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Delusional misidentification syndromes (DMSs) are complex, often multifactorial, neuropsychiatric delusions with a plethora of clinical presentations. These DMSs can coexist, oscillate interchangeably, or exist at different times in an individual's lifetime.[1] As these delusions can coexist at a rate of 29%, a shared mechanism has been postulated.[2] DMSs are often encountered in major neurocognitive disorders such as Alzheimer dementia (15.8%) and Lewy body dementia (16.6%).[3] The 4 core types of DMSs included Capgras syndrome, Frégoli syndrome, intermetamorphosis, and the syndrome of subjective doubles (see Table. Delusional Misidentification Syndromes and Subtypes).[2][1][4] Christodoulou further categorized these core DMSs as "hyper" and "hypo" familiarity regarding heightened over- or underidentification.[1] Table Table. Delusional Misidentification Syndromes and Subtypes . Violence and dangerousness in patients with DMSs and concomitant major neurocognitive disorders are well documented with a significant amount of forensic case reports. A sizable number of patients with a primary psychiatric diagnosis, most notably schizophrenia, with concurrent DMSs, were noted to have a high rate of murder or attempted murders, with approximately half of the violent acts perpetrated with weapons.[8][9] Overlap with the forensic population and DMSs, particularly Frégoli syndrome, has been noted in case studies wherein the patient believes the victim is the actual perpetrator.[10] Studies regarding Capgras Syndrome identified risk factors of violence to include male sex, long-standing delusions, a history of aggressive behavior, a diagnosis of schizophrenia, and comorbid substance use. Delusions of persecution, particularly towards the misidentified person, were common.[11]

Overlap with the forensic population and DMSs, particularly Frégoli syndrome, has been noted in case studies wherein the patient believes the victim is the actual perpetrator.[10] Studies regarding Capgras Syndrome identified risk factors of violence to include male sex, long-standing delusions, a history of aggressive behavior, a diagnosis of schizophrenia, and comorbid substance use. Delusions of persecution, particularly towards the misidentified person, were common.[11] Moreover, as the literature suggests that perhaps more than 50% of patients with DMSs have a primary diagnosis of schizophrenia, clinicians should maintain awareness of specific health disparities, management, treatment complications, caregiver burden, and risk factors. According to studies, patients diagnosed with schizophrenia may have a 5% to 10% lifetime risk of suicide, significantly higher than the overall population.[12] Some authors in this literary space have suggested the integration of DMSs into the evaluation of schizophrenia.[9] The right parietal lobe and temporal lobe have been implicated in DMSs.[7][13]

Earlier models of DMSs focused on psychodynamic interpretations; newer evidence shows distinct structural etiologies. A comprehensive review of DMSs showed right hemisphere lesions (92% of cases) and right frontal lesions (63%) as the most common lesion location.[2] These associations are furthered by studies on patients with a primary psychotic disorder, namely schizophrenia, in which reduced activity in the dorsolateral prefrontal cortex can be observed during rest and executive functions.[14] These cortical regions have also been implicated in select cases regarding limbic encephalitis, resulting in hypometabolism.[15] Furthermore, DMSs found in patients with confirmed Alzheimer disease were found to have significantly decreased cerebral blood flow measurements of the right parietal area with noted severe visuospatial and visuoperceptive deficits.[13] Similarly, these neuroanatomical vascular lesions, multifocal brain atrophy, and medial frontal lobe disease have been supported across literature investigating Cotard syndrome.[16][17] Overlapping structural changes across various DMSs suggest identifiable structural brain abnormalities and may hint at the cause of multiple DMSs in a single patient. The findings can pave the way for further investigation and potential pharmacologic advancements. Other psychiatric diagnoses, including depersonalization and derealization disorder, complex posttraumatic stress disorder, and borderline personality disorder, have shed some light on DMSs. A recently published case study of Charles Bonnet syndrome, a condition in which patients develop hallucinations after the loss of vision, noted a case of ocular delusional parasitosis.[18] Cases of Capgras and reverse Capgras resulting in remission after antipsychotic initiation have outlined acute traumatic events as triggers.[19] Additionally, low socioeconomic status, urban settings, migrant status, and a history of physical or sexual abuse are associated with increased psychotic-like events. These hardships, along with genetic predispositions, may increase the risk of patients developing schizophrenia and subsequent DMSs.[20][21] Additionally, select case studies have also linked medications (eg, ketoconazole, valacyclovir, and cefepime) to various DMSs.[22][23]

