recent research study about schizophrenia and dissociative disorders

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Dissociative Model in Patients With Resistant Schizophrenia

Associated data.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Schizophrenia is a severe mental illness in which, despite the growing number of antipsychotics from 30 to 50% of patients remain resistant to treatment. Many resistance factors have been identified. Dissociation as a clinical phenomenon is associated with a loss of integrity between memories and perceptions of reality. Dissociative symptoms have also been found in patients with schizophrenia of varying severity. The established dispersion of the degree of dissociation in patients with schizophrenia gave us reason to look for the connection between the degree of dissociation and resistance to therapy.

The type of study is correlation analysis. 106 patients with schizophrenia were evaluated. Of these, 45 with resistant schizophrenia and 60 with clinical remission. The Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) scales were used to assess clinical symptoms. The assessment of dissociative symptoms was made with the scale for dissociative experiences (DES). Statistical methods were used to analyze the differences in results between the two groups of patients.

Patients with resistant schizophrenia have a higher level of dissociation than patients in remission. This difference is significant and demonstrative with more than twice the level of dissociation in patients with resistant schizophrenia.

The level of dissociation measured in patients with resistant schizophrenia is as high as the points on the DES in dissociative personality disorder.

Patients with resistant schizophrenia have a much higher level of dissociation than patients in clinical remission. The established difference between the two groups support to assume that resistance to the administered antipsychotics is associated with the presence of high dissociation in the group of resistant patients. These results give us explanation to think about therapeutic options outside the field of antipsychotic drugs as well as to consider different strategies earlier in the diagnostic process.

Schizophrenia is a serious mental illness which is characterized by changes in information processing as a consequence of misinterpretation of stimuli from the external environment. As a result, the clinical picture is characterized by positive symptoms (delusions and hallucinations), negative (apathy, anhedonia, dull affect, and loss of social cohesion), and cognitive ones with changes in attention and working memory. In addition to these clinically important symptoms for the diagnosis of schizophrenia, depressive, anxious, and cognitive symptoms are common if not always present ( 1 ). These psychiatric manifestations are associated with metabolic, lipid, and immune changes, often requiring additional therapeutic approaches ( 2 , 3 ). Interesting observations on the level of serum lipids have been made in patients with schizophrenia and in persons using psychostimulants. Decreases in serum lipid levels were observed in both groups ( 3 ). Studies assessing self-perception and assessment of interpersonal space have been performed ( 4 ). There is evidence that as anxiety increases, interpersonal space increases ( 5 ). Such analyzes have also been performed in patients with schizophrenia who show that they have an increase in interpersonal space ( 6 ). Impaired cognitive assessment of reality and self-perception is associated with changes in behavior and the appearance of typical symptoms of schizophrenia associated with metabolic disorders as well as changes in neural connections between brain regions ( 7 ). This complex picture of changes in perception, behavior, metabolic characteristics, and functional connectivity makes schizophrenia a therapeutic challenge.

This is the reason despite the constant expansion of various therapeutic interventions, a significant percentage of patients remain resistant and pose a serious personal family and social problem. Some authors try to consider patients with resistant schizophrenia as a separate category. This raises the question of looking for different therapeutic approaches in them ( 2 , 8 , 9 ).

Janet presented the concept of dissociation for the first time at the end from 1,800, which is defined as a failure to integrate experiences that are usually related to each other in stream of consciousness ( 10 ). Dissociation is the partial or complete loss of normal integration between memories of the past, awareness of one's identity and immediate sensations, and control of bodily movements ( 11 ). Dissociation is a special form of consciousness in which events that would normally be related are separated from each other ( 12 ). Some authors ( 13 ) believe that dissociation is not only pathological, but may also play a role in some adaptive functions. It is also observed in healthy individuals in certain conditions ( 14 ).

Historically, dissociation as a clinical phenomenon has been associated with the presence of traumatic events leading to dissociative symptoms ( 15 ). A link has been found between dissociative symptoms and traumatic childhood events. Putnam ( 13 ) found that the most important traumas originate from childhood due to physical or sexual abuse with subsequent development of symptoms often after many years. According to the same author, dissociative symptoms also often occur in adults with severe traumatic event or a series of traumatic events. He found this in about half of the cases of dissociation. On the other hand, in direct clinical practice with adult patients, it is difficult to make a retrospective assessment of childhood experiences in order to give them the appropriate clinical weight. The authors found that 59.6% of 468 patients with a proven history of childhood sexual abuse were unable to recall episodes of past violence ( 16 ). Contradictory data are also available. The problem with the analysis of trauma in early childhood in the evaluation of adult patients is related to the fact that the manifestation of false memory experiences for the presence of trauma is often provoked ( 17 ).

It was found a traumagenic neurodevelopmental (TN) model of schizophrenia. Authors find the similarities between the effects of traumatic events on the developing brain and the biological abnormalities found in persons diagnosed with schizophrenia ( 12 ). The current diathesis-stress model of schizophrenia proposes that a genetic deficit creates a predisposing vulnerability in the form of oversenstivity to stress ( 15 ).

Corresponding changes in interpersonal space and self-esteem have been found in patients with dissociative disorders as well as in patients with schizophrenia ( 5 , 18 ). Low levels of serum lipids have been reported ( 19 ) as well as impaired functional connectivity between brain regions ( 20 ).

The connection between dissociation and psychosis has been examined by Eugen Bleuler in patients with schizophrenia ( 21 ). In his Textbook of Psychiatry, he writes ( 21 ): “It is not only in hysteria that one finds an arrangement of different personalities who inherit from each other. Through such a mechanism, schizophrenia gives rise to different personalities existing side by side [( 21 ), p. 138]. Bleuler has suggested that schizophrenia is a division of mental relationships similar to hysteria, but in a very extreme form. Psychotic decompensation of some individuals with psychotic symptoms, such as hallucinations, may occur. There are also a large number of observations showing a high level of dissociation in patients with schizophrenia ( 15 , 22 – 27 ). The above data suggest a close link between schizophrenia and dissociative disorders. Several studies have found surprisingly high coincidences in the symptoms of these diagnoses ( 27 – 30 ). Even the symptoms described by Kurt Schneider as pathognomonic for schizophrenia have been proposed to be more characteristic of dissociative disorders ( 31 , 32 ). Other studies suggest that there are similarities only in hallucinatory production as a characteristic of voices and their expression, but not in the presence of formal thought disorders, bizarre delusions, and negative symptoms ( 33 ). Studies indicate that up to 50% of patients with psychosis have severe dissociative symptoms ( 34 , 35 ). This established overlap of symptoms in schizophrenia and dissociative disorder raises questions about therapy and expectations that a similar pattern of response will be observed. The data show results contrary to expectations. On the one hand, the treatment of schizophrenia is mainly with antipsychotic drugs, and on the other hand, the treatment of dissociative phenomena with antipsychotic drugs is generally ineffective ( 36 ). Examining the relationship between schizophrenia and dissociation, some authors raise the question of the existence of a subtype of schizophrenia, allowing for a new conceptualization of the relationship between them ( 37 ).

Resistance to drug therapy is registered in about 30–50% of patients with schizophrenia ( 38 – 44 ). The analysis of the relationship between dissociation in patients with schizophrenia and the course of the disease in them shows that those with a high degree of dissociation have a more severe course and more pronounced symptoms ( 45 ).

In the analysis of the literature available to us, we did not find a comparative study of the differences in dissociative symptoms in patients with resistant schizophrenia and those in clinical remission.

Working hypothesis: We suppose that the level of dissociation in patients with resistance to therapy will be higher than those in clinical remission.

Materials and Methods

105 patients with schizophrenia were observed. Of these, 45 have resistant s chizophrenia and the remaining 60 are in clinical remission.

Including criteria for patients with resistant schizophrenia are those who have met the resistance criteria of the published consensus on resistant schizophrenia ( 46 ). They are:

• Assessment of symptoms with the Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) scale ( 47 , 48 ).
• Prospective monitoring for a period of at least 12 weeks.
• Administration of at least two antipsychotic medication trials at a dose corresponding to or greater than 600 mg chlorpromazine equivalents.
• Reduction of symptoms when assessed with the PANSS and BPRS scale by less than 20% for the observed period of time.
• The assessment of social dysfunction using the SOFAS scale is below 60.

The exclusion criteria are:

• Mental retardation
• Presence of organic brain damage
• Concomitant progressive neurological or severe somatic diseases.
• Expressed personality change
• Score of MMSI below 25 points.

The Dissociative Experiences Scale (DES) was used to assess dissociative symptoms ( 22 ).

The statistical software package SPSS, was used for statistical data processing.

Descriptive analyzes, correlation analysis, dispersion analysis, ANOVA, and a non-parametric statistical method were used [Mann Whitney U-test, ( 49 )].

The mean age of patients in the group of resistant schizophrenia was 36.98 years. The minimum age is 21 years and the maximum is 60 years.

The mean age of patients in the group of schizophrenia in clinical remission was 37.25 years. The minimum is 23 years and the maximum is 63 years.

We do not find a difference in the mean age of the patients in the both groups at the time of the study.

The mean value of the dissociative symptoms scale found in all patients with schizophrenia was 29.1356, standard deviation was 22.3898, and the lowest and highest values were 0 and 97, respectively.

The mean value of the measured points with the Carlson and Putnam scale in patients with resistant schizophrenia is 42.578, and the standard deviation is 20.8977. Their average level of dissociation is commensurate with the level needed to diagnose dissociative personality disorder according to the interpretation of the scale (requires values above 48 on the scale).

For patients in clinical remission, the mean was 15.907 and the standard deviation was 14.530. Their mean level of dissociation is commensurate with the level required to diagnose schizophrenia according to the interpretation of the scale (requires values of 15.4).

Up to three times the incidence of dissociation values is observed in patients with resistance compared to those in remission. The analysis of the median value in the two groups showed an even greater difference—up to four times higher in the group with patients resistant to therapy ( Table 1 ; Figure 1 ).

Descriptive analysis, the mean values, the median value, the standard deviation, and the standard error in the sample.

The variance of the results measured with DES in both groups of patients. The variance—in blue.

In the analysis of the intragroup distribution of level of dissociation in patients with resistant schizophrenia, it was found that the main grouping of results is in the range of 30–60 on the scale used. This result shows that the majority of patients have a very high level of dissociation.

From the analysis of the distribution of data in patients in clinical remission, we found that the main distribution of patients is grouped in the range from 0 to about 20. We observe a much lower level of dissociation in patients in remission.

The statistical analysis of the results of Mann-Whitney U test is shown in Table 2 (Ranks) and Table 3 (Statistics) ( *** p < 0.001).

Mann-Whitney U test—description.

Mann-Whitney U test—statistics.

A variance analysis of the relationship between the level of dissociation and resistance to treatment is presented in Table 4 .

The variance analysis of the results of the two groups of patients.

*** p < 0.001 .

The difference in the degree of dissociation registered by us in the two groups of patients raised the question: Is there a correlation between the value of dissociation and the values of the PANSS and BPRS scales.

The performed correlation analysis showed the presence of correlation p < 0.05, Table 5 .

The assessed mean values of the PANSS, BPRS, and DES scales.

Conducting a correlation analysis showed that there was a statistically significant correlation between the registered psychotic and dissociative symptoms ( Table 6 ).

Dispersion analysis between the dissociation scale (DES) and the clinical scales PANSS and BPRS.

* p < 0.05 .

Our results show a high degree of dissociation in patients with resistant schizophrenia, which is up to three times higher than in patients in clinical remission. We also find a correlation between the high values of the symptoms measured with the PANSS and BPRS scales and the dissociative symptoms registered with the DES.

Our study of dissociative symptoms coincides with the analysis of other teams, which show the presence of dissociative symptoms in patients with schizophrenia in the range from 11.9 to 44.24 ( 50 – 52 ). Some authors, in addition to assessing the dissociation, also make an analysis in dynamics: in admission and in stabilizing the condition. They do not get much change in the points on the DES from 19.2 to 14.1 ( 53 ). We find a mean score on dissociation level in all patients of 29.1356. Our data occupy an intermediate position compared to those described in the literature. Our results confirm the views of pioneers in schizophrenology such as Eugen Bleuler that schizophrenia is a state of extreme degree of dissociation ( 21 ).

In the previous studies, patients with resistance and those in clinical remission were not considered separately. The results of the points on the scale for dissociative experiences (DES) in patients in remission observed by us coincide with the criteria of the scale for patients with schizophrenia-−15.4. The results of other studies are mixed. We believe that this is because they have not considered patients separately—resistant and those in remission. Given that schizophrenia is a heterogeneous disease, it is also quite understandable the difference in the values of dissociative symptoms described in the individual studies. Over the years, there have been many analyzes of the overlap of symptoms of dissociative personality disorder and schizophrenia. Numerous studies have shown that up to 50% of patients with schizophrenia meet the diagnostic criteria for dissociative personality disorder ( 34 , 35 ). These observations, as well as our data, do not show that in fact a probable reason for the lack of efficiency is the high degree of dissociation, which correlates positively with the high scores made with the PANSS and BPRS scales. This high level of resistance that we observe and register challenge of discussing the term resistance to treatment with “antidopaminergic drugs.” Dissociative disorders and symptoms have no effect from antipsychotic treatment ( 36 ).

