case study 47 bipolar disorder

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5 Psychiatric Treatment of Bipolar Disorder: The Case of Janice

• Published: February 2013
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Chapter 5 covers the psychiatric treatment of bipolar disorder, including a case history, key principles, assessment strategy, differential diagnosis, case formulation, treatment planning, nonspecific factors in treatment, potential treatment obstacles, ethical considerations, common mistakes to avoid in treatment, and relapse prevention.

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Real Life Bipolar Disorder: A Case Study of Susan

Bipolar disorder is a complex and often misunderstood mental health condition that affects millions of individuals worldwide. For those living with bipolar disorder, the highs and lows of life can be dizzying, as they navigate through periods of intense mania and debilitating depression. To truly grasp the impact of this disorder, it’s crucial to explore real-life experiences and the stories of those who have dealt firsthand with its challenges.

In this article, we delve into the fascinating case study of Susan, a woman whose life has been profoundly shaped by her bipolar disorder diagnosis. By examining Susan’s journey, we aim to shed light on the realities of living with this condition and the strategies employed to manage and treat it effectively.

But before we plunge deeper into Susan’s story, let’s first gain a comprehensive understanding of bipolar disorder itself. We’ll explore the formal definition, the prevalence of the condition, and its impact on both individuals and society as a whole. This groundwork will set the stage for a more insightful exploration of Susan’s experience and provide valuable context for the subsequent sections of this article.

Bipolar disorder is more than just mood swings; it is a condition that can significantly disrupt an individual’s life, relationships, and overall well-being. By studying a real-life case like Susan’s, we can gain a personal insight into the multifaceted challenges faced by those with bipolar disorder and the importance of effective treatment and support systems. In doing so, we hope to foster empathy, inspire early diagnosis, and contribute to the advancement of knowledge about bipolar disorder’s complexities.

The Case of Susan: A Real Life Experience with Bipolar Disorder

Susan’s story provides a compelling illustration of the impact that bipolar disorder can have on an individual’s life. Understanding her background, symptoms, and the effects of the disorder on her daily life can provide valuable insights into the challenges faced by those with bipolar disorder.

Background Information on Susan

Susan, a thirty-eight-year-old woman, was diagnosed with bipolar disorder at the age of twenty-five. Her early experiences with the disorder were characterized by periods of extreme highs and lows, often resulting in strained relationships and an inability to maintain steady employment. Susan’s episodes of mania frequently led to impulsive decision-making, excessive spending sprees, and risky behaviors. On the other hand, her depressive episodes left her feeling hopeless, fatigued, and unmotivated.

Symptoms and Diagnosis of Bipolar Disorder in Susan

To receive an accurate diagnosis, Susan underwent a thorough examination by mental health professionals. The criteria for diagnosing bipolar disorder include significant and persistent mood swings, alternating between periods of mania and depression. Susan exhibited classic symptoms of bipolar disorder, such as elevated mood, increased energy, racing thoughts, decreased need for sleep, and reckless behavior during her manic episodes. These episodes were interspersed with periods of deep sadness, loss of interest in activities, and changes in appetite and sleep patterns during depressive phases.

Effects of Bipolar Disorder on Susan’s Daily Life

Living with bipolar disorder presents unique challenges for Susan. The unpredictable shifts in her mood and energy levels significantly impact her ability to function in both personal and professional spheres. During manic phases, Susan experiences heightened productivity, creativity, and confidence, often leading her to take on excessive responsibilities and projects. However, these periods are eventually followed by crashes into depressive episodes, leaving her unable to complete tasks, maintain relationships, or even perform routine self-care. The constant fluctuations in her emotional state make it difficult for Susan to establish a sense of stability and predictability in her life.

Susan’s struggle with bipolar disorder is not uncommon. Many individuals with this condition face similar obstacles in their daily lives, attempting to manage the debilitating highs and lows while striving for a sense of normalcy. By understanding the real-life implications of bipolar disorder, we can more effectively tailor our support systems and treatment options to address the needs of individuals like Susan. In the next section, we will explore the various approaches to treating and managing bipolar disorder, providing potential strategies for improving the quality of life for those living with this condition.

Treatment and Management of Bipolar Disorder in Susan

Managing bipolar disorder requires a multifaceted approach that combines psychopharmacological interventions, psychotherapy, counseling, and lifestyle modifications. Susan’s journey towards finding effective treatment and management strategies highlights the importance of a comprehensive and tailored approach.

Psychopharmacological Interventions

Pharmacological interventions play a crucial role in stabilizing mood and managing symptoms associated with bipolar disorder. Susan’s treatment plan involved medications such as mood stabilizers, antipsychotics, and antidepressants. These medications aim to regulate the neurotransmitters in the brain associated with mood regulation. Susan and her healthcare provider closely monitored her medication regimen and made adjustments as needed to achieve symptom control.

Psychotherapy and Counseling

Psychotherapy and counseling provide individuals with bipolar disorder a safe space to explore their thoughts, emotions, and behaviors. Susan engaged in cognitive-behavioral therapy (CBT), which helped her identify and challenge negative thought patterns and develop healthy coping mechanisms. Additionally, psychoeducation in the form of group therapy or support groups allowed Susan to connect with others facing similar challenges, fostering a sense of community and reducing feelings of isolation.

Lifestyle Modifications and Self-Care Strategies

In addition to medical interventions and therapy, lifestyle modifications and self-care strategies play a vital role in managing bipolar disorder. Susan found that maintaining a stable routine, including regular sleep patterns, exercise, and a balanced diet, helped regulate her mood. Avoiding excessive stressors and implementing stress management techniques, such as mindfulness meditation or relaxation exercises, also supported her overall well-being. Engaging in activities she enjoyed, nurturing her social connections, and setting realistic goals further enhanced her quality of life.

Striving for stability and managing bipolar disorder is an ongoing process. What works for one individual may not be effective for another. It is crucial for individuals with bipolar disorder to work closely with their healthcare providers and engage in open communication about treatment options and progress. Fine-tuning the combination of psychopharmacological interventions, therapy, and self-care strategies is essential to optimize symptom control and maintain stability.

Understanding the complexity of treatment and management helps foster empathy for individuals like Susan, who face the daily challenges associated with bipolar disorder. It underscores the importance of early diagnosis, accessible mental health care, and ongoing support systems to enhance the lives of individuals living with this condition. In the following section, we will explore the various support systems available to individuals with bipolar disorder, including family support, peer support groups, and the professional resources that contribute to their well-being.

Support Systems for Individuals with Bipolar Disorder

Navigating the challenges of bipolar disorder requires a strong support system that encompasses various sources of assistance. From family support to peer support groups and professional resources, these networks play a significant role in helping individuals manage their condition effectively.

Family Support

Family support is vital for individuals with bipolar disorder. Understanding and empathetic family members can provide emotional support, monitor medication adherence, and help identify potential triggers or warning signs of relapse. In Susan’s case, her family played a crucial role in her recovery journey, providing a stable and nurturing environment. Education about bipolar disorder within the family helps foster empathy, reduces stigma, and promotes open communication.

Peer Support Groups

Peer support groups provide individuals with bipolar disorder an opportunity to connect with others who share similar experiences. Sharing personal stories, strategies for coping, and offering mutual support can be empowering and validating. In these groups, individuals like Susan can find solace in knowing that they are not alone in their struggles. Peer support groups may meet in-person or virtually, allowing for easier access to support regardless of physical proximity.

Professional Support and Resources

Professional support is crucial in the management of bipolar disorder. Mental health professionals, such as psychiatrists, psychologists, and therapists, provide expertise and guidance in developing comprehensive treatment plans. Regular therapy sessions allow individuals like Susan to explore emotional challenges and develop healthy coping mechanisms. Psychiatrists closely monitor medication effectiveness and make necessary adjustments. Additionally, case managers or social workers can assist with navigating the healthcare system, accessing resources, and connect individuals with other community services.

Beyond direct professional support, there are resources and organizations dedicated to bipolar disorder education, advocacy, and support. Online forums, websites, and helplines provide information, guidance, and a sense of community. These platforms allow individuals to access information at any time and connect with others who understand their unique experiences.

Support systems for bipolar disorder are crucial in empowering individuals and enabling them to lead fulfilling lives. They contribute to reducing stigma, providing emotional support, and ensuring access to resources and education. Through these support systems, individuals with bipolar disorder can gain self-confidence, develop effective coping strategies, and improve their overall well-being.

In the next section, we explore the significance of case studies in understanding bipolar disorder and how they contribute to advancing research and knowledge in the field. Specifically, we will examine how Susan’s case study serves as a valuable contribution to furthering our understanding of this complex disorder.

The Importance of Case Studies in Understanding Bipolar Disorder

Case studies play a vital role in advancing our understanding of bipolar disorder and its complexities. They offer valuable insights into individual experiences, treatment outcomes, and the overall impact of the condition on individuals and society. Susan’s case study, in particular, provides a unique perspective that contributes to broader research and knowledge in the field.

How Case Studies Contribute to Research

Case studies provide an in-depth examination of specific individuals and their experiences with bipolar disorder. They allow researchers and healthcare professionals to observe patterns, identify commonalities, and gain valuable insights into the factors that influence symptom presentation, treatment response, and prognosis. By analyzing various case studies, researchers can generate hypotheses and refine treatment approaches to optimize outcomes for individuals with bipolar disorder.

Case studies are particularly helpful in documenting rare or atypical presentations of bipolar disorder. They shed light on lesser-known subtypes, such as rapid-cycling bipolar disorder or mixed episodes, contributing to a more comprehensive understanding of the condition. Case studies also provide opportunities for clinicians and researchers to discuss unique challenges and discover innovative interventions to improve treatment outcomes.