According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), delusional disorder has an estimated prevalence of 0.2%. DMSs remain uncommon variants of delusion and have a multitude of subtypes; therefore, no definitive published estimates of prevalence exist. One study noted the prevalence of DMSs in a consecutive sample of 195 inpatient psychiatric admissions was 4.1%.[24] Capgras syndrome, perhaps the most identifiable and common DMS, was estimated to be 1.3% (1.8% for females, 0.9% for males) in a sample size of 920 inpatient psychiatric patients at a university hospital studied over 5 years. Amongst patients identified to have DMSs, approximately half had schizophrenia as the primary diagnosis.[25] An alternative study observed Capgras syndrome in 2.5% of acute psychiatric patients.[26] In a review of 260 case reports of DMSs, 66.9% were noted to have Capgras syndrome. This review furthered the association with schizophrenia, usually paranoid type, which was identified in 73.0% of said patients, while patients with dementia and other organic causes made up 26.4% of the patients with DMSs.[27] A study published in 2011 suggests nearly half of the patients with a delusional disorder in the outpatient setting have at least 1 additional lifetime psychiatric diagnosis, with the most common being depressive disorders.[28] In a study of 392 patients with major neurocognitive disorders, DMSs were identified in 15.8% of cases with Alzheimer dementia and 16.6% of patients with Lewy body dementia; of these DMSs, Capgras delusions were noted to be the most common type. The mean onset time for DMSs observed in patients with Alzheimer dementia was 3.51 years.[3] No concrete age disparities have been reported specifically for DMSs with a primarily psychiatric diagnosis; patients with secondary DMSs were significantly older. A recent meta-analysis studying 119 patients with Frégoli syndrome noted a median age of 60 for secondary causes of psychosis and a median age of 33 for primary psychosis.[29] Males have shown significantly higher rates of co-occurring substance use disorders.[30] Furthermore, as some delusional disorders may not impair daily functioning, they may be underreported. On the contrary, concomitant or dual diagnoses may skew accurate prevalence rates.

A dual mechanism theory has proposed outlining lesions of the right hemisphere and right frontal lobe insult resulting in left frontal lobe overactivity. Right hemisphere dysfunction is associated with poor emotion regulation, control, and stimuli familiarity. Experts have postulated that the left hemisphere creates a narrative to accommodate the right frontal lobe dysfunction, leading to false beliefs and explanations.[31] Delusional belief content in DMSs results from dysfunctional linking between the externally perceived objects and appropriately retrieved internal autobiographical memories associated with these objects.[32][33] Further research on DMSs, such as Cotard and Capgras syndromes, has associated delusions with misfiring in the fusiform face area in the ventral temporal region and the amygdala. These regions are related to face recognition and emotional regulation, respectively.[34] As schizophrenia has been identified as the most associated primary psychotic disorder associated with DMSs, seen in over 50% of cases, similar pathophysiological mechanisms are hypothesized to be present in cases not associated with schizophrenia.[25][27] An element of schizophrenia pathology is excessive dopaminergic activity in the mesolimbic pathway, originating in the ventral tegmental area and projecting to limbic areas, causing "positive" symptoms of schizophrenia, such as hallucinations and delusions. Reduction in dopamine levels in the mesocortical pathway, connecting the ventral tegmental area to the cortex, is associated with the "negative" features of schizophrenia.[35][36][37] This dopaminergic dysregulation seen in schizophrenia is related to assigning salience to environmental stimuli. Misfiring of neurons leads to a decoupling of dopamine from these salient stimuli, resulting in misattribution and adherent processing. This theory may suggest persistent hallucinations and delusions in the presence of otherwise neutral stimuli.[35]