In this sense, the question can be asked whether resistant schizophrenia is a form of dissociative disorder or mixture of the both entities. On the other hand, our results provide a basis for rethinking the diagnostic categories and research criteria used in the context of the relationship between the mind and the brain ( 54 ). The question remains whether high dissociation scales are the cause or consequence of the development of the neurodegenerative process in these patients ( 40 , 55 ). Studies show that in some patients there is a progression of the disease, while in others there is a stationary condition that lasts for years. Magnetic resonance imaging data show that we can distinguish two groups of patients in comparative follow-up. Some have a neurodegenerative process and others do not ( 56 ).

The limitation of our study is related to the fact that we make a cross-section of the patient's condition in terms of dissociative symptoms. Longitudinal studies are needed to determine how the symptoms change over time. On the other hand, it is not clear whether the dissociative symptoms did not develop in parallel over time in patients with schizophrenia from the perspective of hospitalizations and in the process of treatment with various antipsychotic drugs. Some authors in a study found in the general population up to 1.7% of people at high risk of developing psychosis ( 57 ). No data have been established on the level of dissociative symptoms in them. Our study provides direction to consider assessment of dissociation early in the diagnostic process, especially in patients with the first psychotic episode, in order to discuss prognosis and associated therapy.

We find a high degree of dissociation in patients with resistant schizophrenia. There is a high correlation between psychotic symptoms measured with the PANSS and BPRS scales and dissociative symptoms assessed with the DES. We found that the points on the scale for the level of dissociation in patients with resistant schizophrenia are as high as the requirement of the points on the scale for the assessment of dissociative personality disorder. The data we found for a high scale of dissociation in patients with resistance entitles us to seek therapeutic interventions outside the field of antipsychotic drugs. Therapeutic approaches in dissociative disorders may be considered (symptomatic and psychotherapeutic) as well as consideration of earlier use of electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS).

Data Availability Statement

Ethics statement.

The studies involving human participants were reviewed and approved by Ethical committee of the University Hospital of Trakia University. The patients/participants provided their written informed consent to participate in this study.

Author Contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Conflict of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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• April 01, 2024 | VOL. 181, NO. 4 CURRENT ISSUE pp.255-346
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Dissociation in Psychiatric Disorders: A Meta-Analysis of Studies Using the Dissociative Experiences Scale

• Lisa Lyssenko , Dipl.-Psych. ,
• Christian Schmahl , Dr.med. ,
• Laura Bockhacker , Dr.med. ,
• Ruben Vonderlin , M.Sc. ,
• Martin Bohus , Dr.med. ,
• Nikolaus Kleindienst , Dr.rer.hum.biol.

Search for more papers by this author

Dissociation is a complex, ubiquitous construct in psychopathology. Symptoms of dissociation are present in a variety of mental disorders and have been connected to higher burden of illness and poorer treatment response, and not only in disorders with high levels of dissociation. This meta-analysis offers a systematic and evidence-based study of the prevalence and distribution of dissociation, as assessed by the Dissociative Experiences Scale, within different categories of mental disorders, and it updates an earlier meta-analysis.

More than 1,900 original publications were screened, and 216 were included in the meta-analysis, comprising 15,219 individuals in 19 diagnostic categories.

The largest mean dissociation scores were found in dissociative disorders (mean scores >35), followed by posttraumatic stress disorder, borderline personality disorder, and conversion disorder (mean scores >25). Somatic symptom disorder, substance-related and addictive disorders, feeding and eating disorders, schizophrenia, anxiety disorder, OCD, and most affective disorders also showed mean dissociation scores >15. Bipolar disorders yielded the lowest dissociation scores (mean score, 14.8).

Conclusions:

The findings underline the importance of careful psychopathological assessment of dissociative symptoms in the entire range of mental disorders.

Dissociation is a ubiquitous construct in modern psychopathology. DSM-5 defines dissociation as “disruption of and/or discontinuity in the normal integration of consciousness, memory, identity, emotion, perception, body representation, motor control, and behavior” ( 1 ). The corresponding phenomena cover a range from relatively common experiences, such as being completely absorbed by a book or movie, to severe states, such as not recognizing oneself in the mirror ( 2 ). More common experiences have often been linked to mild forms of absorption, that is, focusing on one aspect of experiences and blocking others ( 3 ). More severe dissociative experiences are reflected in the DSM-5 subtypes of dissociative disorders: dissociative amnesia describes the inability to recall autobiographical information; depersonalization/derealization disorders comprise experiences of feeling disconnected or estranged from one’s body, thoughts, or emotions and/or perceiving one’s surroundings as foggy, surreal, or visually distorted ( 1 ).

Beyond the disorders primarily characterized by dissociation, “transient, stress-related severe dissociative symptoms” serve as a criterion for borderline personality disorder ( 1 ), and a dissociative subtype of posttraumatic stress disorder (PTSD) was introduced in DSM-5 ( 4 ). Less noted but equally important research has shown that dissociative features also seem to play a role in the pathology of many other mental disorders, such as schizophrenia ( 5 ), eating disorders ( 6 ), panic disorders ( 7 ), affective disorders ( 8 , 9 ), and obsessive-compulsive disorder (OCD) ( 10 ).

Dissociative symptoms in mental disorders are of high clinical relevance. They have been linked to maladaptive functioning and symptom severity in some disorders, such as executive functioning in borderline personality disorder ( 11 ), neuropsychological performance in depression ( 9 ), number of binge episodes in eating disorders ( 6 ), alexithymia in panic disorders ( 12 ), and anxiety and depression in OCD ( 13 ). Apart from a higher burden of illness, patients may also benefit less from psychotherapeutic interventions. Several studies have indicated that dissociative symptoms can serve as a predictor for nonresponse in psychotherapeutic treatments of PTSD ( 14 – 16 ), OCD ( 17 – 19 ), and panic disorders ( 20 ).

Transdiagnostically, the experience of dissociative symptoms has been linked to acute or chronic stress ( 21 ). Neurobiological findings suggest that dissociative phenomena are likely to disrupt information processing, learning, and memory on various levels ( 22 ). Dissociation has been further linked to physiological processes such as sleep ( 23 ) and fluid intake ( 24 ), as well as to personality variables, such as fantasy proneness and suggestibility ( 25 ). On a cognitive-emotional level, dissociation may be a learned automatic response to reduce or avoid aversive emotional states ( 26 , 27 ). As a secondary process, the experience of dissociation can induce stress itself because it not only disrupts neurocognitive functioning, but can also be perceived as losing control ( 28 ). Recurrent dissociation may therefore reduce the individual’s confidence in reality monitoring ability, perceived control, and sense of self ( 29 , 30 ), which in turn may result in a higher burden of disease.

The transdiagnostic evaluation of those mechanisms is impeded by the fact that neurobiological studies have been mostly conducted in populations of patients who had experienced various traumas, often chronically and/or early in life (e.g., 31 ). Although the statistical association was found to be rather small in some studies ( 27 ), several studies have pointed to a strong association between trauma and dissociation ( 32 – 36 ). Thus, the experience of trauma does not seem to be a conditio sine qua non for pathological dissociation. Studies covering a broader range of mental disorders could shed light on common mechanisms and enhance the development of transdiagnostic treatment modules to deal with dissociative symptoms. The meta-analysis we present here aims to stimulate this line of research by providing an overview of the occurrence of dissociative symptoms across mental disorders.

By far, the most commonly used psychometric instrument for the assessment of dissociative experience is the Dissociative Experiences Scale (DES) ( 2 ). The DES is a self-rating instrument comprising 28 items that build on the assumption of a “dissociative continuum” ranging from mild normative to severe pathological dissociation. Subjects are asked to make slashes on 100-mm lines to indicate where they fall on a continuum for questions on experiences of amnesia, absorption, depersonalization, and derealization—for example, “Some people have the experience of driving a car and suddenly realizing that they don’t remember what has happened during all or part of the trip. Mark the line to show what percentage of time this happens to you” ( 2 , p. 733). As the scoring procedure of the continuous scale was time consuming, a revised version of the scale, the Dissociative Experiences Scale–II (DES-II) ( 37 ) uses an 11-point Likert scale ranging from 0 to 100.

Studies on the psychometric properties of the scale have shown high validity and reliability for both versions, both in clinical and nonclinical populations ( 38 – 42 ). The first, and so far the only, comprehensive meta-analysis on the DES, by van Ijzendoorn and Schüngel ( 43 ), conducted in 1996, shows a mean Cronbach’s alpha of 0.93 in 16 studies, a high predictive validity concerning dissociative disorders and PTSD, as well as a high convergent validity with alternative measures of dissociation (mean Cohen’s d=1.82; N=5,916). While initial studies (e.g., 44 ) found a three-factor structure with the factors amnesia, absorption, and depersonalization/derealization, the factorial structure of the DES remains controversial ( 41 , 42 , 45 , 46 ).

Considering the high number of original publications on the DES (N>2,000), few meta-analyses have been conducted. One meta-analysis on schizophrenia showed a large effect size comparing dissociation scores of patients (N=293) and healthy subjects (N=474) (g=−0.86, 95% CI=−1.13, −0.60), with trauma history being a potential mediator ( 5 ). Scalabrini et al. ( 47 ) compared the dissociation scores in borderline personality disorder with those in other mental disorders and found significantly elevated dissociative symptoms in patients with borderline personality disorder compared with patients with all other disorders (N=2,035; d=0.54, p<0.01) but lower levels of dissociation than in patients with PTSD (d=−0.50, p<0.01) and dissociative disorders (d=−0.35, p<0.05). As noted, the only comprehensive meta-analysis, by van Ijzendoorn and Schüngel ( 43 ), was published about 20 years ago and included 85 individual studies with about 6,000 patients. As expected, the highest scores for dissociation were found for dissociative disorders (mean=35.3), followed by PTSD (mean=32.6), affective disorders (mean=19.4), schizophrenia (mean=19.1), personality disorders (mean=16.6), eating disorders (mean=14.5), and anxiety disorders (mean=10.2). Comparison scores were calculated for healthy samples (mean=11.57) and students (mean=14.27). The authors conclude that “against the background of potential comorbidity and undiscovered dissociation, the means for normals and nondissociative patients were remarkably similar” ( 43 , p. 372).

Since the meta-analysis by van Ijzendoorn and Schüngel ( 43 ), dissociation has been studied in a range of mental disorders that had not been included, such as OCD ( 10 ) and substance abuse ( 48 ). Other research has shown that dissociation plays a role in diseases like panic disorders ( 7 , 31 ), which showed surprisingly low mean dissociation scores in that first analysis. The goal of our meta-analysis is thus to provide an evidence base for the prevalence and distribution of dissociation in adults suffering from mental disorders.

Study Selection

We searched the following databases for primary studies through November 2016: PubMed, PsycINFO, Web of Science, and Academic Search Premier. Our search strategy aimed at articles using the DES or the German version of the scale (FDS) ( 49 , 50 ) in adults with mental disorders. Although there are formal differences between versions I and II of the DES (visual analogue scale versus Likert-type scale, both ranging from 0 to 100), differences in the results for the two versions have been shown to be negligible ( 51 ). Therefore, we decided not to differentiate between the versions of the scale. We developed the search strategy for PsycINFO (“dissoc* exper* scale” OR “FDS”) and adapted it for the other databases. We reviewed relevant review articles and related systematic reviews to identify studies that were missed in the database searches. If full text was not retrievable from online databases or university libraries, we contacted the corresponding authors. There were no language or publication date restrictions.

Two trained investigators independently screened titles and abstracts for relevance. In the full-text screening, the following inclusion criteria were imposed: 1) studying a population with mental disorders diagnosed according to ICD ( 52 ) or DSM; 2) reporting the sample size and the mean score and standard deviation on the DES, or sufficient information to calculate them; and 3) specification of psychometric properties for translations of non-English versions of the DES. Data were extracted by two independent raters using a standard form and systematically screened for full agreement between raters. Every disagreement was resolved by discussion within the review team. The protocol for this meta-analysis is available in PROSPERO (the “International prospective register of systematic reviews”) and can be accessed at http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42015020731 .

Data Synthesis

Diagnostic group, mean and standard deviation of the dissociation score, and number of participants were extracted from the primary studies. For each diagnostic group, the random-effects model described in DerSimonian and Laird ( 53 ) was used to calculate a group-specific mean and the 95% confidence interval. This approach allows for the integration of data from intrinsically heterogeneous populations that result, for example, from the use of different diagnostic systems. To quantify heterogeneity of the dissociation scores between studies, we used I 2 ( 54 )—an index, based on chi-square statistics and degrees of freedom, that was recommended for Cochrane Reviews ( 55 ). Because only descriptive data on dissociation scores were included in the analysis, the risk of bias in the primary studies was assumed to be unlikely and therefore was not assessed. Data synthesis was conducted with R, version 3.2.4 ( 56 ), using the metafor package ( 57 ).