Susan’s Case Study in the Context of ATI Bipolar Disorder

Susan’s case study is an example of how individual experiences can inform the development of Assessment Technologies Institute (ATI) for bipolar disorder. By examining her journey, researchers can analyze treatment approaches, evaluate the effectiveness of various interventions, and develop evidence-based guidelines for managing bipolar disorder.

Susan’s case study provides rich information about the impact of medication, psychotherapy, and lifestyle modifications on symptom control and overall well-being. It offers valuable insights into the benefits and limitations of specific interventions, highlighting the importance of personalized treatment plans tailored to individual needs. Additionally, Susan’s case study can contribute to ongoing discussions about the role of support systems and the integration of peer support groups in managing and enhancing the lives of individuals with bipolar disorder.

The detailed documentation of Susan’s experiences serves as a powerful tool for healthcare providers, researchers, and individuals living with bipolar disorder. It highlights the complexities and challenges associated with the condition while fostering empathy and understanding among various stakeholders.

Case studies, such as Susan’s, play a crucial role in enhancing our understanding of bipolar disorder. They provide insights into individual experiences, treatment approaches, and the impact of the condition on individuals and society. Through these case studies, we can cultivate empathy for individuals with bipolar disorder, advocate for early diagnosis and effective treatment, and contribute to advancements in research and knowledge.

By illuminating the realities of living with bipolar disorder, we acknowledge the need for accessible mental health care, support systems, and evidence-based interventions. Susan’s case study exemplifies the importance of a comprehensive approach to managing bipolar disorder, integrating psychopharmacological interventions, psychotherapy, counseling, and lifestyle modifications.

Moving forward, it is essential to continue studying cases like Susan’s and explore the diverse experiences within the bipolar disorder population. By doing so, we can foster empathy, encourage early intervention and personalized treatment, and contribute to advancements in understanding bipolar disorder, ultimately improving the lives of individuals affected by this complex condition.

Empathy and Understanding for Individuals with Bipolar Disorder

Developing empathy and understanding for individuals with bipolar disorder is crucial in fostering a supportive and inclusive society. By recognizing the unique challenges they face and the complexity of their experiences, we can better advocate for their needs and provide the necessary resources and support.

It is important to understand that bipolar disorder is not simply a matter of mood swings or being “moody.” It is a chronic and often debilitating mental health condition that affects individuals in profound ways. The extreme highs of mania and the lows of depression can disrupt relationships, employment, and overall quality of life. Developing empathy means acknowledging that these struggles are real and offering support and understanding to those navigating them.

Encouraging Early Diagnosis and Effective Treatment

Early diagnosis and effective treatment are key factors in managing bipolar disorder and reducing the impact of its symptoms. Encouraging individuals to seek help and reducing the stigma associated with mental illness are crucial steps toward achieving early diagnosis. Increased awareness campaigns and education can empower individuals to recognize the signs and symptoms of bipolar disorder in themselves or their loved ones, facilitating timely intervention.

Once diagnosed, providing access to quality mental health care and ensuring individuals receive appropriate treatment is essential. Bipolar disorder often requires a combination of pharmacological interventions, psychotherapy, and lifestyle modifications. By advocating for comprehensive treatment plans and promoting ongoing care, we can help individuals with bipolar disorder achieve symptom control and improve their overall well-being.

The Role of Case Studies in Advancing Knowledge about Bipolar Disorder

Case studies, like Susan’s, play a significant role in advancing knowledge about bipolar disorder. They provide unique insights into individual experiences, treatment outcomes, and the wider impact of the condition. Researchers and healthcare providers can learn from these individual cases, developing evidence-based guidelines and refining treatment approaches.

Additionally, case studies contribute to reducing stigma by providing personal narratives that humanize the disorder. They showcase the challenges faced by individuals with bipolar disorder and highlight the importance of support systems, empathy, and understanding. By sharing these stories, we can help dispel misconceptions and promote a more compassionate approach toward mental health as a whole.

In conclusion, developing empathy and understanding for individuals with bipolar disorder is essential. By recognizing the complexity of their experiences, advocating for early diagnosis and effective treatment, and valuing the insights provided by case studies, we can create a society that supports and uplifts those with bipolar disorder. It is through empathy and education that we can reduce stigma, promote accessible mental health care, and improve the lives of those affected by this condition.In conclusion, gaining a comprehensive understanding of bipolar disorder is crucial in order to support individuals affected by this complex mental health condition. Through the real-life case study of Susan, we have explored the numerous facets of bipolar disorder, including its background, symptoms, and effects on daily life. Susan’s journey serves as a powerful reminder of the challenges individuals face in managing the highs and lows of bipolar disorder and emphasizes the importance of effective treatment and support systems.

We have examined the various approaches to treating and managing bipolar disorder, including psychopharmacological interventions, psychotherapy, and lifestyle modifications. Understanding the role of these treatments and the need for personalized care can significantly improve the quality of life for individuals like Susan.

Support systems also play a crucial role in helping those with bipolar disorder navigate the complexities of the condition. From family support to peer support groups and access to professional resources, fostering a strong network of assistance can provide the necessary emotional support, education, and guidance needed for individuals to effectively manage their symptoms.

Furthermore, case studies, such as Susan’s, contribute to advancing our knowledge about bipolar disorder. By delving into individual experiences, researchers gain valuable insights into treatment outcomes, prognosis, and the impact of the condition on individuals and society as a whole. These case studies foster empathy, reduce stigma, and contribute to the development of evidence-based guidelines and interventions that can improve the lives of individuals with bipolar disorder.

In fostering empathy and promoting early diagnosis, effective treatment, and ongoing support, we create a society that actively embraces and supports individuals with bipolar disorder. By encouraging understanding, reducing stigma, and prioritizing mental health care, we can ensure that those affected by bipolar disorder receive the support and resources necessary to lead fulfilling and meaningful lives. Through empathy, education, and continued research, we can work towards a future where individuals with bipolar disorder are understood, valued, and empowered to thrive.

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EP: 1 . Patient Case: 30-Year-Old Male With Bipolar Disorder

Ep: 2 . approaching the treatment of bipolar disorder, ep: 3 . treatment selection for bipolar disorder, ep: 4 . takeaways for bipolar disorder management.

Nidal Moukaddam, MD, PhD: Today, we’re going to talk about a new case. A 30-year-old man has taken short-term disability leave from work due to the progression of a depressive episode. He received a diagnosis of bipolar I disorder about 10 years ago. He had his first episode of mania at the age of 20 and 2 subsequent episodes of mania between the ages of 21 and 29. He was treated with lithium, which was highly effective, but he experienced excessive thirst and developed hyperthyroidism. His lithium level at the time was in the therapeutic range of 0.8 mEq/L. He was switched to valproate; however, valproate lacked the efficacy of lithium and caused adverse effects of sedation and weight gain. During his third manic episode, he started on olanzapine but experienced excessive weight gain. He was then cross-titrated to quetiapine, which improved his manic symptoms. However, weight gain again became an adverse effect, and he also complained of sedation. The patient reported sleeplessness and made unnecessary online purchases when unable to sleep, but the quetiapine sleepiness was unacceptable. Despite these adverse effects, he continued taking] quetiapine until he decompensated into his third depressive episode. The quetiapine was then augmented with lamotrigine, which was titrated up to 300 mg per day but demonstrated no efficacy. At the time of presentation, the patient was adhering to the medications. He did not have a substance use disorder, which was confirmed by a negative toxicology screen. His TSH [thyroid-stimulating hormone] level was in the middle of the normal range, and he had no suicidal ideations or psychotic symptoms.

I think the most important thing to do when somebody comes to you, even if they tell you they have a diagnosis, is to confirm the diagnosis. You want to start by making up your own mind, and sometimes the patient is not a good source of information. But in the case of bipolar disorder without psychosis, you expect the patient to be able to give you a solid history. Typically, the part of the history that’s hardest to nail down is mania. When people experience mania, they have excessive energy and excessive activation that creates the need for sleep, and sometimes they like it. They feel that this is the way it should be, so they don’t point it out as pathological. Now, the DSM-5 [ Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ] criteria tell us that mania that leads to hospitalization or some negative consequence like incarceration is problematic no matter what the duration is. Assuming the patient did not end up in the hospital or in prison, we want to verify the story of mania. In the current case presentation, I can see many of my colleagues saying, “Hey, you’re not giving us enough symptoms of mania. He’s a bit sleepless. He makes frivolous purchases. That’s bipolar disorder but not bipolar I; maybe it’s bipolar II.”

Thus, my first step would be to explain that this patient had at least a week without sleep. During that week, he was spacing, had pressured speech, and was talking fast to the point that others around him commented about it. He became more impulsive, and buying things was the tip of the iceberg. He also became more sexual to the point where it got him in trouble in his relationships, he spent more money than he had planned, etc. These examples of impulsivity often nail down the diagnosis of bipolar disorder. Of course, these symptoms change with the time that we live in. For example, before unlimited plans on cell phones, you would have been taught to ask: “Do you get a very high bill on your phone when you’re manic?” Because patients with mania talk a lot, and the bills would be higher when they call across state lines or internationally. First, I would recommend verifying the diagnosis. My impression of the patient is that this is somebody with a set diagnosis of bipolar I. Three manic episodes is a lot. He has impairment because of it, and it’s affected his job. Thus, my first step is confirming the diagnosis. My second would be a lot of psychoeducation; make sure that the patient understands what he’s up against and why he needs treatment.

