemness in adult stem cell niches. Mechanical signals such as hypoxia affect levels of p53 in these niche cells through the hypoxia inducible factors, HIF-1α and HIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it. Suppression of p53 plays important roles in cancer stem cell phenotype, induced pluripotent stem cells and other stem cell roles and behaviors, such as blastema formation. Cells with decreased levels of p53 have been shown to reprogram into stem cells with a much greater efficiency than normal cells. Papers suggest that the lack of cell cycle arrest and apoptosis gives more cells the chance to be reprogrammed. Decreased levels of p53 were also shown to be a crucial aspect of blastema formation in the legs of salamanders. p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being cancerous.

Other

Apart from the cellular and molecular effects above, p53 has a tissue-level anticancer effect that works by inhibiting angiogenesis. As tumors grow they need to recruit new blood vessels to supply them, and p53 inhibits that by (i) interfering with regulators of humor hypoxia that also affect angiogenesis, such as HIF1 and HIF2, (ii) inhibiting the production of angiogenic promoting factors, and (iii) directly increasing the production of angiogenesis inhibitors, such as arresten.

p53 by regulating Leukemia Inhibitory Factor has been shown to facilitate implantation in the mouse and possibly humans reproduction.

Regulation

p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress, osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. 

The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF. 

In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from the nucleus to the cytosol. Mdm2 also acts as an ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible. On activation of p53, Mdm2 is also activated, setting up a feedback loop. p53 levels can show oscillations (or repeated pulses) in response to certain stresses, and these pulses can be important in determining whether the cells survive the stress, or die.

MI-63 binds to MDM2, reactivating p53 in situations where p53's function has become inhibited.

A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway . This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.

Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells.

USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cytoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2.

Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis. Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity.

Role in disease

Overview of signal transduction pathways involved in apoptosis.

 

A micrograph showing cells with abnormal p53 expression (brown) in a brain tumor. p53 immunostain.

 

If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome. 

The TP53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene. Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype.

Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging. Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option. The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma. It delivers a functional copy of the p53 gene using an engineered adenovirus.

Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by the HPV protein E7, allows for repeated cell division manifested clinically as warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.

The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation. The degradation of the p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function.

Suppression of p53 in human breast cancer cells is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13.

One study found that p53 and Myc proteins were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML.

Experimental analysis of p53 mutations

Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional affects.

The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in TP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe. Recents studies show that p53 isoforms are differentially expressed in different human tissues, and the loss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provides cancer stem cell potential in different tissues. TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.

The dynamics of p53 proteins, along with its antagonist Mdm2, indicate that the levels of p53, in units of concentration, oscillate as a function of time. This "damped" oscillation is both clinically documented  and mathematically modelled. Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as double-stranded breaks (DSB) or UV radiation, are introduced to the system. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation. Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug discovery.

Discovery

p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, working at Imperial Cancer Research Fund (UK) Princeton University/UMDNJ (Cancer Institute of New Jersey), and Memorial Sloan-Kettering Cancer Center, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences in 1982, and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science). The human TP53 gene was cloned in 1984 and the full length clone in 1985.

It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumor cell mRNA. Its role as a tumor suppressor gene was revealed in 1989 by Bert Vogelstein at the Johns Hopkins School of Medicine and Arnold Levine at Princeton University.

Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation. In a series of publications in 1991–92, Michael Kastan of Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage.

In 1993, p53 was voted molecule of the year by Science magazine.

Isoforms

As with 95% of human genes, TP53 encodes more than one protein. In 2005 several isoforms were discovered and until now, 12 human p53 isoforms were identified (p53α, p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, ∆160p53γ). Furthermore, p53 isoforms are expressed in a tissue dependent manner and p53α is never expressed alone.

The full length p53 isoform proteins can be subdivided into different protein domains. Starting from the N-terminus, there are first the amino-terminal transactivation domains (TAD 1, TAD 2), which are needed to induce a subset of p53 target genes. This domain is followed by the Proline rich domain (PXXP), whereby the motif PXXP is repeated (P is a Proline and X can be any amino acid). It is required among others for p53 mediated apoptosis. Some isoforms lack the Proline rich domain, such as Δ133p53β,γ and Δ160p53α,β,γ; hence some isoforms of p53 are not mediating apoptosis, emphasizing the diversifying roles of the TP53 gene. Afterwards there is the DNA binding domain (DBD), which enables the proteins to sequence specific binding. The carboxyl terminal domain completes the protein. It includes the nuclear localization signal (NLS), the nuclear export signal (NES) and the oligomerisation domain (OD). The NLS and NES are responsible for the subcellular regulation of p53. Through the OD, p53 can form a tetramer and then bind to DNA. Among the isoforms, some domains can be missing, but all of them share most of the highly conserved DNA-binding domain. 

The isoforms are formed by different mechanisms. The beta and the gamma isoforms are generated by multiple splicing of intron 9, which leads to a different C-terminus. Furthermore, the usage of an internal promoter in intron 4 causes the ∆133 and ∆160 isoforms, which lack the TAD domain and a part of the DBD. Moreover, alternative initiation of translation at codon 40 or 160 bear the ∆40p53 and ∆160p53 isoforms.

Due to the isoformic nature of p53 proteins, there have been several sources of evidence showing that mutations within the TP53 gene giving rise to mutated isoforms are causative agents of various cancer phenotypes, from mild to severe, due to single mutation in the TP53 gene.