The search in the electronic databases yielded 1,907 different articles ( Figure 1 ). After exclusion of 660 articles during title or abstract screening, 1,247 articles were retrieved for full-text screening, of which 1,026 were subsequently excluded; reasons for exclusion are listed in Figure 1 . Across all diagnostic groups, we included 216 articles with a total of 15,219 individuals.

FIGURE 1. PRISMA Flow Diagram for a Meta-Analysis of Dissociation in Psychiatric Disorders

To calculate meta-analytic statistics, the original studies were grouped according to the DSM diagnosis described in the articles. For some diagnoses, this procedure revealed specific subcategories of DSM chapters (e.g., gambling disorders). For some categories, only articles reporting on broader categories or entire DSM chapters (e.g., bipolar disorders) were found. To avoid the confounding influence of diagnostic specification, we included articles reporting on subcategories in both the relevant subcategory as well as the corresponding broader category. Articles that reported on more than one diagnostic group were included in every category the authors reported dissociation scores on. In cases of co-occurring disorders, we included the individuals in both categories. We included all subcategories in which at least four studies reported data, regardless of whether this subcategory of disorders is still included in DSM-5. In the final step, we excluded five studies because there were not enough studies for each diagnosis: one study each on kleptomania ( 58 ) and pathological Internet use ( 59 ) and three studies on mixed personality disorders ( 60 ).

Diagnostic categories, number of individual studies, and number of individual patients as well as statistics are listed in Table 1 . A graphical illustration of the results is presented in Figure 2 . Forest plots of each diagnostic category are included in the data supplement that accompanies the online edition of this article.

a Articles that reported on more than one diagnostic group were included in every category the authors reported dissociation scores on. Diagnostic groups are sorted in descending order of Dissociative Experiences Scale (DES) mean score. k=number of included studies; N=number of patients included in diagnostic group; I 2 = heterogeneity statistic.

b DSM-5 main category.

TABLE 1. Overview of the Results of a Meta-Analysis of Dissociation in Psychiatric Disorders a

FIGURE 2. Mean Dissociative Experiences Scale Score for Each Diagnostic Group in a Meta-Analysis of Dissociation in Psychiatric Disorders a

a Error bars indicate 95% confidence interval.

The highest dissociation scores were found for dissociative identity disorders, with a mean score of 48.7 (95% CI=46.4, 50.9), based on 29 publications with 1,313 patients ( Figure 3 ; the full reference list of included studies can be found in the online data supplement ).

FIGURE 3. Forest Plot of Dissociative Experiences Scale Scores in Dissociative Identity Disorder a

a Reference numbers refer to the list of analyzed studies included in the online data supplement . DES=Dissociative Experiences Scale.

Scores for posttraumatic stress disorder were the second highest, with a mean score of 28.6 (95% CI=25.6, 31.5), based on 33 publications with 2,106 patients ( Figure 4 ).

FIGURE 4. Forest Plot of Dissociative Experiences Scale Scores in Posttraumatic Stress Disorder a

Scores for borderline personality disorder were third largest, with a mean score of 27.9 (95% CI=25.3, 30.6), based on 27 publications and 1,705 individual patients ( Figure 5 ). Scores for other mental disorders were distributed among (in descending order) conversion disorder (mean=25.6), somatic symptoms disorder (mean=18.8), substance-related and addictive disorders (gambling disorder, mean=19.9; alcohol use disorder, mean=19.7; other substance-related disorders, mean=17.7), feeding and eating disorders (mean=18.6), schizophrenia (mean=17.8), OCD (mean=15.3), depressive disorders (mean=15.3), anxiety disorders (mean=15.2), and bipolar and related disorders (mean=14.8).

FIGURE 5. Forest Plot of Dissociative Experiences Scale Scores in Borderline Personality Disorder a

Only three categories yielded enough studies to analyze dissociation subfactors: borderline personality disorder, dissociative disorders, and schizophrenia. Patients suffering from borderline personality disorder and schizophrenia had the highest scores for absorption, and patients with dissociative disorders had the highest scores for depersonalization/derealization (see Table S1 in the online data supplement for details).

Heterogeneity, as assessed by I 2 , was >70% in all analyses, except for somatic symptom disorders (I 2 =16.1%); the highest heterogeneity was observed in gambling disorders (I 2 =98.5%) (see Table 1 ).

This is the second meta-analysis of dissociation scores in a broad variety of psychiatric disorders. While the first meta-analysis was published more than 20 years ago ( 43 ) and comprised 85 individual studies, our meta-analysis reports on 216 individual studies with more than 15,000 individuals with mental disorders. The largest dissociation scores were found for dissociative disorders, followed by PTSD, borderline personality disorder, and conversion disorder, and the lower range of scores included substance-related and addictive disorders, feeding and eating disorders, schizophrenia, anxiety disorder, OCD, and affective disorders.

Our data confirm some but not all of the results reported in the earlier meta-analysis. Confirming results were found regarding dissociative disorders showing the highest overall dissociation scores. In their analysis, van Ijzendoorn and Schüngel ( 43 ) reported mean dissociation scores of 45.6 for multiple personality disorder (now called dissociative identity disorder), 41.1 for unspecified dissociative disorders, and 35.3 for the category of dissociative disorder not otherwise specified. In our study we differentiated between dissociative identity disorder and depersonalization/derealization disorder, as listed in DSM-5 ( 1 ). Although the existence of dissociative identity disorder has been discussed controversially (e.g., 61 ), our result of a mean dissociation score of 48.7 in a total of 1,313 individuals with this diagnosis indicates very high levels of dissociative experience in this diagnostic group. Interestingly, depersonalization/derealization disorder yielded numerically lower DES scores than PTSD and borderline personality disorder. This may be due to the fact that depersonalization/derealization disorder does not cover the entire spectrum of dissociative symptoms, therefore leading to lower overall dissociation scores.

Dissociation scores in PTSD and schizophrenia in our analysis were close to those reported by van Ijzendoorn and Schüngel ( 43 ), although their study included only one study on schizophrenia (compared with 17 here) and four studies on PTSD (compared with 33 here). Scores in PTSD were the second highest in our analysis, reflecting the importance of dissociation in relation to PTSD ( 62 ), for which a dissociative subtype was introduced in DSM-5. Although dissociative symptoms are less pronounced in schizophrenia (mean score, 17.8), they have been studied intensively in this disorder because of similarities in the description of dissociative phenomena and psychotic symptoms ( 63 ). Empirical studies have yielded varying correlations between schizophrenia and different aspects of dissociation, with depersonalization/derealization showing the strongest relation ( 5 ). Several authors have emphasized the relevance of depersonalization as a mediator between childhood trauma and hallucinatory experiences, thus acting as a risk factor for schizophrenia (e.g., 64 ). It is hypothesized that depersonalization may facilitate a person’s attribution of their own thoughts to external sources ( 65 ), and a trauma-dissociation subgroup within schizophrenia has been proposed ( 66 ).

Our data differ from the earlier meta-analysis ( 43 ) with respect to eating disorders, anxiety disorders, and affective disorders. While eating disorders and anxiety disorders show considerably higher mean dissociation scores in our analysis than in the earlier one (18.6 compared with 14.5 for eating disorders; 15.2 compared with 10.2 for anxiety disorders), we found lower scores for affective disorders (15.3 for depressive disorders and 14.8 for bipolar disorders compared with 19.4 for affective disorders in the earlier analysis). Recent research points to differential relations between dissociation and symptoms of these disorders. In anorexia nervosa, where the highest mean dissociation scores were found (mean score, 24.1), symptoms of depersonalization in the form of body schema distortions have been investigated ( 67 ). In bulimia nervosa, dissociative qualities of amnesia, timelessness, and involuntariness seem to play a role in bingeing behavior and severity ( 6 , 68 ). In anxiety disorders, experiences of depersonalization/derealization have often been described in relationship with panic attacks, although the sequence of incidence is not clear: dissociation might trigger panic attacks—for example, via the fear of losing control—but concomitant symptoms of panic attacks, such as hyperarousal or hyperarousal, might also produce dissociation ( 29 ). In depressive disorders, the research on mechanisms of dissociation is impeded by a strong overlap between depressive symptoms such as emotional numbing, feelings of detachment, and restricted emotional responsiveness ( 69 ), as well as by shared covariates, such as sleep quality and distortions in autobiographic memory ( 23 , 70 ).

Our analysis is the first to report systematically retrieved mean dissociation scores for borderline personality disorder, somatic symptom disorder, conversion disorder, substance-related and addictive disorders, and OCD. Borderline personality disorder showed dissociation scores similar to those of PTSD in 27 studies (mean score, 27.9). Furthermore, our study confirmed the significance of dissociative symptoms in borderline personality disorder, which has been acknowledged by adding dissociative experiences as part of one of the nine criteria for borderline personality disorder in DSM-IV ( 71 ). Although classified as a personality disorder, borderline personality disorder is closely associated with traumatic stress. Rates of adverse childhood experiences have been consistently demonstrated to be higher than 50% ( 72 ). Independent of trauma experience and comorbid diagnoses, almost all patients with borderline personality disorder report identity confusion, unexplained mood changes, and depersonalization ( 73 ).

“Somatic symptom and related disorders” is a new category in DSM-5 ( 1 ) and comprises a broad spectrum of disorders, including somatic symptom disorder (formerly known as somatoform disorders), illness anxiety disorders, conversion disorder (functional neurological symptom disorder), and factitious disorder. Notably, conversion disorder is part of the dissociative spectrum in ICD-10 ( 52 ), and dissociation scores were in a range similar to those of other dissociative and trauma-related disorders in our meta-analysis.

The high mean dissociation scores for addictive disorders—19.9 for gambling disorder, 19.7 for alcohol use disorder, and 17.7 for other substance-related disorders—may be partly related to comorbidities with PTSD, borderline personality disorder, and dissociative disorders ( 74 – 76 ). General findings regarding the link between dissociation and substance abuse have been inconsistent but suggest lower scores in samples without comorbid disorders ( 77 – 79 ). The mean dissociation score of 15.3 for OCD falls within the lower range of dissociative symptoms. Nevertheless, dissociation has gained increasing attention in this area of research. On a symptomatic level, dissociative amnesia has been related to checking compulsion ( 80 ). This effect does not seem to be linked to poorer memory or reality monitoring performance but rather to a reduced confidence in these abilities ( 81 ).

Recent population-based studies show mean dissociation scores in the general population of 8 in a Finnish sample (N=2,001) ( 82 ) and 10 in a Portuguese sample (N=224) ( 83 ). In their meta-analysis, van Ijzendoorn and Schüngel ( 43 ) report a mean score of 11.6 for healthy subjects. Those numbers appear to be considerably lower than all mean dissociation scores calculated for mental disorders in our analysis. Van Ijzendoorn and Schüngel’s conclusion that “the means for normals and nondissociative patients were remarkably similar” ( 43 , p. 372) does not seem to be supported by our results. The variety of mental disorders ranging between 15 and 25 in dissociation scores clearly speaks for dissociative experience as an unspecific and ubiquitous psychopathological phenomenon. From a clinical perspective, this finding underlines the importance of careful evaluation of dissociative symptoms, and not only in patients with dissociative or trauma-related disorders.

Our study has several limitations. Although the overall number of included studies was quite large, the number of studies and subjects per diagnostic category varied substantially. We only included categories with at least four individual studies, but categories varied between four and 66 studies and between 187 and 2,860 subjects. As we had no a priori hypothesis to explain heterogeneity, we did not carry out subgroup analysis. Heterogeneity may be rooted in different factors, including heterogeneity of the diagnostic entity, diagnostic shifts over time, and differences between individual studies, for example, with respect to diagnostic procedures, gender distribution, and the countries of origin. Most likely, comorbidity and trauma experiences also influence dissociation scores and should be systematically considered in future studies. Finally, we note that the DES is a self-rating instrument and that certain dissociative features may be over- or underrepresented in comparison to observer-based ratings ( 84 ).

In summary, our meta-analysis confirms the prevalence of dissociative symptoms not only in dissociative disorders, posttraumatic stress disorder, and borderline personality disorder, but in nearly all mental disorders. Research on the distinct diagnostic categories suggests a variety of mechanisms linking dissociative experiences to a higher burden of illness and detrimental effects on treatment. An evaluation of dissociation should therefore be part of every careful psychopathological assessment, and future studies should engage a transdiagnostic perspective to enhance the development of treatment modules to deal with dissociative symptoms.

The first two authors contributed equally.

Dr. Schmahl has received advisory panel payments from Boehringer Ingelheim. The other authors report no financial relationships with commercial interests.

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Article Contents

Connecting empirical dots, dys-integration of psychic functions: an ontogenetic perspective, phenomenology for differential diagnosis, conclusions.

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Faraway So Close: Schizophrenia and Dissociation From Clinical, Phenomenological, and Ontogenetic Viewpoints

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Michele Poletti, Andrea Raballo, Faraway So Close: Schizophrenia and Dissociation From Clinical, Phenomenological, and Ontogenetic Viewpoints, Schizophrenia Bulletin , Volume 49, Issue 3, May 2023, Pages 542–545, https://doi.org/10.1093/schbul/sbad018

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What is the psychopathological core of the relation between schizophrenia and dissociation? The continuity/discontinuity between them is a vexed question, 1 partly due to the relative neglect of the historical epistemology of the term dissociation and its impact in the early conceptualization of schizophrenia. Nonetheless, the persisting halo of such confusion is palpable in contemporary research, in which, in line with the DSM/ICD, the areas of dissociation and schizophrenia are allocated in 2 independent diagnostic spectra.