Transcript Edited for Clarity

Evaluating the Efficacy of Lumateperone for MDD and Bipolar Depression With Mixed Features

Blue Light Blockers: A Behavior Therapy for Mania

Efficacy of Modafinil for Treatment of Neurocognitive Impairment in Bipolar Disorder

Blue Light, Depression, and Bipolar Disorder

Securing the Future of Lithium Research

An Update on Early Intervention in Psychotic Disorders

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• Published: 29 May 2024

Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study

• Hong Cai   ORCID: orcid.org/0000-0002-7915-1092 2 ,
• Tian Han 1 ,
• Yi-Fan Wang 1 ,
• Juan Li 1 ,
• Xiao-meng Xie   ORCID: orcid.org/0000-0001-6759-9685 1 &
• Xiao Ji   ORCID: orcid.org/0009-0006-9248-0719 1  

Translational Psychiatry volume  14 , Article number:  224 ( 2024 ) Cite this article

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• Bipolar disorder
• Prognostic markers

Testosterone has complex effects on psychological traits and behavior; it is associated with social dominance and competition and is a potential human sex pheromone. This study aimed to investigate the associations between testosterone levels, aggressive behavior, and manic symptoms using a network analysis among bipolar disorder (BD) patients in psychiatric emergency departments (PED). Data from January 2021 and March 2022 BD patients in PED were analyzed. Manic symptoms were assessed using the Young Mania Rating Scale (YMRS). Aggression was assessed with subscale of the PANSS scale (PANSS-AG). The undirected network structures of testosterone levels, aggressive behavior, and manic symptoms were estimated, and centrality and bridge centrality indices were examined. Network stability was examined using the case-dropping procedure. The Network Comparison Test (NCT) was conducted to evaluate whether network characteristics differed by gender. We recruited a total of 898 BD patients, with the mean YMRS score as 13.30 ± 9.58. The prevalence of level II aggression was 35.6% (95%CI = 32.5%–38.7%), level III aggression was 29.5% (95%CI = 26.3%–32.6%), and level VI aggression was 7.0% (95%CI = 5.4%–8.8%). The male participants had a mean testosterone level of 391.71 (Standard Deviation (SD):223.39) compared to 36.90 (SD:30.50) for female participants in the whole sample. Through network analysis, “Increased motor activity-energy” emerged as the central symptom, with the highest centrality expected influence, followed by “Emotional Instability” and “Disruptive/aggression behavior”. Notably, “Emotional Instability” appeared to be the bridge symptom linking manic symptoms to aggressive behavior. Within the flow network model, “Speech rate and amount” exhibited the strongest positive correlation with testosterone levels, followed closely by “Disruptive/aggression behavior”. The constructed network model demonstrated robust stability, with gender showing no significant impact on the structure. In this study, “Increased motor activity-energy” stood out as the most influential symptom, and “Speech rate and amount” acted as the main bridge symptom linking testosterone levels, aggressive behavior, and manic symptoms. Targeting the central and bridge symptoms may improve the outcomes of aggression interventions implemented among BD patients in psychiatric emergency care.

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Introduction.

Bipolar disorder (BD) is a potentially lifelong condition characterized by extreme changes in mood with high incidences of hyperactivity, irritability, grandiosity, poor judgment, and other symptoms, all of which are highly likely to lead to aggressive behavior [ 1 ]. Impulsive aggression is common amongst BD patients. Notably, aggressive behavior in BD patients show a direct prognostic value, which links to suicidal behaviors, more frequent hospitalizations, higher severity of mania symptoms, mixed symptoms, and comorbid borderline personality disorder [ 2 ]. A characteristic of BD emerges as hindrance towards an individual’s ability to perceive risk and protect themselves, which make them vulnerable to physical assault [ 3 ]. Given the risk of hurting others and self-harm, patients with BD have profound effects on society and family numbers.

The etiology of BD is unknown; however, factors such as genetics, biological traits, and environment have been proposed for consideration in the pathogenesis of BD [ 4 ]. For patients with BD who are experiencing disease episode, emergency departments or psychiatric emergency department (PED) are often their preferred choice for medical treatment. The highest prevalence of aggressive behavior occur in acute care settings (12.5–61.8%) [ 5 , 6 ]. Psychiatric emergency department is suitable place to study the relationship for testosterone levels, aggressive behavior, and manic symptoms among patients with BD.

Several lines of evidence indicates that testosterone may be involved in the pathophysiology of aggressive behavior [ 7 , 8 ]. Testosterone, an androgenic steroid hormone that is regulated by the hypothalamus-pituitary-gonadal (HPG) axis, has traditionally been associated with the manifestation of aggression, partly due to its close relationship with dominance behavior and competitive tendencies [ 9 ]. A study reported that administering exogenous testosterone can rapidly increase aggressive behavior in adult males [ 10 ]. Testosterone maintains have a complex relationship with BD; it can impact emotions, with elevated levels of testosterone associated with increasing incidences of depressive and hypomania symptoms [ 11 ]. Some gender differences have been observed with respect to the clinical course in patients with BD [ 12 ]. This evidence suggests a relationship between testosterone levels and aggressive behavior need to be discuss.

Hence, we need to establish a interaction assessment model, which is helpful for understanding the pathogenesis of aggressive behavior in patients with BD. Clinicians could then establish suitable biomarkers for the purposes of screening, risk appraisal, and subsequent therapeutic interventions [ 13 ]. In recent years, network analysis has experienced an expanding application in the field of psychology and psychiatry [ 14 ]. Network analysis is an innovative and analytical method that elucidates a biological system by anticipating the inter-relationships among multiple syndromes [ 15 ]. To further probe the inter-relationship between testosterone and aggressive behavior in BD patients, we incorporated network analysis into this investigation and identify symptoms as robust central symptoms, bridge symptoms and short paths between testosterone and aggrresive behavior within such populations in psychiatric emergency care. We hypothesize that high levels of testosterone may represent a key link point in neurobiological activity, which might contribute to aggression by exacerbating emotional instability.

Patients and study sites

A cross-sectional survey was conducted between January 2021 and March 2022 in Beijing Anding Hospital’s psychiatric emergency department, which is the only 24-h psychiatric hospital emergency service in the Beijing municipality and neighboring provinces. During the study, all patients who had received psychiatric emergency service were recruited consecutively for the survey. Eligible participants had to meet the following criteria: (1) receiving emergency maintenance treatment for a major psychiatric disorder; (2) provided written informed consent; (3) clinical diagnosis of a manic episode (F30–F39 in the ICD-10) (i.e., the Young Mania Rating Scale (YMRS) total score of ≥20 (Ouyang et al. [ 41 ]). Ethical approval was obtained from the Ethics Committee of Beijing Anding Hospital.

The basic socio-demographic and clinical data (e.g., age, onset age, gender, education level, marital status, employment status, illness duration, family history of psychiatric disorders) were collected using a form designed for this study through a review of medical records and confirmation from a clinical interview.

Blood collection and assays of testosterone

The routine blood collections were performed for clinical evaluations during psychiatric emergency visits. Serum samples were collected from all patients between 7:30 AM and 8:30 AM. Controlling for age and gender, the levels of 8 (7.30–8.30) AM serum were assayed for Testosterone (μg/dl) using chemiluminescence. The laboratory personnel were blind to all clinical information. Samples and data were processed following standard operating procedures with the appropriate approval of the Ethics and Scientific Committee of Capital Medical University, and all subjects provided written informed consent.

Measurement

In this study, aggressive behavior was assessed through interviews conducted by a trained attending psychiatrist within 12 h after admission. The aggressiveness of the subjects was graded using the standardized scale delineated by the local health authority and extensively employed in Chinese clinical practice. The severity of aggression is assessed in three domains: verbal aggression, aggression towards property, and physical aggression towards individuals. Verbal aggression, in this context, pertains to yelling or screaming, exhibiting hostile or offensive gestures, or uttering profanities. The standardized scale determines the intensity of each possible form of aggression on a scale of I to VI, with a level above II considered as aggression. We also used the aggression subscale of the PANSS scale (PANSS-AG), which includes supplementary components for the risk aggression profile (such as anger, difficulty in delaying gratification, and emotional instability) [ 16 ]. The PANSS had been validated in the Chinese population and demonstrates satisfactory psychometric properties (Cronbach’s alpha = 0.84) [ 17 ].

The Youth Mania Rating Scale (YMRS) [ 18 ] is an 11-item clinical rating scale used to assess the severity of manic symptoms. Seven of the eleven individual YMRS items were scored on a 0–4 scale: appearance, insight, language-thought disorder, increased motor activity-energy, elevated mood, sleep, and sexual interest, while the remaining four items were scored on a 0–8 scale: disruptive/aggressive behavior, content of morbid thinking, irritability, and speech–rate and amount. The YMRS total score, with a range of 0–60, is a summation of each of the eleven individual scores, with higher total scores signifying a more severe manifestation of mania.

Statistical analyses

Data were analyzed with the IBM Statistical Package for Social Science (SPSS) software version 24.0 and R software version 4.2.3. Normality of the data was assessed using the Kolmogorov–Smirnov test. Using the R software [ 19 ], a network model of aggression severity and testosterone level was built. To examine the edges of the network, we computed the polychoric correlations between all items and estimated the Graphical Gaussian Model (GGM) using the graphic least absolute shrinkage and selection operator (LASSO), and the Extended Bayesian Information Criterion (EBIC) using the R package graph [ 20 ].

The importance of each node in the network was examined by estimating centrality indices of the network structure with the R package “graph” [ 21 ]. Specifically, the centrality index of expected influence (EI) was computed for each node in the network (i.e., the sum of the weights of the connections, in absolute value), because EI is the most stable and interpretable centrality index [ 20 ]. The thickness of the edge represents the strength of the association. Additionally, previous studies [ 22 ] on comorbid psychiatric syndromes found that “Testosterone” was commonly reported to link different symptom communities as a key node. Therefore, the node-specific predictive betweenness of “Testosterone” (i.e., how often a node lies on the pathways between two other nodes, always with the “Testosterone” node as either of them across 1000 nonparametric bootstrap iterations) was estimated [ 23 ]. To identify particular symptoms that were directly associated with “Testosterone”, the “flow” function in the R package ‘qgraph’ was used [ 21 ].