As schizophrenia has been identified as the most associated primary psychotic disorder associated with DMSs, seen in over 50% of cases, similar pathophysiological mechanisms are hypothesized to be present in cases not associated with schizophrenia.[25][27] An element of schizophrenia pathology is excessive dopaminergic activity in the mesolimbic pathway, originating in the ventral tegmental area and projecting to limbic areas, causing "positive" symptoms of schizophrenia, such as hallucinations and delusions. Reduction in dopamine levels in the mesocortical pathway, connecting the ventral tegmental area to the cortex, is associated with the "negative" features of schizophrenia.[35][36][37] This dopaminergic dysregulation seen in schizophrenia is related to assigning salience to environmental stimuli. Misfiring of neurons leads to a decoupling of dopamine from these salient stimuli, resulting in misattribution and adherent processing. This theory may suggest persistent hallucinations and delusions in the presence of otherwise neutral stimuli.[35] Moreover, the incomplete remission of delusions and hallucinations seen in primary psychotic disorders such as schizophrenia after the initiation of D2-receptor antagonist antipsychotic medications suggests the involvement of other neurotransmitters, including GABA and glutamate. Delays in response and treatment resistance suggest secondary pathways and microcircuits are at play, prompting the need for further investigation and pharmacological interventions.[35] A recent case report described a patient diagnosed with Capgras syndrome secondary to an acute thromboembolic cerebrovascular accident who demonstrated improvement on mirtazapine after symptoms continued on a first-generation antipsychotic.[38] Capgras syndrome observed in patients with Parkinson disease dementia appeared to occur in the "off" periods, with delusions regressing upon addressing dopamine levels via L-DOPA.[39] A case study involving limbic encephalitis secondary to diffuse large B-cell lymphoma resulted in Capgras syndrome without remission with antipsychotic medication. Authors note that using positron emission tomography (PET) with fludeoxyglucose F 18 showed diffuse hypometabolism in frontal, parietal, and lateral temporal cortices, correlating with previously published lesion locations.[15]

Clinicians should exclude underlying medical causes for delusions when clinically assessing patients for DMSs, including acute infection, medication changes, substance use, and co-occurring psychiatric and neurocognitive disorders, before making a formal diagnosis. Additionally, clinicians should inquire about personal and family psychiatric diagnoses while also being aware of potential shared delusions while maintaining cultural sensitivity and awareness. Misdiagnosis or overdiagnosis may occur when culturally normative behavior is misinterpreted as psychopathology.[40] A recent study reported that 15% to 25% of Capgras syndrome cases resulted in a folie à deux.[41]

No gold-standard laboratory or imaging studies can confirm or exclude DMSs. Furthermore, no national nor international guidelines exist for evaluating DMSs, highlighting the importance of ruling out reversible and organic etiologies. A thorough mental status exam should be conducted, as deficiencies in particular areas of the mental status exam may guide treatment. For example, pertinent positives, including auditory hallucinations or disorganized thought processes, may point to another primary psychotic disorder. In cases of DMSs secondary to a neurocognitive disorder, the patient will likely exhibit an impaired level of cognitive functioning, which warrants further testing. A Montreal Cognitive Assessment (MoCA), a sensitive tool for cognitive testing, may also indicate management approaches. More informative and intricate neuropsychological testing can be administered if clinically indicated. Some research shows common etiologies included ischemic stroke, hemorrhagic stroke, and trauma, with the onset of DMSs having a median lag time of 60 days.[2] Per DSM-IV-TR diagnostic criteria, delusional disorder will likely have preserved cognitive functioning. Furthermore, comprehensive reviews and case studies show a slight but notable fraction of patients exhibiting multiple DMSs.[2][42] These complexities emphasize the importance of collateral information when available, as the patient may be able to mask symptoms.