Bleuler’s unitary definition of the “group of schizophrenias” was based on the idea of a Spaltung (aka “splitting,” “dissociation,” or “scission”) of the psychic functions as the common generative disorder underlying the syndromic plurality of (“accessory”) symptoms of schizophrenia. Bleuler’s core concept of spaltung 1 , 2 is reminiscent of the original notion of dissociation, earlier proposed by Janet to characterize a “disaggregation of the psyche.” 3 , 4 At the time, the central metaphor of a disarticulation of psychic functions was allegedly implied in a wide spectrum of conditions ranging from schizophrenia to hysteria, and was captured by a multiplicity of terms not systematically accompanied by clear descriptive borders, nor by specific nosological constraints. Nonetheless, different pathogenetic pathways were evoked as preeminent in the 2 pathological conditions: ie, neurobiological vulnerability in schizophrenia and adverse/potentially traumatic experiences in dissociative conditions. Similarly, some qualitative shades of dissociation were ascribed a diagnostically relevant character for schizophrenia: Jung noted that “[in schizophrenia] dissociation is no longer fluid and changeable as it is in the neuroses, it is more like a mirror broken into splinters. The unity of the personality […] is definitely shattered into fragments” (p 235). 5

Although contemporary classificatory systems allocate schizophrenia and dissociative disorders in distinct categorical silos, undeniable affinities, and overlaps appear at a dimensional level. Elevated degrees of dissociative symptoms are documented in schizophrenia as well as elevated levels of psychotic symptoms (eg, first-rank auditory verbal hallucinations) in dissociative disorders (particularly in dissociative identity disorder). 6

Furthermore, there is meta-analytical evidence that psychotic and dissociative dimensions are associated in both clinical and nonclinical populations ( r = 0. 437), with similarities in terms of strength of association across different specific positive symptoms ( r = 0.461 for hallucinations, r = 0.418 for delusion, r = 0.447 for paranoia, and r = 0.346 for disorganization) and dissociative symptoms ( r = 0.460 for absorption, r = 0.357 for amnesia, and r = 0.405 for depersonalization/derealization). 7 Finally, the network structure between dissociative symptoms, schizophrenic symptoms, and trauma history 8 indicates that emotional distress bridges between the dissociative and schizophrenic symptom clusters, and mediates the associations between positive and negative schizophrenic symptoms and trauma. This pattern suggests that dissociation and psychosis are plausibly related on a pathogenetic level rather than just being a random copresence of psychopathological features. Furthermore, given the alleged etiopathogenetic value of traumatic events in dissociation, the high retrospective prevalence of adverse/traumatic experience in psychosis 9 suggests that there might be a synergistic coaggregation of risk. Therefore, it is plausible that trauma exposure and consequent traumagenic processes 10 increase a broad proclivity to develop a schizophrenia spectrum disorder or lead to subvariants of schizophrenia prominently characterized by dissociative processes. 11

Studies on offspring show that the presumed genetic risk for schizophrenia (aka schizotaxic vulnerability) is early expressed in the neuromotor domain through neurological soft signs such as motor dyscoordination and sensory-motor dys-integration. 12 , 13 This is presumably due to alterations in the neurophysiological mechanism of corollary discharge, ie, a copy of motor commands used to form a prediction of the sensation from self-generated movements. 14 , 15 Enduring alterations of corollary discharges represent an early specific constraint for the infant sensorimotor exploration of the surrounding world and the subsequent experiential ontogenesis of the feeling of agency 16 (ie, the implicit subjective experience of intentionally controlling one’s own acts that arises when the predicted sensation matches the actual sensation). 17 An early, recursive impairment at this level, interfering with the ontogenesis of the feeling of agency, might be an accelerating factor for the emergence, in subsequent developmental stages, of basic self-disorders (BSDs), that are trait-like nonpsychotic anomalies of subjective experience described in the schizophrenia spectrum. 18–21 BSDs imply a disorder of the minimal self (MS: the pre-reflective, tacit level of selfhood, and involving the implicit awareness that all experience articulates itself in first person perspective as “my” experience), 22 with an attenuation of the senses of mineness and agency, which are the phenomenological preconditions for more structured psychotic experiences that entail the loss or externalization of control of psychic phenomena. This is the case of passivity delusions (where the person feels that her own thoughts, feelings, or actions are under external control), thought broadcasting (when the person hears her thoughts spoken aloud) and auditory verbal hallucinations (when the person reports of externalized commenting “voices”).

Since childbirth, the ontogenesis of the MS and the related feeling of agency is dependent also on the intersubjective milieu, scaffolded by parental sensitivity, and early interpersonal attunement, for example by experiences of joint attention. 23 , 24 Therefore, also profound alterations of such early milieu, due to enduring parental neglect or abuse, besides interfering with attachment, may hamper the ontogenesis of the MS. 25

Overall, altered corollary discharges and persistent inadequate parental responsiveness 26 both represent early latent vulnerabilities 27 for the integration of distinct levels of the self emerging along development. The early MS, indeed, emerges since birth at the beginning of the sensory-motor stage of development (ie, from birth to 2 years), while the reflective self (RS: Involving conscious processes, in which one’s self is largely an object of awareness) progressively unfolds in later childhood developmental phases. 22 This ontogenetic process is usually harmonic and integrated, unless a horizontal dys-integration between hierarchically distinct levels of the self (ie, MS and RS) intervenes ( figure 1A ). 28

( A ) Horizontal dys-integration interferes with the tacit, immediate, coherent integration of minimal, and reflective features of the Self, facilitating the emergence of anomalous subjective experiences of detachment. Co-occurring endogenous (eg, early neurobiological constraints such as altered corollary discharges) and exogenous factors (eg, early enduring adverse intersubjective experiences, especially related to inadequate parenting) may lead to such horizontal dys-integrative effects and mutually reinforce their effects in early developmental sensitivity period. ( B ) Vertical dys-integration caused by acute traumatic events occurring after the sensitive period for the ontogenesis of the Self and the related integration of minimal and reflective Self layers may induce dissociative symptoms of compartmentalization. In the extreme case of dissociative identity disorder, the vertical dys-integration may cause distinct, compartmentalized parcels of minimal and reflective selves (MS 1- RS 1… MS n - RS n ), unaware of each other, except for the mutual intrusions of dissociated contents.

Therefore, early enduring adverse experiences have a greater pathogenetic potential towards dissociative detachment experiences (eg, depersonalization, derealization) 29 the more they recur in the sensitive period for the early intersubjective ontogenesis of the self. 30 The converging liability of schizotaxic risk (which is better conceptualized as broadly familial-environmental rather than merely genetic-neurobiological) 31 and early adverse environment as potential triggers for horizontal dys-integration between MS and RS, could explain (1) the high prevalence of dissociative process of detachment and its association with the positive dimension in schizophrenia, 32 and (2) the presence of a subvariant of schizophrenia prominently characterized by dissociative processes. 11 In this regard, families affected by mental disorders such as schizophrenia represent a peculiar ecological niche in which the intergenerational transmission of severe mental disorders is boosted by the hyper-aggregation of putatively genetic plus early and late environmental risk factors, including poor parenting. 31

On the contrary, acute and discrete traumatic experiences in more advanced developmental ages (ie, once the integration of distinct levels of the self is more consolidated), are more likely to produce a vertical dys-integration, that compartmentalizes distinct but integrated layers of the MS and the RS through a top-down clivage ( figure 1B ). Dissociative identity disorder prototypically represents the extreme of such process of vertical dys-integration, leading to distinct, compartmentalized parcels of integrated MS and RS, unaware of each other, except for the mutual intrusions of dissociated contents. Vertical and horizontal dys-integrative processes could also combine, especially when acute traumatic experiences impact a continuum of previous early adverse experiences.

Experiential anomalies that hyper-aggregate in schizophrenia spectrum disorders, such as experiences of alienation from the Self, from one’s own body, from the affective immersion in the world (see the Examination of Anomalous Self-Experience ), 33 have a surface affinity to those depersonalization-derealization states, that could occur in panic disorder and dissociative disorders. However, on a phenomenological level, it is crucial to distinguish trait-like experiences from circumscribed, intensive and instantaneous, state-like feelings that are not expressive of a fundamental structural change of subjectivity. Schizophrenic BSDs coaggregate in a more continuous and complex gestalt, 21 , 34 that typically entails a solipsistic and hyper-reflexive attitude, while anomalous subjective experiences outside schizophrenia tend to be more occasional, transitory, and isolated. 35 Therefore, exploring the subjective (autobiographical and temporally articulated) substrate in which phenotypically similar experiences emerge is essential for differential diagnosis.

The historical use of the term dissociation as a synonym of Bleulerian Spaltung has inadvertently contributed to the confusion on its use to describe dissociative disorders, facilitating the tendency to consider dissociative symptoms (such as depersonalization and derealization) as extensively trans-diagnostic. A more precise phenomenological dissection of such experiences and a look at the sensitive period in the ontogenesis of the Self might be crucial for differential diagnosis and pathogenetic research. While in dissociative disorders, these anomalous subjective experiences of detachment seem to be more contextual and not expressive of an ongoing basic disorder of consciousness (ie, it is the RS rather than the MS to be eminently involved), in the schizophrenic spectrum, the dys-integration of Self is more profound, presumably reflecting an earlier impairment in the ontogenesis of MS and RS. When such early developmental harmonization process is hampered, the psychopathological ground for the experiential emergence of BSDs in childhood and adolescence is laid, increasing the risk of progressing toward schizotypal configurations or secondary schizophrenia spectrum symptoms such as psychosis.

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• Published: 05 April 2024

Neuropsychiatric disorders

Support for network theories of schizophrenia

• Martijn P. van den Heuvel   ORCID: orcid.org/0000-0003-1570-1195 1 , 2 &
• Sara L. Seoane   ORCID: orcid.org/0000-0002-8321-018X 1  

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A computational neuroimaging study has shed new light on the relationship between morphological changes in the brain in schizophrenia and the network architecture of the brain, providing evidence to support two network theories of the disorder.

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Acknowledgements

M.P.v.d.H is supported by a European Research Council consolidator grant (ID 101001062 CONNECT) to M.P.v.d.H.

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MINI REVIEW article

Dissociative symptoms and disorders in patients with bipolar disorders: a scoping review.

• Department of Psychiatry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India

Dissociative disorders are an important group of trauma-related disorders associated with significant disability. The co-occurrence of dissociative disorders (DD) and symptoms (DS) in bipolar disorder has been relatively understudied, but there is some evidence that this comorbidity may have significant mechanistic and clinical implications. This paper presents the results of a scoping review of the frequency and correlates of DS and DD in bipolar disorder. Based on the available evidence, DS/DD are more common in bipolar disorder than in healthy controls or in unipolar depression, are related to childhood trauma, and are associated with psychotic symptoms, suicide attempts, and a poorer response to treatment in patients with bipolar disorder. The implications of these findings, and possible mechanistic pathways underlying them, are discussed based on the current literature. Clinicians should be aware of the frequent occurrence of significant DS or DD when treating patients with bipolar disorder. A tentative future research agenda for this field, based on clinical, risk factor-related and neurobiological considerations, is outlined.

Introduction

Bipolar disorders are a group of mental illnesses characterized by recurrent episodes of elevated and depressed mood, associated with significant levels of morbidity and an elevated mortality risk ( 1 ). Comorbidity with other psychiatric disorders is seen in over 50% of patients with BD, particularly with anxiety, attention-deficit/hyperactivity and substance use disorders ( 2 ). The presence of comorbid diagnoses in BD is associated with poorer treatment response and a more severe illness course; patients with these diagnoses often require more intensive or complex treatment regimens ( 3 – 6 ).

Dissociative disorders (DD), which are characterized by disruption or discontinuity in the integration of one's consciousness, memory, identity and behavior, are associated with risks of hospitalization, self-injury and suicide comparable to BD ( 7 ). Though the comorbidity of DD and BD has been relatively under-studied ( 8 ), there is evidence from the literature of several potential clinical and mechanistic links between them. BD and DD appear to share a genetic substrate to some extent ( 9 , 10 ) and the onset of symptoms of DD may be a herald of subsequent BD in adolescents ( 11 , 12 ). DD may be underdiagnosed in patients with BD because of diagnostic criteria that do not allow DD to be diagnosed in the presence of depression ( 13 ), confusion arising from similar symptoms ( 14 ), or a reluctance to diagnose DD among mental health professionals ( 15 ). A further problem is posed by patients with BD who have features of dissociation that are clinically significant, but do not fulfill criteria for DD; these are referred to as “pathological dissociation” or “dissociative symptoms” (DS).

The present of DD or DS in BD raises several important questions. How frequent and severe is this comorbidity? What is the impact of DD/DS on the clinical features and prognosis of BD? Are there any specific environmental risk factors, such as childhood adversity, that are associated with the presence of DD/DS? Are DD/DS in BD associated with specific genetic factors or other biomarkers? The current scoping review aims to address these questions in a preliminary manner.