Following previous studies [ 24 , 25 ], the differences in network characteristics between male and female participants were compared using the R “NetworkComparisonTest” package (Version 2.2.1) [ 26 ] with 1000 permutations. The difference in network structure (e.g., distributions of edge weights), global strength (e.g., total absolute connectivity among the symptoms), and each specific edge between subsamples (i.e., females vs. males) were also examined.

A total of 915 patients were invited to participate in this study; 898 patients met the study criteria and were included in analyses, in which the response rate was 98.1%, the rest of them were not included in the analysis due to incomplete information. The prevalence of level II aggression was 35.6% (95%CI = 32.5%–38.7%), level III aggression was 29.5% (95%CI = 26.3%–32.6%), and level VI was 7.0% (95%CI = 5.4%–8.8%). The male participants had a mean testosterone level of 391.71 ± 223.39 ng/dl (reference range 260–1590 ng/dl for ♂) compared to 36.90 ± 30.50 ng/dl for female participants (reference range 15–80 ng/dl for ♀). The demographic and clinical characteristics of the study population are summarized in Table 1 .

Network structure

Figure 1 illustrates the network structure representing the comorbid severity of aggression, manic symptoms, and testosterone levels in participants diagnosed with BD. The network model reveals that the strongest positive association among manic symptoms is between YMRS1 (“Elevated mood”) and YMRS2 (“Increased motor activity-energy”), followed by YMRS7 (“Language-thought disorder”) and YMRS8 (“Content of morbid thinking”), as well as YMRS5 (“Irritability”) and YMRS9 (“Disruptive/aggression behavior”).

AS aggression severity, FE facial expression, SI anger, S2D delyed graftification, S3E Emotional instability, T testosterone, YMRS1 high mood, YMRS2 increased behavioral activity, YMRS3 sexual interest, YMRS4 sleep, YMRS5 ittitability, YMRS6 language speed and quantity, YMRS7 language thinking disturbed, YMRS8 patients thinking, YMRS9 attack and sabotage, YMRS10 appearance, YMRS11 self-control.

Regarding EI centrality, the node YMRS2 (“Increased motor activity-energy”) exhibits the highest value, followed by S3E (“Emotional instability”) and YMRS9 (“Disruptive/aggression behavior”) within the network (Fig. 1 ). In terms of bridge EI, S3E (“Emotional instability”) emerges as the most critical bridge symptom connecting aggression and manic symptoms, succeeded by YMRS9 (“Disruptive/aggression behavior”) and S2D (“Delaying gratification”) (Fig. 1 ). Furthermore, the flow network model demonstrates that YMRS6 (“Speech–rate and amount”) exhibits the strongest positive correlation with testosterone, followed by YMRS1 (“Elevated mood”) (Fig. 2 ). In addition, we found that YMRS6 (“Speech–rate and amount”) has the strongest positive association with testosterone in the flow network model, followed by the YMRS1 (“Elevated mood”) (Fig. 2 ).

Flow network of Testosterone.

Regarding network stability, the EI centrality demonstrates an exceptional level of stability (i.e., CS-coefficient = 0.75 (95% CI: 0.675-1)), indicating that the network structure would not change significantly even if 75% of the sample was removed (Fig. 3 ). The bootstrap difference test revealed that most comparisons between edge weights were statistically significant.

The stability of centrality and bridge centrality indices using case-dropping bootstrap.

Node-specific predictive betweenness measure

Researchers have found that “Testosterone” plays an important role in aggressive behavior in previous studies [ 22 ]. Figure 4 shows the node-specific predictive betweenness values for each node in the network. The white dots represent the node-specific predictive betweenness in the study sample, while the black lines represent the variability of the measure across 1000 nonparametric bootstrap iterations. YMRS6 (“Speech–rate and amount”) has the highest node-specific predictive betweenness score, followed by YMRS5 (“Irritability”). This finding suggests that “Speech–rate and amount” and “Irritability” may be the main bridge symptoms between testosterone levels, manic symptoms, and aggression (Fig. 4 ).

Node-specific predictive betweenness.

Network comparison tests by gender

The comparison of the network model by gender did not reveal significant differences in network global strength (network strength: 11.37 in female participants; 11.40 male participants; M = 0.214, P = 0.571) and edge weights (S = 0.026, P = 0.969, Supplementary Figs. S1 – S4 ).

The study is the first network analysis of the association between testosterone levels and aggressive behavior among patients with BD in China PED. Within the assessed network model, “Increased motor activity-energy”, “Emotional instability” and “Disruptive/aggressive behavior” stood out as the most influential symptoms. Notably, “Speech rate and amount” acted as the main bridge symptom linking testosterone levels, manic symptoms, and aggression, followed by “Elevated Mood” and “Difficulty in delaying gratification”.

Our network analysis highlighted “Increased motor activity-energy” and “Emotional instability” as central symptoms in patients arriving at the emergency room due to aggressive tendencies. Patients with BD often displays alcohol or substance abuse, which can increase behavioral activity, leadings to an increased prevalence of aggressive behavior possibly up to 12% [ 27 ]. Consistent with previous findings, aggression was associated with more severe manic symptoms, as measured by the YMRS in acute manic episodes [ 28 ]. People in the manic phase are often highly motivated to engage in goal-oriented activities. However, due to lack of insight, patients may not realize their behavior is abnormal and prone to harmful consequences. Patients become extremely aggressive and irritable, and are more likely to harm themselves or others and destroy property through verbal or physical aggression [ 29 ]. This observation also shed light on the identification of “Difficulty in delayed gratification” as another bridge symptom. Previous functional magnetic resonance imaging (fMRI) studies have observed responses in the amygdala, periaqueductal gray matter, and the prefrontal lobe when BD patients were frustrated by the denial of a reward. This neural response can potentially stimulate aggressive impulses, transforming unfulfilled desires into the urge to attack [ 30 ].

“Speech–rate and amount” acted as the main bridge symptoms linking testosterone levels, manic symptoms, and aggression, succeeded by “Elevated Mood”. “Speech–rate and amount” and “Elevated mood” are typical symptoms of manic episodes, and previous imaging studies have shown abnormalities in neuronal coupling in the sensory-motor subcortical-cortical circuit in patients with highly excited brains, compared to healthy controls [ 31 ]. Testosterone may act through receptors located in key regulatory regions to increase the connectivity between subcortical regions of the brain while weakening connections between the cortex and subcortical regions [ 32 ], causing the patient in highly excited state. Abnormal regulation of the HPG axis is critical for homeostatic regulation of synthesis and secretion of testosterone and the most potent androgen dihydrotestosterone (DHT) by the testis [ 33 ]. Dysregulation of the HPG axis may cause depressive symptoms, which are associated with high cortisol inhibition [ 34 ]. Moreover, compared to bodybuilders who did not take exogenous testosterone, there was a higher rate of hypomanic episodes among those who did [ 35 ]. The release of testosterone will increase the motivation of BD patients to seek dominance and take impulsive risks, which are often poorly thought-out and prone to adverse consequences [ 36 ]. High levels of testosterone have been found to reduce activity and functional connectivity in the prefrontal cortex, altering the function of prefrontal-mediated emotion regulation, thereby impairing the ability to control aggressive impulses [ 37 ].

Regarding the gender for the network model of comorbid aggression severity, manic symptoms, and testosterone levels among patients with BD, there were none significant differences shown in this study. The existing evidence suggests that testosterone concentrations in early life influence the development of some human behaviors, with certain gender differences [ 38 ]. One study from community recruiters suggested that adolescent males with higher plasma testosterone levels were more irritable and likely to overreact to provocation and threats [ 39 ]. Previous studies on depressive episode status in patients with BD have found that male patients have significantly lower testosterone levels, while female patients have significantly higher levels [ 40 ].

The strengths of this study include a substantial sample size, the utilization of standardized assessment instruments, and the employment of network analysis techniques. These techniques were tailored to investigate the structure of the model assessing testosterone levels and aggressive behavior in patients with BD. Such insights may pinpoint potential targets for treatment and prevention measures, particularly for patients with BD in psychiatric emergencies exhibiting these problems. Nonetheless, several methodological limitations in our study warrant attention. First, the cross-sectional design precludes establishing causal relationships between variables, and there was an absence of a control/naive group. Future longitudinal research is essential to elucidate the time-bound causal links between testosterone levels and aggressive behavior in patients with BD. Secondly, though routine blood collections were performed for clinical evaluations during psychiatric emergency visits, additional measurements, such as thyroxine, should be added to the study analysis. Subsequently, we hope to carry out relevant radiological research to further explore the specific relationship between testosterone levels and aggressive behavior in BD patients. Lastly, our sample was consecutively drawn from one major psychiatric emergency department (PED) in China, which may limit the generalizability of our findings in other psychiatric contexts.

To summarize, within the aggression-bipolar disorders network model, as well as the association with testosterone levels, “Increased motor activity-energy,” “Emotional instability,” and “Disruptive/aggressive behavior” were the most pivotal symptoms among BD patients in PED. Our study showed no significant gender differences in testosterone levels observed in BD patients during the manic episode phase. These specific symptoms, which are potential intervention targets, should be at the forefront of physicians’ evaluation protocols.

Data availability

The data of the investigation will be made publicly available if necessary.

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The study was supported by the National Clinical Key Specialty Construction Project Fund (3-2-2021-PT40).

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Yi Liu, Tian Han, Yi-Fan Wang, Juan Li, Xiao-meng Xie & Xiao Ji

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Liu, Y., Cai, H., Han, T. et al. Network analysis of comorbid aggressive behavior and testosterone among bipolar disorder patients: a cross-sectional study. Transl Psychiatry 14 , 224 (2024). https://doi.org/10.1038/s41398-024-02957-1

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Case Studies

Hypothetical patient case 47-year-old woman with bipolar depression.