As no definite standard of care exists for treating DMSs, treatment should be individualized, accounting for the patient's comorbid conditions and potential medication interactions. A multifaceted approach involving mental health professionals and appropriate interprofessional specialties should be utilized to optimize patient care. Antipsychotic Medications The mainstay of treatment for delusional disorders is antipsychotic medications, which are typically administered orally or in a long-acting injectable (LAI) formulation. Second-generation antipsychotics, such as amisulpride, clozapine, risperidone, and olanzapine, have shown more significant effect sizes than first-generation antipsychotics, as well as more favorable adverse effect profiles.[43] Case-study level evidence includes: Aripiprazole LAI 882 mg [44] Olanzapine [42] Clozapine [45] Ziprasidone augmented with mirtazapine [38] Paliperidone augmented with valproic acid and clozapine [46] Nonpharmacological Therapies Recent case reports highlight the effectiveness of electroconvulsive therapy in treatment-resistant patients with failed trials of second-generation antipsychotics.[47] Moreover, a case report highlighting the use of electroconvulsive therapy in the postpartum period noted a faster onset of symptom relief and a lack of secretion in breast milk.[48] Recently, a nonpharmacological approach for DMSs secondary to major neurocognitive disorders was proposed. The authors conducted an intervention that consisted of 2 daily 15-minute sessions over 10 weeks. The 2 patients viewed and reengaged with the digital therapeutic programs. The Neuropsychiatric Inventory, the Misidentification Delusion Questionnaire (MDQ), the Zarit Caregiver Burden Scale, and the Quality of Life in Alzheimer's Disease Scales for both patients with MaND and their spouse (QoL-AD) were provided. Both patients were deemed to have failed pharmacological interventions as the first patient failed to have an adequate response on quetiapine and mirtazapine, and the second had a suboptimal response to quetiapine and previous failed trials of escitalopram, donepezil, buspirone, risperidone, and melatonin. Both patients showed improvements on the MDQ scale with reduced caregiver burden.

Differential diagnoses that should be considered when evaluating patients for DMSs include: Obsessive-compulsive disorder (OCD): Patients with OCD may present with absent insight into beliefs related to their obsessions and compulsions and fully believe the contents of those thoughts. They are diagnosed with an additional specifier "with absent insight/delusional beliefs." Body dysmorphic disorder: Patients with body dysmorphic disorder may present with absent insight into their self-image, similar to OCD. They would also be diagnosed with the "with absent insight/delusional beliefs" specifier. Delirium: Presents with fluctuating attention and positive psychotic symptoms, including delusions, and will resolve when the underlying medical cause is treated. Major neurocognitive disorder: Delusions are common in Alzheimer disease and can be diagnosed with neuropsychiatric testing. Careful history taking, collateral, and timeline may indicate a major neurocognitive disorder. Cognitive functioning is usually preserved in delusional disorder. Schizophrenia: Schizophrenia will also present with other positive symptoms such as hallucinations, cognitive symptoms such as disorganized speech and thoughts, and negative symptoms such as social isolation. Mood disorder with psychotic features: Patients in a mood episode (depression or mania) may present with psychotic symptoms, including delusions. If the delusion exists outside of the mood symptoms for more than 2 weeks and is void of hallucinations, a delusional disorder can be diagnosed. Substance-induced psychotic disorder: This disorder is often seen in patients using amphetamine or cocaine and is most frequently associated with persecutory delusions.

If an identifiable organic cause is found, the prognosis is favorable. Reversible causes include adverse effects of medications, vitamin deficiencies, encephalitis undergoing treatment, or a tumor. DMSs do not have published data on prognosis; delusional disorder as a whole has nearly 50% response to medications.[49] In a recent longitudinal study, 65% of patients diagnosed with delusional disorder maintained the diagnosis 4 years later, while the rest met the criteria for schizophrenia. The patient's ability to socialize or work, quality of life, and overall cognitive functioning were similar between groups.[50] As schizophrenia is highly associated with DMSs, patients may have significantly lower life expectancy. A meta-analysis over multiple continents showed an associated average of 14.5 years of potential life with higher rates for me. Potential life lost was the least amongst patients in Asia and most significant in Africa.[51] In patients with an identifiable lesion, a delay (median 60 days) between injury and the delusion was often noted, with a median duration of 42 days before resolution. Medical or psychiatric decompensation leads to reoccurrence and longer durations.[2]