Methodology

Given the lack of a single specific question and the paucity of literature in this area, a scoping review was carried out instead of a systematic review ( 16 ). This review was carried out in accordance with the PRISMA guideline for scoping reviews (PRISMA-ScR) ( 17 ). The PubMed, Scopus and ScienceDirect databases were searched using combinations of the key words “bipolar disorder”, “bipolar disorders”, “bipolar spectrum”, “bipolar I disorder”, “bipolar II disorder” in association with “dissociative disorders”, “dissociative amnesia”, “dissociative identity disorder”, “depersonalization”, “derealization”, “dissociative symptoms”, “pathological dissociation”. All studies published up to April 15, 2022 were included in this review. Studies were included if they measured the frequency and/or correlates of the presence of DD/DS in BD, with or without the inclusion of comparator groups. Any study that provided information on the frequency, severity, clinical impact, association with environmental risk factors, or neurobiological correlates of DS/DD in patients with bipolar disorder was included in this review. Case reports/series, editorials, commentaries and general review articles were excluded.

A total of 471 citations were retrieved; after removal of duplicates, 333 citations were screened; after exclusion of 226 unrelated abstracts, 107 citations were tabulated and their full text was examined for relevance. Of these, 27 were included in the final review ( 18 – 44 ). This process is illustrated through a PRISMA-ScR flow diagram in Figure 1 .

Figure 1 . PRISMA-ScR flow diagram for the current scoping review.

Following tabulation, study results were sorted thematically according to the objectives of this review, as follows:

• Frequency of comorbid DD in BD or vice versa

• Frequency of significant DS in BD

• Comparison of DD/DS in BD compared to other groups (major depression, other psychiatric diagnoses, healthy controls)

• Associations with BD subtype (e.g. type I vs type II)

• Associations with BD course (e.g., age at onset, number of episodes)

• Associations with BD symptomatology (e.g., mixed features, psychotic symptoms, suicide attempts)

• Associations with BD outcome (e.g., treatment response, disability, quality of life)

• Associations with other comorbidities in BD (e.g., anxiety disorders, substance use disorders)

• Associations with environmental factors in BD (e.g., childhood trauma, current stressors)

• Associations with other psychological variables (e.g., temperament, personality traits)

• Associations with neuropsychological deficits in BD (e.g., attention or memory deficits)

• Associations with genetic or other biological markers (e.g., specific genetic polymorphisms, levels of hormones or inflammatory markers)

The same schema was followed when reporting the results.

A complete description of the included studies is provided, in chronological order, in Table 1 .

Table 1 . Studies examining the association between dissociative symptoms or disorders and bipolar disorder, with a summary of their key findings.

Characteristics of the Included Studies

The majority of the studies included in this review ( n = 21) were cross-sectional clinical studies measuring the severity or correlates of DS in patients with BD. Three studies examined the association between syndromal DD and BD ( 21 , 29 , 40 ), while one study each examined associations with cognitive test performance ( 25 ) and polymorphisms of specific genes considered to be related to dissociation ( 23 ).

Comorbidity Between BD and DD

Only one study directly measured the frequency of DSM-IV categorical diagnoses of DD in patients with BD. In this study, 35.4% of BD patients fulfilled criteria for one or more DD, with depersonalization disorder (17.6%) being the most frequent ( 40 ). A community-based study found that DD were 2.4 times more likely to be diagnosed in patients with mood disorders, but did not distinguish between BD and unipolar depression ( 21 ). A study of patients with conversion disorder found a significant association between comorbid diagnoses of DD and BD ( 35 ). Finally, a study of discharge records found that 11.4% of patients discharged with BD received a comorbid diagnosis of “anxiety, somatoform or dissociative disorder” as per ICD-9 criteria, but details of individual diagnoses within this group were not reported by the authors ( 29 ).

Presence of Clinically Significant DS in BD

Of the six studies providing estimates of clinically significant DS in BD, as indicated by symptom scores above a specified cut-off, five yielded very similar values in the range of 10–20% ( 18 , 33 , 34 , 39 , 43 ). A single study yielded a much higher estimate of 51%, but in this study, the control group also reported high levels of DS (24%), suggesting concerns related to methodology or sample selection ( 28 ).

Comparisons of DS Severity Between BD and Other Disorders

Five studies have compared the severity of DS in patients with BD and major depressive disorder (MDD), have measured DS during depressive episodes. In four of these studies, DS were more prominent in BD than in MDD ( 22 , 26 , 30 , 38 ), while in the other, they were comparable ( 44 ). Studies comparing the severity of DS between BD and other, non-affective psychiatric disorders found that DS were significantly less in BD than in somatoform disorders and DD ( 18 , 19 , 32 ), complex post-traumatic stress disorder (PTSD) ( 32 ), atypical psychosis in adolescents ( 20 ), and borderline personality disorder ( 36 ). DS were comparable in BD and schizophrenia in a single study ( 43 ). However, DS scores were significantly higher in patients with BD than in their asymptomatic first-degree relatives ( 23 ) and were consistently higher in BD than in healthy controls ( 28 , 33 , 34 , 37 , 39 , 43 ).

Relationship of DS to BD Subtype

Though some researchers have reported no difference in DS severity scores between BD-I and BD-II ( 23 , 24 ), there is some evidence that DS and particularly depersonalization symptoms may be more severe in BD-I ( 30 , 42 ). Only one study assessed DS in patients with other BD subtypes (BD-III and BD not otherwise specified) along with BD-I and BD-II, but the small number of cases in this subgroup precluded a meaningful comparison ( 41 ).

Relationship of DS to Symptomatology in BD

DS scores have been associated with the severity of psychotic symptoms ( 42 , 44 ); both positive and null results have been reported for associations between DS and depressive symptom severity ( 31 , 41 ). DS severity has also been associated with general symptom severity across psychopathological dimensions ( 31 ), with the severity of symptoms of social anxiety, panic disorder and obsessive-compulsive disorder ( 33 , 41 ), with the presence of mixed symptoms ( 42 ), with suicide attempts ( 40 , 42 ) and with aggression ( 42 ).

Relationship of DS/DD to Illness Course in BD

Five studies found a negative correlation between the severity of DS and the age at onset of BD (AAO), suggesting an association between dissociation and an early AAO ( 24 , 26 , 28 , 34 , 40 ). This association appeared to be more specific for depersonalization-related symptoms ( 24 , 26 , 34 ). Only one study reported no association between DS and AAO in BD ( 38 ). Associations between DS severity and episode frequency ( 37 ), total number of episodes ( 42 ) and frequency of manic ( 25 ) and depressive episodes ( 39 ) have been reported in individual studies. However, a lack of association with episode number has also been reported ( 38 ).

Relationship of DS to Outcome in BD

The severity of DS appears to be associated with treatment response; associations with a higher dose requirement for mood stabilizers ( 25 ), with a higher risk of antidepressant-induced mania ( 42 ) and with a poorer response to treatment ( 42 ) have all been observed. DS are also associated with a poorer quality of life in the “social activities” domain in euthymic BD patients ( 25 ).

Relationship of DS to Other Comorbidities in BD

Higher DS scores have been associated with elevated rates of comorbid obsessive-compulsive disorder (OCD) ( 22 ) and panic disorder ( 24 ) in BD; no other specific associations with any comorbid diagnosis have been reported.

Relationship of DS to Environmental Risk Factors in BD

Six studies have examined the association between childhood abuse or neglect and DS in BD; four of these found a positive association between childhood trauma and DS severity ( 23 , 33 , 41 , 44 ), while two failed to do so ( 37 , 43 ). A single study examined the relationship between DS and current stress related to the COVID-19 pandemic, but did not find any significant association between the two ( 43 ).

Relationship of DS to Temperament and Other Psychological Variables in BD

Cyclothymic temperament, considered to be a developmental precursor of BD, was associated with the presence of DS in BD patients in one study ( 22 ) but not in another ( 24 ). DS severity has also been associated with measures of alexithymia in BD ( 37 ).

Neuropsychological Correlates of DS in BD

A study examining the association between DS and performance on tests of cognition (attention, concentration, executive function and verbal fluency) found no significant association between DS severity and scores on these tests ( 25 ).

Genetic and Biomarker Studies of DS in BD

Only one study has examined the potential genetic correlates of DS in BD; in this study, an interaction between childhood trauma and a functional polymorphism of the COMT gene, as well as an additive effect of the BDNF gene, was found to predict the severity of DS ( 23 ). No other study of any specific biomarker associated with DS/DD in BD has been conducted to date.

Certain features emerge clearly from an overview of the current literature. A significant minority of patients (10–20%) with bipolar disorder experience significant DS, even during the euthymic phase. The overall severity of DS is higher in BD than in healthy controls and in major depression, but is lower in BD when compared with “trauma spectrum disorders” such as DD, complex PTSD and borderline personality disorder. When considering the clinical profile of BD, replicated results suggest that DS are associated with psychotic symptoms, suicide attempts, and a poorer response to treatment. DS also appear to be associated with the severity of childhood trauma in patients with BD. Results related to other symptom domains, episode number and frequency, and quality of life, though of interest, require replication.

The above findings are consistent with the existing literature on DS/DD. Both pathological dissociation and DD are considered part of the “trauma spectrum” of disorders, which are related to exposure to traumatic stress, particularly in childhood ( 45 ). This group also includes PTSD and borderline personality disorder; it is perhaps significant that these conditions are also often comorbid with BD ( 46 , 47 ). Given that childhood adversity is itself a risk factor for BD ( 48 ) and was associated with DS in the reviewed studies, this factor may explain a significant proportion of the co-occurrence of DD/DS and BD. Moreover, dissociation is an important mediator of the links between childhood abuse and both psychotic symptoms ( 49 ) and suicide ( 50 ), which is consistent with the findings observed in patients with BD.

Recent research has shed some light on the neurobiological correlates of dissociative symptoms ( 51 ). Some of the replicated biomarkers of pathological dissociation, such as reduced hippocampal and thalamic volumes and elevated peripheral levels of oxytocin, have also been identified in bipolar disorder ( 52 – 54 ), suggesting common neuroanatomical and biochemical substrates for these conditions. It should however be noted that for other biomarkers of dissociation, such as levels of tumor necrosis factor alpha, findings in bipolar disorder are in the opposite direction ( 55 ). This suggests that there may be shared mechanistic pathways, but not a complete overlap, between BD and dissociative symptoms.

Besides exposure to childhood trauma or other environmental stressors, the link between DS/DD and BD may be partly mediated through genetic vulnerability. While earlier researchers suggested that this might result from variations in single genes, such as the serotonin transporter ( 56 ), more recent results suggest that the overlap between bipolar and dissociative disorders may be polygenic in origin ( 10 ).

These findings must be interpreted in the light of important limitations in study design and methodology in the existing literature. The majority of reviewed studies are cross-sectional and focus on clinical variables, with very few studies examining neuropsychological or neurobiological correlates of DD or DS in BD. Most studies have been conducted in remitted, euthymic or clinically stable BD patients, and have measured DS using standardized scales instead diagnosing comorbid DD using standard criteria. There is also substantial heterogeneity in the measurement of DS, with some studies focusing on a subset of DS such as depersonalization/derealization or somatoform dissociation. Sample sizes for BD were generally low (mean: 61.2 ± 47.8), suggesting that some studies may have been underpowered to detect significant differences. Further, in some studies, associations between DS and clinical or environmental variables of interest were not estimated even when the data was available. These factors limit both the value of the conclusions that can be drawn from individual studies and the likelihood of their replication, and suggest the need for better designs even if the research questions are purely clinical in nature.

A further limitation arises from the fact that the link between DS/DD and BD may be non-specific. Dissociative symptoms of severity comparable to or slightly greater than those reported in BD have been observed in a wide range of psychiatric disorders, including schizophrenia, anxiety disorders, eating disorders and substance use disorders ( 57 ). These findings suggest that dissociation may be better considered from a dimensional rather than a categorical perspective, or that it may be related to a common genetic substrate that cuts across traditional psychiatric diagnoses ( 58 ).

Despite these limitations, the above review suggests that the presence of DS/DD in patients with BD may have significant clinical and research implications. From a clinical perspective, practitioners should be aware of the co-occurrence of these conditions, and maintain a high index of clinical suspicion; in cases of doubt, a standardized rating scale such as the DES can aid decision-making. Given the replicated associations with psychotic symptoms, suicidality, and poor treatment response, these patients may require more intensive clinical management. Lithium therapy, which has been shown to reverse the hippocampal and thalamic volume reductions common to bipolar disorder and dissociation ( 51 , 52 ), may be a useful therapeutic option. Bipolar patients with DS/DD should be screened for other comorbid anxiety disorders as well as post-traumatic stress disorder ( 22 , 24 , 33 , 41 ). Given the link between childhood trauma and dissociation in BD, a sensitive inquiry into possible childhood abuse or neglect should be made when patients are clinically stable. Finally, when there are significant DS or a syndromal DD, appropriate psychological interventions should be provided ( 59 ).