• Name: Jennifer S.
• Sex: Female
• Race/Ethnicity: African American, White
• Occupation: Telecom worker
• BP: 145/95 mm Hg
• Current problems:
• Bipolar disorder
• Hypertension
• Prediabetes
• Current medications:
• Metformin 500 mg BID
• Lamotrigine 100 mg BID
• Escitalopram 20 mg qam
• Olanzapine 10 mg qhs
• Benztropine 2 mg BID
• Lorazepam 1 mg qam and 2 mg qhs
• Current diagnosis: Bipolar disorder
• Previous psychiatric diagnoses: Current depressive episode with mixed features (4 months)
• Current psychiatric medication:
• Past psychiatric medications:
• Lithium 300 mg 1 qam and 2 qhs
• Risperidone 2 mg qhs
• Sertraline 100 mg qam
• Quetiapine 200 mg qhs
• Haloperidol 5 mg IM prn while in hospital
• History of tremor/rigidity after treatment with haloperidol IM during psychiatric hospitalization, diagnosis of drug-induced parkinsonism
• Benztropine prescribed while in hospital
• Movements in her lips, tongue, and fingers
• Patient reports embarrassment and increase in anxiety due to movements at home and at work
• Abnormal, involuntary movements of lips and hands
• Lip pursing, finger tapping
• Movements are irregular in rhythm
• Patient’s gait is not disrupted and arm movements are normal
• When antipsychotic dose was decreased, movements worsened
• Duration of movements: ~2 years
• No improvement with benztropine
• Provided education about TD and available treatment options
• Shared decision to initiate treatment with a VMAT2 inhibitor
• Follow-up in 1 month

The Ketogenic Diet as a Treatment for Mood Disorders

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• Published: 28 May 2024

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• Elif Ozan MD 1 ,
• Virginie-Anne Chouinard MD 1 , 2 &
• Christopher M. Palmer MD 2 , 3  

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Purpose of Review

The ketogenic diet is a low carbohydrate, moderate protein, and high fat diet which results in a metabolic state known as ketosis, in which fats are broken down into ketone bodies. The ketogenic diet is a 100-year-old evidence-based treatment for epilepsy and is gaining popularity as a treatment for various mental disorders, including mood disorders. Our objective is to explain the potential mechanisms through which ketogenic diets may improve the pathophysiology of mood disorders and provide a comprehensive review of recent clinical literature on the topic

Recent Findings

Mood disorders are associated with several proposed pathophysiological mechanisms, including mitochondrial dysfunction, oxidative stress, inflammation, and insulin resistance. The ketogenic diet shows promise in addressing these underlying pathophysiological mechanisms and emerging clinical data suggest that ketogenic diets may improve symptoms in people with mood disorders.

The ketogenic diet shows promise in the treatment of mood disorders. This metabolic intervention has the potential to directly target underlying disease mechanisms, potentially reduce the need for medications, and reduce common side effects and comorbidities, such as weight gain and insulin resistance.

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Introduction

Mood disorders are chronic and recurrent psychiatric conditions that affect emotions, energy, and motivation. Mood disorders include depressive disorders and bipolar disorders. Depression affects more than 264 million people worldwide. In the United States, major depressive disorder (MDD) affects approximately 7% of the adult population in a given year [ 1 ]. Bipolar Disorder (BD) is also a chronic mental health condition with a lifetime prevalence of approximately 1.5–2.4% [ 2 ] and a high risk of recurrence. In recent years, there has been an increase in the rates of mood disorders [ 2 , 3 ]. Moreover, many people do not respond adequately to standard treatments, which usually include medications and psychotherapy. It is estimated that 30% of people with major depressive disorder and bipolar depression are resistant to treatment [ 4 •], while many remain at risk for illness recurrence and disability [ 5 , 6 ]. There is thus an urgent need to develop new treatment modalities for mood disorders.

Recent evidence points to the potential for metabolic therapies to improve symptoms and functional outcomes in mood disorders [ 7 ]. The ketogenic diet is one such metabolic therapy, which is an eating pattern low in carbohydrate, high in fat, and moderate in protein that results in increased synthesis of ketone bodies (β-hydroxybutyrate, acetone, acetoacetate) leading to ketosis. It is a 100-year-old, evidence-based treatment for epilepsy [ 8 ]. The ketogenic diet has been demonstrated to reduce and remit seizures, including in treatment-resistant epilepsy [ 9 ]. The production of ketone bodies provides the brain with an alternate fuel source to glucose. Ketone bodies bypass several crucial steps in glucose transport and glycolysis and ketosis provides ketones as an alternative source of Acetyl CoA to enable the tricarboxylic acid cycle when glucose metabolism is impaired, and this reduces glycolytic energy production and consequently lactate accumulation. The ketogenic diet directly addresses metabolic dysfunction by lowering both blood glucose levels and insulin secretion [ 10 ]. Interestingly, other treatments for epilepsy are routinely used in the treatment of mood disorders, with some anticonvulsant medications being FDA-approved for the treatment of bipolar disorder, while others are routinely used off-label for the treatment of mood disorders more broadly. There is growing interest in the use of the ketogenic diet as a treatment for mood disorders.

There is compelling evidence that the ketogenic diet can target underlying pathophysiologic mechanisms in mood disorders. This article aims to assess the status of the use of the ketogenic diet in bipolar disorder and explore its potential as a therapeutic approach for mood disorders. In this review, we hope to present data from randomized clinical trials, case series and new areas of research in recent years.

Pathophysiologic Targets of the Ketogenic Diet in Mood Disorders

Multiple biological mechanisms have been proposed as potential contributors to mood disorders, encompassing mitochondrial dysfunction, inflammatory pathways, oxidative stress, and insulin resistance [ 11 , 12 , 13 , 14 ]. The ketogenic diet is known to improve all of these.

Mitochondrial Dysfunction

Mitochondria, integral cellular structures, play critical roles in numerous biological functions, particularly in the generation of energy. Within the brain, where ATP consumption is elevated and storage capacity is limited [ 15 ], mitochondria play a vital role in regulating neuronal activity, influencing both short-term and long-term neuronal plasticity, bolstering cellular resilience, and facilitating behavioral adaptations [ 16 , 17 , 18 ]. There is converging evidence for energy dysregulation in mood disorders [ 19 , 20 ]. Studies using brain 31P magnetic resonance spectroscopy have identified abnormalities related to redox regulation and bioenergetics, including NAD + /NADH imbalance [ 19 ] and decreased generation of ATP with energy demand [ 19 , 20 ]. Recently, therapies with the potential to improve mitochondrial function have been investigated as complementary therapies alongside existing pharmacological treatments for mood disorders [ 21 ].

The ketogenic diet has been shown to enhance mitochondrial biogenesis and function, a process vital for energy production, by increasing the expression of genes involved in energy metabolism. This dietary approach shifts the body's energy reliance from glucose to ketone bodies, which are more efficient substrates for mitochondria, leading to improved energy efficiency and cellular health [ 22 , 23 ]. Studies by Veech and colleagues have shown an improvement in mitochondrial function with the ketogenic diet [ 24 , 25 ]. Furthermore, the ketogenic diet can reduce oxidative stress and inflammation, further supporting mitochondrial function and overall cellular resilience [ 22 , 26 , 27 ].

Inflammation

A substantial body of evidence suggests associations between inflammation and mood disorders [ 28 , 29 , 30 , 31 , 32 ]. Heightened levels of inflammatory markers, including tumor necrosis factor (TNF) alpha, C-reactive protein, and interleukins IL-1, IL-2, IL-6, and IL-10 are observed in individuals with MDD and BD [ 29 ].

The ketogenic diet has been associated with significant reductions in inflammatory biomarkers. A meta-analysis by Masood et al. highlighted the diet's efficacy in reducing C-reactive protein, a key marker of inflammation, across several studies, suggesting a systemic anti-inflammatory effect. Another meta-analysis by Li et al. of 44 randomized, controlled trials found that adherence to a ketogenic diet can improve inflammatory biomarkers, including TNF-α and IL-6 [ 33 , 34 ].

Oxidative Stress

Recent studies provide growing evidence that oxidative stress may be a fundamental mechanism in bipolar disorder [ 14 , 35 , 36 •]. Reactive oxygen species (ROS) naturally arise as by-products of cellular energy metabolism and function. The majority of these free radicals are generated during oxidative phosphorylation and are subsequently neutralized through a series of biochemical pathways [ 37 ]. Levels of oxidative damage are linked to mood states, with both manic and depressed states exhibiting heightened oxidative stress, while euthymic states do not. Meta-analyses indicate a notable rise in specific ROS among individuals with bipolar disorder [ 38 , 39 ]. Persistent cellular damage is likely to result in disruptions in neurotransmission, potentially leading to the manifestation of symptoms observed in bipolar disorder.

Consuming a ketogenic diet has been shown to impact mitochondrial functions and oxidative stress [ 40 , 41 , 42 ]. The beneficial impacts of ketones and the ketogenic diet on oxidative stress via the augmentation of the NAD + /NADH ratio have been extensively recorded in animal studies, ex vivo experiments, and cellular models [ 43 , 44 ].

Obesity and Insulin Resistance

Major depressive disorder and bipolar disorder are conditions characterized by symptom profiles that can affect appetite, energy, sleep, and motivation [ 45 ]. The prevalence of obesity in individuals with MDD and BD is nearly double compared to the general population [ 46 ].

Extensive research has focused on unravelling the mechanisms linking mood disorders and obesity, suggesting that various facets of depression's neurobiology may contribute to an elevated risk of obesity [ 47 ]. Longitudinal studies validate that depression during adolescence significantly predicts higher body mass index (BMI) in adulthood, while individuals with obesity are also at increased risk of MDD compared to those within a healthy weight range [ 48 ]. Pharmacotherapy serves as a significant mediator in the relationship between depression, bipolar disorder, and obesity, frequently causing sedation and heightened appetite, thereby impacting both physical health and treatment adherence [ 49 , 50 ]. Moreover, weight gain and the medical comorbidities it brings about might diminish the probability of favorable clinical responses to pharmacological treatments [ 50 ].