DMSs can lead to several complications, including: Violence and aggression: Approximately 60% of patients with DMSs have physically attacked someone about the misidentification. Anger and delusions involving persecution, spying, and conspiracy are associated with an increased risk of violence.[5][52] Self-harm and suicide risk: Cotard syndrome, a type of DMSs where the individual believes they are dead or missing body parts, is associated with an elevated risk of suicide.[52] Social isolation: Patients may refuse to interact with family members or caregivers they believe to be imposters, leading to social withdrawal and isolation.[19] Difficulty with treatment: The fixed nature of the delusions can make it challenging to establish therapeutic alliances and implement effective treatments. Cognitive impairment: DMSs are often associated with deficits in memory, executive function, and visuospatial abilities, particularly in cases resulting from neurological injuries. Delayed recognition and diagnosis: The onset of DMSs symptoms may be delayed by months from the time of injury, potentially leading to delayed treatment. Multiple concurrent DMSs: About 29% of patients with lesion-related DMSs experience various types of misidentification delusions simultaneously, complicating clinical presentation and management. Impaired daily functioning: The false beliefs about identity can significantly interfere with a patient's ability to navigate daily life and maintain relationships. Caregiver burden: Managing patients with DMSs can be challenging for caregivers, potentially leading to increased stress and burnout. Legal and ethical issues: In some cases, DMSs may raise complex legal and moral questions, mainly when patients refuse to interact with family members or make decisions based on their delusions.[5] Notably, while DMSs can be persistent, many cases are self-limited, especially those resulting from focal neurological injury. Proper diagnosis, medication management, and psychotherapy can help mitigate these complications and improve outcomes for patients with DMSs.

Patients with DMSs lack insight and judgment and often refuse care. The treatment team should respect the patient’s autonomy, particularly when the patient does not pose a threat to themselves, can refuse treatment, and can care for themselves. A discussion regarding risks, benefits, adverse effects, and alternative options such as nonpharmacological approaches should be explored. Adverse effects may result in discontinuations and possible decompensation; an appropriately trained clinician should be able to address these concerns to curtail discontinuation. Family Education and Counseling In a 2-year epidemiological survey regarding violence in first-break psychosis, authors postulated a high-risk triad of valued beliefs (ie, anger, being spied on, and conspiracy) mediated by anger. They identified targets as risk factors for aggression and violence.[53] Close relatives or attachment figures have been established as having significantly higher target risk. Prompt identification of medical and psychiatric decompensation is paramount to avoid detrimental effects on quality of life and potential target violence.

The effective management of DMSs requires an interprofessional approach to ensure patient-centered care, safety, and improved outcomes. Physicians and advanced practitioners are pivotal in diagnosing DMSs and tailoring treatment plans to address the interplay between neurocognitive disorders and psychiatric conditions like schizophrenia. They guide the appropriate use of antipsychotic medications while monitoring for efficacy and complications. Pharmacists play a crucial role in ensuring medication adherence, minimizing adverse effects, and preventing drug-drug interactions that could worsen patient outcomes. Their expertise is essential in optimizing pharmacologic regimens and supporting the overall care strategy. Nurses are integral in creating structured and supportive care environments, especially in nursing homes or day-treatment programs. They help maintain daily routines, ensure safety, and monitor changes in the patient’s condition. Interprofessional communication among healthcare practitioners enhances coordination of care, integrating medical, psychiatric, and community resources to address the patient’s and caregivers’ needs. By fostering an effective doctor-patient relationship and leveraging community support, healthcare teams can improve insight, judgment, and quality of life for patients while mitigating risks associated with these complex disorders.