From a research perspective, the following areas require particular attention in the study of the links between dissociation and bipolarity:

• Replications of findings related to clinical and psychological variables of interest, such as affective temperaments, alexithymia, cycle length and the presence of mixed features

• Accurate studies of the prevalence of comorbid DD in BD, and of comorbid BD in DD, using standard diagnostic criteria

• Longitudinal studies of the impact of DS or DD on the course and outcome of BD

• Studies of high-risk youth (e.g., with a family history of BD or with a history of childhood abuse) with DS or DD, to assess their subsequent risk of BD and the possibility of early intervention ( 12 , 60 )

• Studies of structural, functional and biochemical markers of the link between BD and DD; areas that could be immediately explored include associations with peripheral levels of cytokines ( 61 ) and functional brain imaging studies focusing on key frontal and subcortical regions implicated in both disorders ( 49 , 62 )

• Assessment of the utility of a dimensional rather than a categorical approach to the study of dissociation in patients with BD, and of the correlations between DS and other symptom dimensions in BD ( 63 )

• Genome-wide association studies using either a narrower definition of DD (i.e., without lumping them with anxiety and somatoform disorders) or a continuous measure of DS, to identify specific and shared genetic loci associated with vulnerability to pathological dissociation in patients with BD

• Evaluation of the efficacy of specific pharmacological (mood stabilizer, antipsychotic), brain stimulation (rTMS) and psychotherapeutic (trauma-focused) approaches in patients with BD and DD/DS ( 64 , 65 ).

Though research on dissociative symptoms and disorders in patients with bipolar disorders is still in its infancy, existing evidence suggests that these symptoms are significantly associated with both risk factors—particularly childhood abuse—and a specific illness profile in bipolar disorder. It is hoped that the findings reviewed and summarized above will be of use to clinicians working with patients with bipolar disorder. Moreover, the tentative research agenda outlined above could improve our understanding of this specific comorbidity, leading to improved strategies for early intervention as well as treatment in subsequent stages of bipolar disorder.

Author Contributions

RR selected the review topic and method, conducted the literature search and article selection, analyzed and summarized the results, and wrote and edited the manuscript.

Conflict of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Abbreviations

AAO, age at onset; BD, bipolar disorders; BD-I, bipolar I disorder; BD-II, bipolar II disorder; BDNF, brain-derived neurotrophic factor; CADSS, Clinician-Administered Dissociative States Scale; CDS, Cambridge Depersonalization Scale; COMT, catechol O-methyltransferase; DAT, dopamine transporter; DID, dissociative identity disorder; DRD4, dopamine type 4 receptor; DD, dissociative disorders; DD-NOS, dissociative disorder not otherwise specified; DES, Dissociative Experiences Scale; DSM-IV, Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition; HAM-D, Hamilton Rating Scale for Depression; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; PTSD, post-traumatic stress disorder; SCI-DER, Structured Clinical Interview for Depersonalization/Derealization Spectrum; SCL-90-R, Symptom Checkist-90 Revised; SDQ-20, Somatoform Dissociation Questionnaire-20; SERT, serotonin transporter.

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Keywords: bipolar disorders, dissociative disorders, depression, depersonalization, derealization, comorbidity

Citation: Rajkumar RP (2022) Dissociative Symptoms and Disorders in Patients With Bipolar Disorders: A Scoping Review. Front. Psychiatry 13:925983. doi: 10.3389/fpsyt.2022.925983

Received: 22 April 2022; Accepted: 03 May 2022; Published: 26 May 2022.

Reviewed by:

Copyright © 2022 Rajkumar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Ravi Philip Rajkumar, ravi.psych@gmail.com

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Dissociative identity disorder and schizophrenia: Differential diagnosis and theoretical issues

• Published: 24 September 2008
• Volume 10 , pages 217–222, ( 2008 )

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Schizophrenia and dissociative identity disorder (DID) are typically thought of as unrelated syndromes—a genetically based psychotic disorder versus a trauma-based dissociative disorder—and are categorized as such by the DSM-IV . However, substantial data exist to document the elevated occurrence of psychotic symptoms in DID; awareness of these features is necessary to prevent diagnostic confusion. Recent research has also pointed out that schizophrenia and DID overlap not only in psychotic symptoms but also in terms of traumatic antecedents, leading to a number of suggestions for revision of our clinical, theoretical, and nosologic understanding of the relationship between these two disorders.

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Foote, B., Park, J. Dissociative identity disorder and schizophrenia: Differential diagnosis and theoretical issues. Curr Psychiatry Rep 10 , 217–222 (2008). https://doi.org/10.1007/s11920-008-0036-z

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DOI : https://doi.org/10.1007/s11920-008-0036-z

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Pilot study shows ketogenic diet improves severe mental illness

A small clinical trial led by Stanford Medicine found that the metabolic effects of a ketogenic diet may help stabilize the brain.

April 1, 2024 - By Nina Bai

A study led by researchers at Stanford Medicine showed that diet can help those with serious mental illness. nishihata

For people living with serious mental illness like schizophrenia or bipolar disorder, standard treatment with antipsychotic medications can be a double-edged sword. While these drugs help regulate brain chemistry, they often cause metabolic side effects such as insulin resistance and obesity, which are distressing enough that many patients stop taking the medications.

Now, a pilot study led by Stanford Medicine researchers has found that a ketogenic diet not only restores metabolic health in these patients as they continue their medications, but it further improves their psychiatric conditions. The results, published March 27 in Psychiatry Research , suggest that a dietary intervention can be a powerful aid in treating mental illness.

“It’s very promising and very encouraging that you can take back control of your illness in some way, aside from the usual standard of care,” said Shebani Sethi , MD, associate professor of psychiatry and behavioral sciences and the first author of the new paper.

Making the connection

Sethi, who is board certified in obesity and psychiatry, remembers when she first noticed the connection. As a medical student working in an obesity clinic, she saw a patient with treatment-resistant schizophrenia whose auditory hallucinations quieted on a ketogenic diet.

That prompted her to dig into the medical literature. There were only a few, decades-old case reports on using the ketogenic diet to treat schizophrenia, but there was a long track record of success in using ketogenic diets to treat epileptic seizures.

“The ketogenic diet has been proven to be effective for treatment-resistant epileptic seizures by reducing the excitability of neurons in the brain,” Sethi said. “We thought it would be worth exploring this treatment in psychiatric conditions.”

A few years later, Sethi coined the term metabolic psychiatry, a new field that approaches mental health from an energy conversion perspective.

Shebani Sethi

In the four-month pilot trial, Sethi’s team followed 21 adult participants who were diagnosed with schizophrenia or bipolar disorder, taking antipsychotic medications, and had a metabolic abnormality — such as weight gain, insulin resistance, hypertriglyceridemia, dyslipidemia or impaired glucose tolerance. The participants were instructed to follow a ketogenic diet, with approximately 10% of the calories from carbohydrates, 30% from protein and 60% from fat. They were not told to count calories.

“The focus of eating is on whole non-processed foods including protein and non-starchy vegetables, and not restricting fats,” said Sethi, who shared keto-friendly meal ideas with the participants. They were also given keto cookbooks and access to a health coach. 

The research team tracked how well the participants followed the diet through weekly measures of blood ketone levels. (Ketones are acids produced when the body breaks down fat — instead of glucose — for energy.) By the end of the trial, 14 patients had been fully adherent, six were semi-adherent and only one was non-adherent.

The participants underwent a variety of psychiatric and metabolic assessments throughout the trial.

Before the trial, 29% of the participants met the criteria for metabolic syndrome, defined as having at least three of five conditions: abdominal obesity, elevated triglycerides, low HDL cholesterol, elevated blood pressure and elevated fasting glucose levels. After four months on a ketogenic diet, none of the participants had metabolic syndrome.

On average, the participants lost 10% of their body weight; reduced their waist circumference by 11% percent; and had lower blood pressure, body mass index, triglycerides, blood sugar levels and insulin resistance.

“We’re seeing huge changes,” Sethi said. “Even if you’re on antipsychotic drugs, we can still reverse the obesity, the metabolic syndrome, the insulin resistance. I think that’s very encouraging for patients.”

The participants reported improvements in their energy, sleep, mood and quality of life.

The psychiatric benefits were also striking. On average, the participants improved 31% on a psychiatrist rating of mental illness known as the clinical global impressions scale, with three-quarters of the group showing clinically meaningful improvement. Overall, the participants also reported better sleep and greater life satisfaction.

“The participants reported improvements in their energy, sleep, mood and quality of life,” Sethi said. “They feel healthier and more hopeful.”

The researchers were impressed that most of the participants stuck with the diet. “We saw more benefit with the adherent group compared with the semi-adherent group, indicating a potential dose-response relationship,” Sethi said.

Alternative fuel for the brain

There is increasing evidence that psychiatric diseases such as schizophrenia and bipolar disorder stem from metabolic deficits in the brain, which affect the excitability of neurons, Sethi said.

The researchers hypothesize that just as a ketogenic diet improves the rest of the body’s metabolism, it also improves the brain’s metabolism.

“Anything that improves metabolic health in general is probably going to improve brain health anyway,” Sethi said. “But the ketogenic diet can provide ketones as an alternative fuel to glucose for a brain with energy dysfunction.”

Likely there are multiple mechanisms at work, she added, and the main purpose of the small pilot trial is to help researchers detect signals that will guide the design of larger, more robust studies.  

As a physician, Sethi cares for many patients with both serious mental illness and obesity or metabolic syndrome, but few studies have focused on this undertreated population.

She is the founder and director of the metabolic psychiatry clinic at Stanford Medicine.

“Many of my patients suffer from both illnesses, so my desire was to see if metabolic interventions could help them,” she said. “They are seeking more help. They are looking to just feel better.”

Researchers from the University of Michigan; the University of California, San Francisco; and Duke University contributed to the study.

The study was supported by Baszucki Group Research Fund, the Kuen Lau Fund and the Obesity Treatment Foundation.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

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• Published: 09 April 2024

Association of major depression, schizophrenia and bipolar disorder with thyroid cancer: a bidirectional two-sample mendelian randomized study

• Rongliang Qiu 1 , 2 ,
• Huihui Lin 3 ,
• Hongzhan Jiang 3 ,
• Jiali Shen 3 ,
• Jiaxi He 4 &
• Jinbo Fu 1 , 2  

BMC Psychiatry volume  24 , Article number:  261 ( 2024 ) Cite this article

Metrics details

Major depressive disease (MDD), schizophrenia (SCZ), and bipolar disorder (BD) are common psychiatric disorders, and their relationship with thyroid cancer has been of great interest. This study aimed to investigate the potential causal effects of MDD, SCZ, BD, and thyroid cancer.

We used publicly available summary statistics from large-scale genome-wide association studies to select genetic variant loci associated with MDD, SCZ, BD, and thyroid cancer as instrumental variables (IVs), which were quality controlled and clustered. Additionally, we used three Mendelian randomization (MR) methods, inverse variance weighted (IVW), MR–Egger regression and weighted median estimator (WME) methods, to estimate the bidirectional causal relationship between psychiatric disorders and thyroid cancer. In addition, we performed heterogeneity and multivariate tests to verify the validity of the IVs.

We used two-sample bidirectional MR analysis to determine whether there was a positive causal association between MDD and thyroid cancer risk. The results of the IVW analysis (OR = 3.956 95% CI = 1.177–13.299; P  = 0.026) and the WME method (OR = 5.563 95% CI = 0.998–31.008; P  = 0.050) confirmed that MDD may increase the risk of thyroid cancer. Additionally, our study revealed a correlation between genetic susceptibility to SCZ and thyroid cancer (OR = 1.532 95% CI = 1.123–2.088; P  = 0.007). The results of the WME method analysis based on the median estimate (OR = 1.599 95% CI = 1.014–2.521; P  = 0.043) also suggested that SCZ may increase the risk of thyroid cancer. Furthermore, our study did not find a causal relationship between BD and thyroid cancer incidence. In addition, the results of reverse MR analysis showed no significant causal relationships between thyroid cancer and MDD, SCZ, or BD ( P  > 0.05), ruling out the possibility of reverse causality.

Conclusions

This MR method analysis provides new evidence that MDD and SCZ may be positively associated with thyroid cancer risk while also revealing a correlation between BD and thyroid cancer. These results may have important implications for public health policy and clinical practice. Future studies will help elucidate the biological mechanisms of these associations and potential confounders.

Peer Review reports

Cancer is recognized as a disease that poses a serious threat to human health, and it has been reported that in the United States alone, more than 609,360 people are expected to lose their lives to cancer in 2022 [ 1 ]. However, the mechanisms underlying the development of most cancers are still not fully understood, which has led to delays in the diagnosis and treatment of cancers, contributing to the increasing incidence and mortality of cancer worldwide. Thyroid cancer is one of the most common endocrine tumours, and its incidence has been steadily increasing worldwide over the last three decades due to the widespread use of diagnostic imaging techniques and ultrasound-guided fine needle aspiration (US-FNA) [ 2 , 3 ]. Despite the continued increase in the incidence of thyroid cancer, its mortality trend has remained relatively stable. Risk factors for thyroid cancer include metabolic syndrome (including diabetes mellitus, hypertension, obesity, etc.), poor lifestyle habits, and environmental pollution, but these factors do not fully explain the mechanism of thyroid cancer development. Therefore, identifying other potentially modifiable risk factors, such as psychiatric disorders, is important for the prevention and treatment of thyroid cancer.