People with BD face a threefold higher risk of diabetes compared to the general population [ 51 ]. This cannot be attributed solely to the side effects of BD medications, as there is also a high prevalence of type 2 diabetes (T2DM) in medication-naïve patients [ 52 ]. Given the substantial occurrence of insulin resistance in BD, coupled with findings indicating compromised neuronal glucose metabolism and the association with diabetes comorbidity, neuronal insulin resistance likely plays a role in the development of BD. Evidence from research suggests that hyperinsulinemia in BD is associated with hyperinsulinemia in the brain, which may inhibit oxidative phosphorylation and result in a shift toward glycolytic energy production and mitochondrial dysfunction.

The ketogenic diet directly addresses metabolic dysfunction by lowering both blood glucose levels and insulin secretion [ 53 , 54 ]. A meta-analysis revealed a reduction in fasting blood glucose levels and HbA1c rates following a ketogenic diet intervention compared to pre-intervention levels [ 55 ]. Reports indicate improvements in mood, energy, sleep, mental clarity, and affective stability associated with the adoption of low-carbohydrate and ketogenic diets in individuals with type 2 diabetes and obesity [ 56 ]. Hence, the ketogenic diet might hold significant relevance in the management of mood disorders.

Bipolar Disorder

1-case reports and case series.

Several case reports and case series suggest that the ketogenic diet may play a role in the treatment of bipolar disorder.

One was of a 27-year-old male diagnosed with bipolar affective disorder with rapid cycling who was treated with ketogenic diet therapy for 2 years in addition to pharmacotherapy after no response to depressive symptoms in 4 years of pharmacotherapy [ 57 ]. After the first year of treatment, the patient's mood improved and stabilized, cognitive functions and concentration improved and anxiety disappeared. In the second year of treatment, the beneficial effects continued. The patient experienced complete remission of his chronic depression, even with a reduction in pharmacologic treatment [ 57 ].

Another case report was a 69-year-old woman with bipolar II symptoms who started a ketogenic diet. After two years on the diet, the patient noticed a decrease in her anxiety, anger attacks and depressive symptoms [ 58 ]. Another patient in the same case report was a 30-year-old woman with type II bipolar illness. After experiencing the side effects of multiple medications, she started using the ketogenic diet. She reported experiencing mood-stabilizing effects after treatment [ 58 ].

In another case report, a 33-year-old single man diagnosed with schizoaffective disorder showed persistent positive and negative symptoms despite multiple drug trials. Over the course of a year, he predominantly adhered to a ketogenic diet and noted a decrease in both types of symptoms. Throughout the diet, his functionality notably improved [ 59 ]. The second case was of a 31-year-old woman with a psychiatric history encompassing major depression and anorexia nervosa, ultimately diagnosed with schizoaffective disorder. Despite undergoing electroconvulsive therapy and numerous drug trials, her positive and negative symptoms persisted. By the fourth month of adhering to the ketogenic diet, she experienced a reduction in both types of symptoms [ 59 ].

In another case study [ 60 ], a 60-year-old woman diagnosed with type 1 bipolar disorder started a ketogenic diet for treatment-resistant mood and psychotic symptoms. She experienced significant improvement in mood and anxiety symptoms [ 60 ].

In another case, a 49-year-old woman with a history of early-onset, treatment-resistant bipolar disorder had been managed with various mood stabilizers and neuroleptic medications. Alongside antipsychotic treatment, the patient followed two distinct ketogenic diets. However, there was no discernible clinical improvement, weight loss or urinary ketosis noted during this time. Although this case report suggested that the ketogenic diet failed to improve her symptoms, she never achieved urinary ketosis, implying that she never fully complied with the treatment [ 61 ].

A larger case series included 31 adults with treatment-resistant major depressive disorder, bipolar disorder, and schizoaffective disorder. They were prescribed a ketogenic diet [ 62 ]. Twenty-eight patients were able to adhere to the diet. Overall, all of the patients adherent to the diet experienced at least some improvement in symptoms, with 43% of the patients achieving clinical remission of illness [ 62 ]. In addition, 10 patients diagnosed with schizoaffective disorder reported improvement in positive and negative symptoms [ 62 ].

2-Clinical Trials

Two recent clinical trials indicate encouraging outcomes in utilizing the ketogenic diet for bipolar disorder treatment. One pilot study was conducted to assess the feasibility and acceptability of implementing the ketogenic diet in people with bipolar disorder [ 63 ••]. Participants, aged 18 and 70 years, were clinically euthymic for a minimum of three months. Out of 26 enrolled participants, 20 adhered to the diet until their 6- to 8-week follow-up, with 18 completing the entire 8-week intervention period. Most participants successfully achieved and sustained ketosis, with ketosis present in 91% of all daily ketone readings, suggesting a high level of adherence to the diet. One-third of participants experienced reduction in psychiatric symptoms and 95% participants had improvement in cardiometabolic risk parameters. Higher blood beta-hydroxybutyrate levels were associated with improvement in mood and energy levels, along with reduced impulsivity and anxiety [ 64 ••]. All but one of the participants (n = 20) for whom baseline and follow-up data were completed lost weight during the intervention period. 52.6% of participants achieved significant weight loss (≥ 5% body weight). Participants' mean BMI decreased by 5.3% and mean systolic blood pressure decreased by 7.4 mmHg. During the period of diet cessation, one-third of participants who reported reduced mood variability chose to stay on the ketogenic diet. Adverse events were predominantly mild and manageable. The study documented 11 minor side effects, such as fatigue, constipation, drowsiness, and hunger, alongside one serious adverse event, which involved euglycemic ketoacidosis in a participant using an SGLT2 inhibitor [ 63 ••]. This research identified lactate as a biomarker, suggesting that increased levels of lactate may indicate impaired oxidative phosphorylation and a compensatory increase in glycolysis. The study revealed noteworthy changes in metabolites, including decreased lactate levels, increased citrate (which contributes to oxidative phosphorylation through the tricarboxylic acid cycle), and heightened levels of the ketone body beta-hydroxybutyrate. These findings suggest that ketosis may prompt a transition towards heightened mitochondrial activity, enhanced oxidative phosphorylation, and reduced glycolysis [ 64 ••].

A 4-month pilot study was conducted to investigate the effects of KD on individuals with schizophrenia or bipolar disorder. Twenty-three participants were enrolled in a single-arm study. Based on ketone levels in this study, fourteen participants were fully adherent to the diet (above 80% of the time ketone measures > 0.5), six participants were semi-adherent (ketones > 0.5 above 60–80% of the time), and one participant was nonadherent (ketones > 0.5 < 50% of the time.) Results showed improvements in metabolic health and no participant met criteria for metabolic syndrome at the end of the study. In psychiatric measures, participants with schizophrenia showed a 32% reduction in Brief Psychiatric Rating Scale scores. Overall Clinical Global Impression (CGI) severity improved by an average of 31%. 79% of all participants improved by at least 1 point on CGI (92% for those who were adherent with treatment and 50% for those who were semi-adherent). According to the Clinical Mood Monitoring assessments, the proportion of participants who were on neuroleptic medication at baseline and in recovery increased from 33% at baseline to 75% at the end of the study. In the adherent group, 100% were in recovery at the end of the study. Overall, for both the bipolar and schizophrenia populations, 43% of participants achieved improvement during the study (50% for adherent and 33% for semi- adherent). Cohort-wide psychiatric improvements included increased life satisfaction (17%) and improved sleep quality (19%) These results suggest that the intervention had a positive impact on participants' mental health and well-being. Moreover, beneficial changes in weight, body composition and metabolic markers, including insulin sensitivity, were also observed in a metabolically vulnerable population. Common side effects of the ketogenic diet such as headaches, fatigue and constipation were documented at baseline. These side effects decreased significantly and reached minimal or negligible levels after the third week of the study [ 65 ••].

Major Depression

Preclinical studies.

Preclinical studies have suggested potential efficacy of the ketogenic diet in alleviating depressive symptoms in animal models.

One line of research suggests that the ketogenic diet can enhance the presence of Akkermansia, a probiotic, in the gut of rodents [ 66 , 67 ]. In animal stress models, this augmentation of Akkermansia has exhibited properties akin to antidepressants, suggesting a potential role of the ketogenic diet in fostering antidepressant effects [ 68 ].

Another study analyzed the brain structure and behavior of mice exposed to KD during gestation followed by a standard diet (SD) after birth [ 69 ]. Adult offspring exposed to KD showed reduced susceptibility to anxiety and depression and exhibited increased levels of physical activity compared to their counterparts exposed to both prenatal and postnatal SD. These results suggest that prenatal exposure to KD programs the neuro-anatomy of offspring and influences adult behavior.

The impact of medium- and long-chain ketogenic diets on cerebral electrical activity and the propagation of cortical spreading depression (CSD) [ 70 ] has also been examined. Weaned rats were divided into three groups: one received a control diet, the other a medium-chain triglyceride KD and the third a long-chain triglyceride KD. Results indicated that short-term KD treatment significantly reduced the rate of CSD spread compared to the control group. However, long-term administration of KD showed no effect on the CSD rate, suggesting that short-term KDs have a favorable impact on reducing cerebral excitability in young animals [ 70 ].

Finally, other evidence suggests that the ketogenic diet may have antidepressant properties, evidenced by rats on the diet showing reduced "behavioral despair" in the Porsolt test, a model for depression, compared to those on a control diet [ 71 ].

Case Reports and Case Series

As detailed in a case study, a 65-year-old female diagnosed T2DM and major depressive disorder engaged in a 12-week ketogenic diet regimen [ 72 ]. Following the intervention, notable improvements were evident across both physiological and psychological realms. Alongside reductions in HbA1C and blood glucose levels, the patient reported amelioration of depressive symptoms and enhanced adherence to diabetes management. Notably, after the 12-week period, medication usage decreased by 75%. Moreover, the patient experienced heightened self-assurance, increased self-efficacy, elevated energy levels, enhanced sleep quality, and greater bodily stability [ 72 ].

In another case report, a 21-year-old female with obesity, a mood disorder, and comorbid conditions including emotion dysregulation, body dysmorphic disorder, and an eating disorder, underwent a 4-week ketogenic diet. Following the 4-week dietary regimen, notable improvements were observed, including stabilized mood, decreased anxiety, and normalization of the circadian rhythm. Additionally, the patient reported the absence of suicidal thoughts, alongside recorded weight loss [ 73 ].

In a study of individuals with chronic epilepsy, a retrospective survey was carried out among those who adhered to the Modified Atkins Diet (MAD) for a minimum of 1 month and up to 2 years. The MAD involves restricting net carbohydrates to 20 g per day while permitting high fat and unlimited protein intake [ 74 ]. Consequently, a reduction in depressive and anxiety symptoms was noted among the participants, with this decrease directly correlating with the duration of the diet. Additionally, it was observed that some individuals who did not experience a reduction in seizures opted to continue the diet due to the observed improvement in their mood and anxiety. Notably, changes in seizure frequency did not exhibit a significant correlation with alterations in measures of depression or anxiety severity. This implies that the noted improvement cannot solely be attributed to a decrease in seizures [ 74 ].

Clinical trials

Significant results of ketogenic diet were found in clinical trials conducted in groups of patients showing depressive symptoms with previous comorbidity.

In a randomized, controlled, 4-month trial of the ketogenic diet in children and adolescents aged 1–18 years old diagnosed with epilepsy, it was observed that KD patients initially exhibited higher levels of mood symptoms. However, at the 4-month follow-up, the children experienced a decrease in anxiety, tension, and hostility levels [ 75 ]. Regarding social-emotional functioning, individuals in the KD group demonstrated decreased levels of anxious and mood disorder behavior after 4 months, a change that was not associated with improvements in seizure control. Furthermore, an enhancement in their overall functionality was noted at the 4-month mark, which was not linked to the reduction in seizures [ 75 ].

In another randomized, controlled trial, overweight or obese adults participated in a 6-week controlled feeding intervention involving hypocaloric diets, which comprised approximately 75% of their energy expenditure. The KD groups were divided into two: the first group received ketone salt (KD + KS; n = 12) twice daily, while the second group received a mineral-free, flavor-matched placebo (KD + PL; n = 13) [ 76 ]. Additionally, a third group of age- and BMI-matched adults was subsequently assigned to the isoenergetic low-fat diet (LFD; n = 12) for comparison with the KD. Mood assessments were conducted using the abbreviated Profile of Mood States and Visual Analog Mood Scale questionnaires. A noteworthy interaction between diet and time was observed regarding depression scores. Specifically, the results indicated that the KD + PL group exhibited higher depression scores compared to the KD + KS group at week 2. While there was a non-significant increase in depression scores for the LFD group at week 4, it's important to note that throughout the study, the KD + KS group consistently demonstrated lower depression scores compared to the other groups [ 76 ••].

A substantial non-randomized, open-label investigation examined alterations in depressive symptoms over 2 years among 262 predominantly non-depressed individuals with Type 2 diabetes. These participants engaged in a continuous remote care intervention focused on carbohydrate restriction. Subclinical depressive symptoms declined within the initial 10 weeks and persisted for up to 2 years. This study suggests that an increase in blood ketone levels, which serve as a marker for adherence to a low-carbohydrate diet, is associated with a reduction in depressive symptoms [ 77 ••].

The ketogenic diet reveals an intriguing intersection between metabolic health and psychiatric conditions. The synthesis of evidence from preclinical studies, case reports, and clinical trials underscores the potential of dietary interventions as a treatment for mood disorders.

Central to the discussion is the ketogenic diet's mechanistic underpinnings, which suggest a multifaceted approach to mitigating mood disorder pathology. Mitochondrial dysfunction, inflammation, oxidative stress, and insulin resistance are key biological mechanisms implicated in the etiology of mood disorders. The ketogenic diet's ability to enhance mitochondrial function, reduce inflammation and oxidative stress, and improve insulin sensitivity presents a novel pathway through which dietary interventions can impact psychiatric health. Notably, the diet's efficacy in epilepsy—a condition with established therapeutic overlaps with mood disorders—further validates the potential translational benefits of this dietary approach to mental health.

The evidence presented in this review, particularly from case reports and series, indicates variable yet promising outcomes for individuals with bipolar disorder and major depressive disorder. While some case reports illustrate remarkable improvements in mood stabilization, cognitive function, and overall quality of life, others highlight the challenges and limitations, including adherence to the diet and variability in response. These findings underscore the necessity for individualized assessment and monitoring when considering the ketogenic diet as a treatment for mood disorders.

Clinical trials add a layer of rigor to the evaluation of the ketogenic diet's impact on mood disorders, with studies showing improvements in mood, energy levels, and metabolic health biomarkers. These trials, however, also emphasize the importance of monitoring for potential adverse effects and the need for further research to optimize dietary protocols and identify patient populations most likely to benefit.

The growing body of evidence supporting the ketogenic diet's role in mood disorder treatment aligns with a broader shift towards integrative approaches in psychiatry, which encompass lifestyle and dietary modifications alongside conventional pharmacotherapy and psychotherapy. This holistic perspective acknowledges the complex interplay between brain function and metabolic health, offering a more comprehensive approach to mental health care.

The ketogenic diet presents a promising, albeit preliminary, treatment for mood disorders. The diet's potential to address key pathological mechanisms common to both mood disorders and metabolic dysregulation warrants further investigation. Future research should focus on larger, well-designed clinical trials to confirm these preliminary findings, elucidate mechanisms of action, and identify predictive markers of response to dietary interventions. Ultimately, the integration of dietary strategies into mental health care could offer a more nuanced and personalized approach to treating mood disorders, potentially improving outcomes for individuals for whom conventional treatments are insufficient.

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E.O. wrote the draft of the manuscript and prepared the tables and V.C. and C.P. reviewed and edited the manuscript. All authors contributed studies for inclusion in this review.

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Neurotrophic factor levels and executive functions in children of parents with bipolar disorder: A case controlled study

Affiliations.

• 1 Department of Child and Adolescent Psychiatry, Sivas Numune Hospital, Sivas, Turkey. Electronic address: [email protected].
• 2 Department of Child and Adolescent Psychiatry, Diamind Zihin Akademisi, Konya, Turkey.
• 3 Department of Biochemistry, School of Medicine Selçuk University, Konya, Turkey.
• 4 Department of Child and Adolescent Psychiatry, Konya City Hospital, Konya, Turkey.
• 5 Department of Child and Adolescent Psychiatry, School of Medicine Selçuk University, Konya, Turkey.
• 6 Department of Psychiatry, Special Clinic, Konya, Turkey.
• PMID: 38795781
• DOI: 10.1016/j.jad.2024.05.112

Background: In the current study, it was aimed to evaluate neurotrophic factor levels and their relationship with executive functions in high-risk children and adolescents (high-risk group) whose parents were diagnosed with bipolar disorder (BD) but not affected by any psychiatric disease,and in order to determine possible vulnerability factors related to the disease.

Methods: The study sample consisted of 32 high-risk group and 34 healthy controls. The Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version-Turkish Adaptation (KSADS-PL-T), Stroop Test, Serial Digit Learning Test (SDLT) and Cancellation Test to evaluate executive functions were administered to all participants by the clinician.Serum levels of neurotrophic factors were measured using commercial enzyme linked immunosorbent assay kits.

Results: Serum BDNF, NT-3, NT-4 levels and SDLT scores were significantly lower in the high-risk group for BD compared to the healthy control group. A moderate negative correlation was found between BDNF levels and the Cancellation Test scores in the high-risk group. In addition to these results, the odds ratios of age, NT-4, SDLT scores for being in the risky group in terms of BD diagnosis were 1.26, 0.99 and 0.86 respectively.

Limitations: This was a cross-sectional study. Causality between study results is therefore difficult to establish. The relatively small sample size of the study is another limitation.

Conclusion: The results of the present study suggest that BDNF, NT-3, NT-4 may play a role in the physiopathology of BD and may be associated with impaired executive function areas such as attention and response inhibition in the high-risk group.

Keywords: Bipolar offspring; Executive function; High-risk group; Neurotrophic factor.

Copyright © 2024 Elsevier B.V. All rights reserved.

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Stress, Dysregulation of Rhythms, and Bipolar Disorder: A Challenging Field of Research

Mauro giovanni carta.

1 Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy; moc.liamg@atracgoruam

Elie Georges Karam

2 St. George Hospital University Medical Center, University of Balamand, Beirut 11002807, Lebanon; gro.caardi@marakge

Giulia Cossu

Clarifying the mechanisms by which circadian rhythms regulate biology is a central issue in directing life choices in the immediate future and presents an interesting challenge for current scientific research. The importance of this research aspect is well established by the Nobel Prize in Physiology and Medicine awarded in 2017 to Hall, Rosbash, and Young, who uncovered key elements of biological rhythm systems, including those in human bodies. Specifically, their work demonstrated how the biological rhythms of the body align with the Earth’s rhythms.

The internal coordination of physiological and behavioral activities with daily environmental variations is regulated by 24-h ‘circadian’ cycles [ 1 ]. Misalignment of the circadian clock alters the sleep–wake cycle, resulting in ineffective responses to environmental cues. It has been hypothesized that the abnormal division of cancer cells is also linked to disruptions in circadian rhythms, and associations have been found between changes in circadian rhythms and some cancers [ 2 , 3 ], with a specific role noted for light pollution in breast cancer [ 4 ]. Dysregulation of circadian rhythms has also been identified as a risk factor for cardiovascular diseases, obesity, asthma, and diabetes [ 5 , 6 ]. Indeed, both internal and external signals influence the clock, but light is the most significant factor [ 1 ].