Major depressive disease (MDD), schizophrenia (SCZ), and bipolar disorder (BD) are all serious psychiatric disorders that overlap genetically and clinically, suggesting that they may share common aetiological mechanisms [ 4 ]. The results of a study suggest that quantitative changes in plasma lipids affect several individual characteristics, including those affected by serious psychiatric disorders (MDD, SCZ and BD) [ 5 ]. Moreover, clinical studies have shown that patients with MDD, SCZ and BD have altered Homer1a levels in specific regions and cell types of the brain. A growing body of research confirms the close connection between these three disorders [ 6 ]. MDD is ranked by the World Health Organization as one of the most burdensome diseases in the world; it seriously damages people’s physical and mental health and is associated with a variety of endocrine disorders, such as hypothyroidism and hyperthyroidism [ 7 , 8 , 9 , 10 , 11 ]. Studies have shown that patients with hyperthyroidism and hypothyroidism differ in the presentation of depressive symptoms and disorders [ 12 , 13 ]. Specifically, hyperthyroidism was associated with more depressive symptoms (e.g., insomnia and weight loss) [ 14 ], whereas hypothyroidism was associated with fewer depressive symptoms (e.g., energy deficit and fatigue) [ 15 ]. In addition, individuals with hyperthyroidism have a higher incidence of MDD [ 13 ]. The relationship between depression and cancer has long been of interest, and some observational studies have suggested that depression may be an important risk factor for cancer [ 16 ]. A cross-sectional study from Korea revealed a 5.6% incidence of depression in thyroid cancer patients [ 17 ]. Another study from Germany showed that cancer patients were five times more likely to be depressed than was the general population, and thyroid cancer patients with a detectable high burden of depressive symptoms were 9.3 times more likely to be depressed than was the general population [ 18 ]. However, despite observational studies revealing a correlation between MDD and thyroid cancer, the relationship between MDD and thyroid cancer has not been systematically explored.

SCZ is a chronic psychiatric disorder accompanied by inconsistent behavioural and cognitive symptoms and has profound effects on both individuals and society. More than 50% of those diagnosed have intermittent and chronic psychiatric problems [ 19 ]. This results in a particularly high risk of disengagement from the labour market, with employment rates ranging from 10 to 30%, unemployment rates as high as 89–95%, and a 15–20 year reduction in life expectancy [ 20 , 21 ]. There is growing evidence that thyroid function may be altered in patients with SCZ, but the results of observational studies have been inconsistent [ 22 , 23 ]. In addition, the role of the thyroid gland in the pathophysiology of SCZ is poorly understood, and the relationship between thyroid disorders and SCZ is unclear.

SCZ and BD are considered part of the psychiatric continuum and share similar clinical features. BD is a chronic, disabling illness and a major contributor to the global burden of disease. BD can cause mood swings ranging from depression to mania. Patients exhibit fluctuations during the course of the illness, with some patients experiencing episodes only every few years, while others experience episodes almost continuously. A large body of evidence confirms the association between abnormal thyroid hormone levels and different psychopathological conditions, triggering neuropsychiatric symptoms [ 24 ]. However, observational studies may find an association between psychiatric disorders and thyroid disorders, but confounding factors and reverse causality cannot be excluded.

To explore the causal association between psychiatric disorders (MDD, SCZ and BD) and thyroid cancer risk, we used a two-sample bidirectional Mendelian randomization (MR) study. MR studies [ 25 ] use genetic variation as an instrumental variable closely related to the exposure of interest to explore the causal effect between the exposure and the outcome, thereby improving the reliability of causal inference. Because of the random segregation of alleles at the meiotic stage and the stochastic nature of germline genetic variation at fertilization, MR analyses can avoid confounding factors and reverse causation. In this study, we utilized a two-sample bidirectional MR approach to explore the associations between MDD, SCZ, BD, and thyroid cancer based on statistically pooled data from a genome-wide association study (GWAS). This study aimed to gain insights into the potential link between psychiatric disorders and thyroid cancer and to provide new perspectives and insights for the prevention and treatment of thyroid cancer.

This study is an analysis of previously collected and published public data, including statistical aggregations related to MDD, SCZ, BD, and thyroid cancer, from large public GWASs. Due to the source and nature of the data, no additional ethical review or informed consent was required for this study. Two-sample bidirectional MR analyses were used to assess the causal relationship between psychiatric disorders (MDD, SCZ, BD) and thyroid cancer. We chose psychiatric disorders (MDD, SCZ, BD) as the exposure factor and thyroid cancer as the outcome indicator. Moreover, we conducted a reverse two-sample MR analysis with thyroid cancer as an exposure factor and psychiatric disorders (MDD, SCZ, BD) as an outcome indicator. A flow chart of the MR research design constructed according to this paper is shown in Fig.  1 .

Flowchart of the design of a Mendelian randomized study of the causal association between psychiatric disorders and thyroid cancer. Blue solid lines represent associations between instrumental variables (SNPs) and exposure and between exposure and outcome. The red solid line represents reverse causality. psychiatric disorders include major depression, schizophrenia, and bipolar disorder

Data sources for patients with major depression, schizophrenia, bipolar disorder, or thyroid cancer

The summary-level dataset used for GWASs for MDD in this study was obtained from a meta-analysis of GWAS data conducted by Howard et al. [ 26 ]. It comprises three large-scale GWASs, the Psychiatric Genomics Consortium (PGC), the UK Biobank, and 23andme. Of the three GWASs, only the UK Biobank and the PGC publish summary statistics on genetic variation. The dataset included 500,199 European subjects, including 170,756 cases and 329,443 controls. In the UK Biobank, Howard et al. used a broad definition of depression and asked participants if they reported neurological, anxiety, tension, or depression symptoms to their general practitioner or psychiatrist. At the PGC, Wray et al. diagnosed depression in participants according to international consensus diagnostic criteria (DSM-IV, ICD-9, or ICD-10). See Table  1 for details.

Statistical summary data for SCZ and BD were obtained from the most recent PGC’s GWAS summary statistics. The data for SCZ [ 27 ] are based on a major meta-analysis of multiple groups, including Europeans, East Asians, African Americans, and Latinos, including 76,755 cases and 243,649 control participants. BD [ 28 ] was based on a summary analysis of European ancestry and included 20,352 cases and 31,358 control participants. See Table  1 for detailed information.

To perform two-sample bidirectional analyses, we used independent genome-wide significant single nucleotide polymorphisms (SNPs) as exposure indicators for MDD (50 SNPs), SCZ (217 SNPs), and BD (16 SNPs). The F-statistics of the above SNPs are all greater than 10, indicating that they are strongly correlated instrumental variables (IVs). The detailed information is specified in the Supplementary Material: Tables  1 , 2 and 3 .

Data on genetic variants associated with thyroid cancer were obtained by Deutsches the Krebsforschungszentrum (DKFZ) through GWAS [ 29 ] and included 1080 European participants, including 649 in the case group and 431 in the control group, as detailed in Table  1 . For the bivariate analyses, we used independent genome-wide significant SNPs as indicators of exposure to thyroid cancer (347 SNPs). All 347 SNPs had F-statistics greater than 10, indicating that they were strongly correlated IVs. Specific SNP information is provided in the Supplementary Material: Table  4 .

Selection of genetic instrumental variables

This study was conducted in strict accordance with the quality control steps. First, we selected exposure-related GWAS data and screened SNP loci with genome-wide significance ( p  < 5 × 10 − 8 ) for pooled aggregation. Second, to avoid linkage disequilibrium (LD) from affecting the results, we performed a clustering process by setting the parameter (r 2 ) threshold (r 2  < 0.001 and region width = 10,000 kb) to assess LD among SNPs to ensure independence. SNPs need to fulfil three basic assumptions to serve as IVs for exposure factors, and the fulfilment of these assumptions will enhance the testing power and estimation accuracy of IVs: (1) the association assumption: genetic variants are associated with exposure; (2) the independence assumption: genetic variants are independent of confounders between exposure and outcome; and (3) the exclusivity assumption: genetic variants affect the outcome only through exposure [ 30 ]. Next, we extracted summary statistics of eligible SNPs from the outcome GWAS; finally, we determined that the SNPs included in the dataset met the instrumental variable requirements. The palindromic sequences were excluded to ensure that the effects of SNPs on exposure and outcome were from the same allele. This series of steps finalized the identification of SNPs that served as genetic IVs for this study.

Statistical analysis

After coordinating the GWAS effect alleles for MDD, SCZ, BD, and thyroid cancer, we selected three MR approaches. The inverse variance weighted (IVW) test, MR–Egger regression, and weighted median estimator (WME) were used to assess the causal relationship between psychiatric disorders and thyroid cancer risk. The main method of analysis was IVW, while WME and MR–Egger regression were used as complementary methods to IVW estimation, as they provide more reliable estimates under more relaxed conditions [ 31 ]. The Cochran’s Q test was used to estimate the heterogeneity of the causal effects of individual gene variants. If horizontal pleiotropy or heterogeneity is detected, fixed-effects IVW analysis should be chosen, and vice versa for random-effects IVW analysis [ 32 , 33 ]. The IVW method does not take into account the presence of an intercept term and uses the variance of the outcome as the fitting weight. In contrast, the MR–Egger regression method, which is an MR method for assessing the causal effect of genetic variation on the relationship between exposure and outcome, takes into account the presence of an intercept term [ 34 ]. This method corrects for polytropic bias and detects directed polytropy but is susceptible to instrumental variable assumptions. When the Egger intercept of a linear regression is close to zero, it indicates the absence of directional pleiotropy, thus satisfying the exclusivity assumption. The weighted median method is a method that combines data from multiple genetic variants into a single causal estimate and requires that more than 50% of the weights come from valid IVs to obtain a reliable estimate of the causal effect [ 31 ]. To ensure the reliability of the MR estimates, we also detected outliers that may affect our MR estimates by looking at forest plots, funnel plots, scatter plots, and leave-one-out methods.

To test the first hypothesis of correlation, we also assessed the strength of the relationship between IVs and phenotype using the F-statistic (F = beta 2 / se 2 , with beta being the allele effect value and SD being the standard deviation), with F > 10 indicating the presence of strongly correlated IVs [ 35 ].

All of the above MR-related statistical analyses were implemented using TwoSampleMR in R 4.1.1 software.

Three sets of genetic instruments were constructed for the forwards MR study after a series of quality control steps. First, we merged the exposure (MDD)- and outcome (thyroid cancer)-related datasets, and after removing 2 palindromic sequences (rs4936276 and rs4730387), we ultimately included 26 SNPs for analysis. The second set of genetic tools was constructed after the same quality control steps, combining the exposure (SCZ) and outcome (thyroid cancer) datasets and deleting six palindromic sequences (rs12363019, rs217310, rs2470951, rs2944821, rs7709645, rs9925915) before finally including 111 SNPs that were analysed. A third set of genetic instruments was constructed following the same quality control steps, combining exposure (BD) and outcome (thyroid cancer), and after deleting 2 palindromes sequences (rs10455979, rs5758065), and finally included 9 SNPs for analysis. The F-statistics of the above SNPs were greater than 10, indicating that they were strongly correlated with each other (Supplementary Material: Tables  1 , 2 and 3 ).

Three sets of genetic instruments were constructed in the reverse MR study after a series of quality control steps. First, we combined exposure (thyroid cancer) and outcome (MDD)-related datasets, resulting in the inclusion of 331 SNPs for analysis. The second set of genetic instruments was constructed following the same quality control steps, combining the exposure (thyroid cancer) and outcome (SCZ) datasets, resulting in the inclusion of 338 SNPs for analysis. A third set of genetic instruments was constructed following the same quality control steps, combining the exposure (thyroid cancer) and outcome (BD) data and ultimately including 338 SNPs for analysis. The F values of the above IVs were all > 10, indicating reliable results without weak bias.

Mendelian randomization analysis

In our study, we explored the causal relationship between psychiatric disorders (MDD, SCZ, and BD) and thyroid cancer using psychiatric disorders as exposure factors. The results of the IVW analysis showed a significant association between MDD and the risk of thyroid cancer (OR = 3.956 95% CI = 1.177–13.299; P  = 0.026), confirming the possibility of an increased risk of thyroid cancer due to MDD. These findings were reinforced by the results obtained by the WME method (OR = 5.563 95% CI = 0.998–31.008; P  = 0.050), which were consistent with those of the IVW method. However, the results of the MR–Egger regression (OR = 76.975 95% CI = 0.008-766576.333; P  = 0.364) showed that the difference in the effect of MDD and thyroid cancer was not statistically significant (Table  2 ), which may be due to the high false-positive rate of false-negative results from this method. Nevertheless, the IVW and WME methods suggest that MDD may increase the risk of thyroid cancer.

In addition, we found that genetic susceptibility to SCZ was correlated with thyroid cancer (OR = 1.532 95% CI = 1.123–2.088; P  = 0.007). The results of the WME method analysis based on the median estimate (OR = 1.599 95% CI = 1.014–2.521; P  = 0.043) also support that SCZ may increase the risk of thyroid cancer (Table  2 ).