It is known that sleep rhythm is a central element in both bipolar disorders and in individuals with hyperactivity and high energy levels, even in the absence of mood disorders [ 7 , 8 ]. Thus, misalignment of personal and social rhythms—such as those for sleeping, eating, and social commitments and contacts, which are closely connected with circadian biorhythms—has been associated with what is called ‘the spectrum of bipolar disorders’. In a neo-Kraepelinian view, the term ‘bipolar spectrum’ refers to a pyramid of conditions. At the apex are the most severe forms of bipolar disorders, and at the base are many individuals characterized by hyperactivity, high energy, and a tendency for novelty-seeking, but without clear mood disorder connotations. In the middle, moving towards the apex, are all the vulnerability scenarios with sub-clinical symptoms that transition into mood disorders ranging from the mildest to the most severe, including depression, impulse control disorders, mood swings, anxiety disorders, personality disorders, and substance abuse disorders [ 9 , 10 , 11 , 12 , 13 , 14 ]. In this perspective, various temperaments could represent sub-clinical forms of bipolar disorder or simply be a risk factor for them [ 15 , 16 ].

There is evidence of vulnerability in the spectrum of bipolar disorders towards triggers capable of altering social rhythms and biorhythms. Light pollution has been found to be associated with a high prevalence of hypomania in megacities and may even play a role in the genesis of these disorders [ 17 , 18 , 19 , 20 , 21 ]. Socio-economic and cultural changes in current lifestyles have led to substantial modifications in light patterns, which may be one of the causes for the increase in bipolar disorders in our society, or at least for a paradoxical stability over time for such a strongly disadvantageous disease. This suggests that, at least the sub-threshold forms of the bipolar spectrum, have an adaptive connotation in modern life [ 20 ].

This perspective transcends the standard nosographic categorical approach to studying the continuum of hyperthymic traits and attitudes that can be adaptive depending on external stimuli, thus embracing a dimensional approach that can also improve the characterization of prodromal symptoms and assess symptomatology. In fact, it has been found that non-pathological personality characteristics and traits of hyper-energy/hyperactivity (without any diagnoses of mood disorders) frequently have genetic variants associated with bipolar disorder. That is, those genetic characteristics would not be typical of bipolar disorder “itself” but of hyper-energy/hyperactivity and novelty-seeking traits, including in people with the disorder as a sort of “tip of the iceberg” [ 22 , 23 , 24 , 25 ].

According to this approach, the onset of a case of bipolar disorder could be attributed to the convergence of genetic variants associated with hyper-energy and hyperactivity, in association with certain types of stress conditions in different life phases, particularly those of heightened vulnerability [ 26 , 27 , 28 ].

The recent pandemics and the subsequent implementation of lockdowns in several countries have inadvertently subjected people to a kind of environmental experiment, which has altered many risk factors for bipolar spectrum disorders, creating a convergence of stressors and the dysregulation of social and biological rhythms [ 29 , 30 ].

This framework has led to the following observations:

Older adults with dysregulation of social and personal rhythms before the pandemic and lockdown were found to be at risk for depressive episodes during the lockdown [ 31 , 32 ].

Stricter lockdown measures triggered more depressive episodes in people with bipolar disorders compared to less strict lockdown measures in two geographically proximate cities (i.e., Cagliari, Italy vs. Tunis, Tunisia) [ 33 ]. Healthcare workers, who were under significant pressure due to the pandemic and had more dysregulation of personal and social rhythms, were found to be at greater risk for burnout syndrome and mood disorders [ 34 , 35 , 36 , 37 ]. The dysregulation of social rhythms negatively impacts the course and outcomes of chronic diseases and immune responses [ 38 , 39 ].

The attention to the misalignment of personal rhythms related to stress has prompted reflection on the observation that individuals with a positive score on screening instruments designed for bipolar disorder, such as the Mood Disorder Questionnaire (MDQ), have been found to exhibit dysregulation of personal rhythms, particularly in relation to sleep [ 40 , 41 , 42 , 43 ]. In fact, the MDQ was considered useless by many researchers as a screening tool because it identified too many false positives [ 44 , 45 ]. Some researchers have suggested that it may be the diagnostic criteria for bipolar disorder itself that set too high a standard, and that a positive MDQ score may identify a clinically significant spectrum that is closely associated with bipolar disorder [ 46 ]. Indeed, MDQ positivity has been found to be associated with low levels of health-related quality of life, even in individuals without psychiatric diagnoses [ 46 ].

This line of research has led to the hypothesis of the existence of three different levels of hyperactivation/hyper-energy (ranging from normality to pathology) [ 47 , 48 ].

The first level represents an adaptive increase in energy, as observed in athletes achieving excellent results [ 49 ]. The second level is characterized by strong and prolonged stimulation of stress hormones and is identified by a positive score on the MDQ (without the individual receiving a diagnosis of bipolar disorder), as seen in healthcare workers experiencing burnout syndromes.

The third, most severe level involves hyperactivity/hyper-energy during manic episodes [ 47 , 48 ].

Consequently, a dysregulation of mood, energy, and social rhythms syndrome (DYMERS), corresponding to the second level of the ranking, has been proposed as a hypothesis. This perspective views DYMERS as a vulnerable condition that could potentially evolve into other disorders, with a significant risk for bipolar disorder, among others. The nature of this evolution is determined by individual-specific susceptibility based on genetic profiles and specific sensitivity to particular stresses arising from gene–environment interactions [ 47 , 48 ].

• Conclusions

The scenario outlined in our discussion of current research on stress, dysregulation of rhythms, and the bipolar spectrum provides fertile ground for future investigation. This Special Issue aims to contribute to this field, offering an important step forward and serving as a stimulus for future research endeavors in the years to come. While our contribution may not provide conclusive answers at present, it undoubtedly represents a significant advancement in our understanding of these complex issues.

Funding Statement

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

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Depression, schizophrenia and bipolar disorder linked with ancient viral DNA in our genome – new research

Research Fellow, King's College London

Professor of Immunology in Medicine, Cornell University

Senior lecturer, King's College London

Disclosure statement

Rodrigo Duarte received funding from the National Institutes of Health, USA.

Douglas Nixon receives funding from the National Institutes of Health, USA.

Timothy Powell receives funding from the National Institute for Health and Care Research, the National Institutes of Health, and the Medical Research Council.

King's College London provides funding as a member of The Conversation UK.

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Around 8% of human DNA is made up of genetic sequences acquired from ancient viruses . These sequences, known as human endogenous retroviruses (or Hervs), date back hundreds of thousands to millions of years – with some even predating the emergence of Homo sapiens .

Our latest research suggests that some ancient viral DNA sequences in the human genome play a role in susceptibility to psychiatric disorders such as schizophrenia, bipolar disorder and major depressive disorder.

Hervs represent the remnants of these infections with ancient retroviruses. Retroviruses are viruses that insert a copy of their genetic material into the DNA of the cells they infect. Retroviruses probably infected us on multiple occasions during our evolutionary past. When these infections occurred in sperm or egg cells that generated offspring, the genetic material from these retroviruses was passed on to subsequent generations , becoming a permanent part of our lineage.

Initially, scientists considered Hervs to be “junk DNA” – parts of our genome with no discernible function. But as our understanding of the human genome has advanced, it’s become evident that this so-called junk DNA is responsible for more functions than originally hypothesised.

First, researchers found that Hervs can regulate the expression of other human genes. A genetic feature is said to be “expressed” if its DNA segment is used to produce RNA (ribonucleic acid) molecules. These RNA molecules can then serve as intermediaries leading to the production of specific proteins , or help to regulate other parts of the genome .

Initial research suggested that Hervs regulate the expression of neighbouring genes with important biological functions. One example of this is a Herv that regulates the expression of a gene involved in modifying connections between brain cells.

Hervs have also been found to produce RNAs and even proteins in blood and brain samples . These molecules have the potential to exert a wide range of functions, as they can travel across cellular compartments to execute different roles.

Scientists have also found evidence suggesting certain human genes are derived from Hervs. This indicates there were instances during evolution where Hervs were co-opted for specialised biological functions. For example, the human genes syncytins 1 and 2, which are derived from Hervs, play pivotal roles in placental development .

HERVs in psychiatric disorders

Considering the abundance of Hervs in the genome and their potentially numerous functions, we wanted to better understand whether genetic susceptibility to certain psychiatric disorders was associated with differences in Herv expression.

In our study , we profiled Herv expression in nearly 800 autopsy brain samples. This helped us identify DNA variations that influenced Herv expression in the brain.

We then cross-referenced this information with findings from large genetic studies which had compared genetic differences between tens of thousands of people – both with and without mental health conditions. These studies identified variations in DNA associated with different psychiatric conditions.

We found that that the expression of four Hervs was linked with genetic susceptibility to major psychiatric disorders. The expression of two of these Hervs was associated with schizophrenia, one Herv with both schizophrenia and bipolar disorder, and one with depression. These results suggest that Hervs may be playing a more important role in the brain than initially thought.

Read more: Discovering how genetic 'dark matter' plays a role in mental illness is just the tip of the iceberg for human health

There are many genes involved in psychiatric disorders – and Hervs are only a part of this puzzle. Although the precise impact of these Hervs on brain cells and on a person’s susceptibility to certain psychiatric disorders requires further research, our study is the first to show that genetic susceptibility for a psychiatric disorder also acts through these ancient viral DNA sequences.

It’s still too early to determine the practical applications of our findings – and whether they might be used to develop new treatments. But we’re optimistic about this line of research. By linking Herv expression in the brain with psychiatric disorders, our research recognises the importance of these mysterious sequences in the human genome, which have been ignored for years.

• Schizophrenia
• Bipolar disorder
• Retroviruses
• Psychiatric disorders

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