However, no causal relationship between BD and thyroid cancer was found in any of the MR analyses. In addition, we performed reverse MR analysis, which showed no evidence of a causal relationship between genetic susceptibility to thyroid cancer and psychiatric disorders (MDD, SCZ, and BD), ruling out the possibility of reverse causation (Supplementary Material: Table  5 ).

Sensitivity analysis

For sensitivity analysis, we first tested for heterogeneity of results using Cochran’s Q for IVW and MR–Egger regression. The results showed that the p values of the analyses were greater than 0.05, which indicated that there was no significant heterogeneity in our study. Similarly, the MR–Egger intercept method results also showed no horizontal pleiotropy (all p values greater than 0.05). We also constructed funnel plots and leave-one-out plots. The funnel plot was roughly symmetrical, indicating a relatively low risk of bias and high reliability of the results. A leave-one-out plot was generated to reject SNPs one by one, and the analysis showed that the causal relationship between psychiatric disorders and thyroid cancer was largely not driven by a single SNP. We also examined scatter plots, in which each point represents an instrumental variable. Each horizontal solid line in the forest plot reflects a single SNP estimated using the Wald ratio method. Leave-one-out, scatter, funnel, and forest plots can be found in the supplementary materials.

In the inverse sensitivity analyses, Cochran’s Q test revealed heterogeneity between the effects of thyroid cancer on MDD, SCZ, and BD. Therefore, IVW analysis under a random effects model was chosen to balance the heterogeneity of the results. However, it is noteworthy that no heterogeneity was found in thyroid cancer patients with MDD or SCZ. p values for the MR–Egger intercept method were all greater than 0.05, suggesting that there was no horizontal pleiotropy in the results. Leave-one-out, scatter, funnel, and forest plots can be found in the supplementary materials.

With the increasing prevalence of psychiatric disorders and thyroid cancer, there is an increasing overlap between them, prompting us to delve deeper into their relationship. This study is the first two-sample bidirectional MR study of psychiatric disorders (MDD, SCZ, BD) and thyroid cancer. Our MR study showed a significant causal association between MDD and SCZ and thyroid cancer, whereas no such association was found between BD and thyroid cancer. Reverse MR analysis ruled out the possibility of reverse causation.

MR studies have the advantage of effectively avoiding confounding bias. Because SNPs are randomly assigned at conception, MR is also able to exclude reverse causality effects relative to observational studies, thus enhancing the credibility of causal inferences. We suggest the following possible mechanisms for the positive causal relationship between MDD and thyroid cancer: First, MDD may lead to abnormal functioning of the hypothalamic–pituitary–thyroid (HPT) axis, which in turn affects thyroid hormone levels and thyroid-stimulating hormone (TSH) secretion. TSH is a key factor in promoting thyroid cell proliferation, and abnormal TSH levels may increase the risk of thyroid nodules and cancer. Patients with early-stage MDD may suffer from thyroid and metabolic dysfunction [ 36 ]. Data from the study showed that 26.2% of depressed patients had abnormal thyroid function, 18.3% of whom had MDD, and 62.4% of the study population was female [ 37 ]. The results of a multicentre study by the European Antidepressant Study Group showed that the prevalence of hypothyroidism and hyperthyroidism in patients with MDD was 13.2% and 1.6%, respectively [ 38 ]. These results imply that MDD may regulate thyroid hormone levels through the HPT axis, thereby affecting thyroid function and structure. Abnormal HPT axis function has been the focus of research on neuroendocrine mechanisms in patients with psychiatric disorders, and our findings provide insight into the relationship between genetic susceptibility to MDD and thyroid cancer. Second, MDD leads to elevated peripheral inflammatory marker levels [ 39 , 40 ], which induce chronic inflammation and gene mutations in the thyroid gland. These peripheral inflammatory markers include interleukins (ILs), tumour necrosis factor (TNF), and C-reactive protein (CRP), which can affect thyroid tissues through blood circulation or neuroendocrine pathways. Chronic inflammation can mediate tumour development, and the two are interconnected through endogenous and exogenous pathways. Chronic inflammation of the thyroid gland may contribute to genetic defects through the secretion of high levels of mutagenic agents (e.g., reactive oxygen species and nitric oxide) [ 41 ]. Finally, MDD may be associated with type C personality, which is characterized by abnormal emotional expression and abnormal emotion regulation that may affect the immune system and endocrine function [ 42 , 43 , 44 ]. Some scholars [ 43 ] regard negative emotions as an independent risk factor for the occurrence of thyroid cancer and believe that the persistence or recurrence of depression and anxiety is a stress factor for the human body and that stress causes changes in the cerebral cortex and hypothalamus, which can directly or indirectly suppress the immune system and interfere with the endocrine function of the body [ 44 ], thus affecting the normal synthesis and release of thyroid hormones and triggering thyroid nodules and increasing the likelihood of thyroid cancer.

There may be different aetiologies regarding the genetic susceptibility of patients with SCZ to an increased risk of thyroid cancer. Beginning in the late 19th century, when hypothyroidism was connected with psychiatric disorders, an increasing number of clinical studies have shown a strong independent association between SCZ and hypothyroidism [ 45 ]. A recent community-based cross-sectional study comparing patients with SCZ ( n  = 1252) and healthy controls matched for age, sex, socioeconomic status and ancestry ( n  = 3756) revealed that the incidence of hypothyroidism in patients with SCZ increased after treatment but not before diagnosis [ 22 ]. Similarly, in observational studies, patients with SCZ are more likely to have abnormal thyroid function after initiating treatment with antipsychotics [ 46 , 47 ]. Thus, the use of antipsychotics may lead to abnormalities in thyroid function, although it is not clear whether the HPT axis can be directly affected. A systematic review and meta-analysis summarizing 19 studies suggested that TSH levels may be reduced at the onset of psychosis and elevated in patients with multiple episodes of psychosis [ 48 ]. Studies have shown that dopamine or dopamine agonists inhibit TSH secretion, and a possible explanation for the elevated TSH levels lies in the fact that antidopaminergic drugs used to treat SCZ inhibit dopamine neurotransmission, which may cause elevated TSH levels [ 49 ]. Thus, there may be a causal relationship between hypothyroidism or elevated TSH levels and the manifestations of SCZ. Thyroid hormones not only play a role in the dopaminergic system but also in the regulation of serotonergic, glutamatergic, and GABAergic networks [ 50 ]. During neurodevelopment, thyroid hormones play a critical role, and their deficiency may severely impair the development of neural tissues, leading to abnormalities and damage in the cerebellar cortex and cerebral cortex [ 51 ]. In the adult brain, thyroid hormone interacts with glial cells to regulate immune responses and neurotransmitter release and to control neuronal metabolism.

However, our study did not find conclusive evidence to support a causal role between genetic susceptibility to BD and thyroid cancer risk. To date, the association between affective disorders and thyroid cancer has not been widely reported. Although previous epidemiologic studies using case–control methods have suggested an association between BD and abnormal thyroid function [ 52 , 53 , 54 ], this topic has yet to be thoroughly investigated. One large meta-analysis reported that thyroid hormones may affect neurodevelopment by modulating the brain’s serotonin system [ 43 ]. The current preferred mood stabilizer for maintenance treatment of BD is lithium, although lithium alters thyroid functional status [ 55 ]. However, little is known about the pathophysiologic role of thyroid hormones in BD, and genetically, our study did not find a direct relationship between BD and thyroid cancer. However, further validation with larger datasets is needed in the future.

Our study has important implications for understanding the potential link between psychiatric disorders and thyroid cancer, as well as providing new ideas and strategies for the prevention and treatment of these common psychiatric disorders. For example, we can reduce the risk of thyroid cancer by screening and treating psychiatric disorders or improve the clinical management of psychiatric disorders by monitoring and regulating thyroid hormone levels. Specifically, we could conduct thyroid function testing and interventions in patients with psychiatric disorders, along with psychological assessment and treatment in patients with thyroid cancer. This integrated approach is expected to mitigate, to some extent, the adverse effects of psychiatric disorders and thyroid cancer on patients’ quality of life and socioeconomic status. In addition, our study provides clues and research directions for in-depth exploration of the potential relationships between MDD and thyroid cancer and between SCZ and thyroid cancer. More experimental and clinical studies are needed in the future to validate our findings and reveal the molecular cellular mechanisms underlying the causal relationship between psychiatric disorders and thyroid cancer.

In conclusion, our study is the first two-sample bidirectional MR study on the causal relationship between psychiatric disorders and thyroid cancer. Although our study provides useful insights for obtaining a deeper understanding of the relationship between psychiatric disorders and thyroid cancer, there are several limitations to consider. First, we used European population-based GWAS data to select IVs and obtain exposure data, which may limit the generalizability and applicability of our results. Second, our IVs were based on the use of a single nucleotide polymorphism-based design, which may not fully capture genetic variability in exposure or outcome. Finally, due to the limitations of the dataset, the number of thyroid cancer patients in the study was relatively small, which may have led to bias.

In summary, our study provides some suggestive evidence that MDD and SCZ are positively associated with thyroid cancer. This finding may have implications for health care policies regarding psychiatric disorders and thyroid cancer. Considering the high prevalence of psychiatric disorders and thyroid cancer in the general population, revealing the causal relationship between psychiatric disorders and thyroid cancer is important for public health policies for early prevention and timely prevention.

Data availability

Major depression：https://gwas.mrcieu.ac.uk/datasets/ieu-b-102/;Schizophrenia;https://gwas.mrcieu.ac.uk/datasets/ieu-b-5099/; Bipolar disorder:https://gwas.mrcieu.ac.uk/datasets/ieu-b-41/; Thyroid caencer:https://gwas.mrcieu.ac.uk/datasets/ieu-a-1082/;

Abbreviations

• Major depressive disease

schizophrenia

bipolar disorder

• Mendelian randomization

instrumental variables

inverse variance weighted

ultrasound-guided Fine Needle Aspiration

genome-wide association study

Psychiatric Genomics Consortium

single nucleotide polymorphisms

Deutsches the Krebsforschungszentrum

linkage disequilibrium

Weighted Median Estimator

hypothalamic–pituitary–thyroid

thyroid-stimulating hormone

interleukins

tumour necrosis factor

C-reactive protein

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Acknowledgements

This analysis benefited from the valuable data sets provided by various researchers and the summary statistics of multiple GWAS shared by the research community. We thank them for their contributions.

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Rongliang Qiu & Jinbo Fu

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School of Nursing, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China

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Conception and design: QRL, FJB. Development of methodology: JHZ, LHH. Analysis and interpretation of data: SJL, HJX. Writing of the manuscript: QRL, LHH. Study supervision: FJB.

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Qiu, R., Lin, H., Jiang, H. et al. Association of major depression, schizophrenia and bipolar disorder with thyroid cancer: a bidirectional two-sample mendelian randomized study. BMC Psychiatry 24 , 261 (2024). https://doi.org/10.1186/s12888-024-05682-7

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High-Fat Keto Diet Helped 69% of Bipolar Patients in New Study

The popular weight-loss plan may be beneficial in addition to traditional treatment, new research says

The keto diet may help those with bipolar disorder and schizophrenia , a new study says, with 69% of those with bipolar disorder seeing an improvement after going on the diet.

A four-month study of 23 people — most with bipolar disorder, but some with schizophrenia — has “shown promise in the treatment of psychiatric illness,” the report, published in Science Direct , says.

Using the Clinical Global Impressions scale — which the National Institute of Health explains is a way for “the non-researcher clinician to quantify and track patient progress and treatment response over time" — the study found that for bipolar participants, the “severity of mental illness assessments show average improvement of 31%” with “the severity of mental illness (through CGI assessments) showed improvements of >1 point in 69% of participants.”

“Psychiatric outcomes for the full cohort include an average of 17% improvement in life satisfaction,” the study says. 

Bipolar disorder , the Mayo Clinic explains, is “is a mental health condition that causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression).”

Schizophrenia is “a serious mental disorder in which people interpret reality abnormally,” the Mayo Clinic explains, adding that it “may result in some combination of hallucinations, delusions, and extremely disordered thinking and behavior that impairs daily functioning, and can be disabling.”

And while there are treatments for these disorders, the study points out that “many individuals can experience treatment resistance, or major metabolic side effects, which can result in non-adherence of prescribed treatments.”

That’s why researchers looked to the keto diet , a low-carb, moderate protein and high-fat eating plan. It's been used to help patients with epilepsy and diabetes, and has grown in popularity for weight loss.

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“The working theory is that we’re providing energy to the brain that circumvents these metabolic deficits,” Shebani Sethi, clinical associate professor of psychiatry and behavioral sciences at Stanford Medicine and the lead author of the study, told The Washington Post.

As a result of doing the keto diet for four months, the study found that “79% of participants with baseline symptoms experienced clinically meaningful improvement.”

The study’s authors point out that keto should supplement — not replace — traditional treatment.

“Our results show that a ketogenic diet intervention is a feasible and acceptable supplemental treatment to neuroleptic medication,” the study says, advocating for “further research into the relationship between mental health and metabolic health.”

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