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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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Ethics Commentary: Ethical Issues in Bipolar Disorder: Three Case Studies
- Laura Weiss Roberts , M.D., M.A.
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Sound ethical decision making is essential to astute and compassionate clinical care. Wise practitioners readily identify and reflect on the ethical aspects of their work. They engage, often intuitively and without much fuss, in careful habits—in maintaining therapeutic boundaries, in seeking consultation from experts when caring for difficult or especially complex patients, in safeguarding against danger in high-risk situations, and in endeavoring to understand more about mental illnesses and their expression in the lives of patients of all ages, in all places, and from all walks of life. These habits of thought and behavior are signs of professionalism and help ensure ethical rigor in clinical practice.
Psychiatry is a specialty of medicine that, by its nature, touches on big moral questions. The conditions we treat often threaten the qualities that define human beings as individual, as autonomous, as responsible, as developing, and as fulfilled. The conditions we treat often are characterized by great suffering, disability, and stigma, and yet individuals with these conditions demonstrate such tremendous adaptation and strength as well. If all work by physicians is ethically important, then our work is especially so.
As a service to FOCUS readers, in this column we endeavor to provide ethics commentary on topics in clinical psychiatry. We also proffer clinical ethics questions and expert answers in order to sharpen readers’ decision-making skills and advance astute and compassionate clinical care in our field.
Ms. Genera is a 36-year-old woman with bipolar II disorder, first diagnosed in college, who is brought to the psychiatric emergency room by her boyfriend of 5 years. He is hoping that she will be admitted to the hospital “before she goes all-the-way manic.” He reports that she “almost lost her job last time!”
Over the past 6 weeks, he reports that Ms. Genera has needed “less and less” sleep, has been cleaning the house “around the clock,” and has “wanted a lot of sex even though she is really pissed off all of the time.” The patient states that she is “fine, more than fine, in fact.” She says that she has not been able to sleep “because of the neighbors.” She says that they talk loudly at night and that she and the baby will “fix that” because babies are “noisy at night too!” Her boyfriend is confused by this comment, saying that they have no children—“I don’t know why she says stuff like that. I know it’s the manic-depressive, but it is pretty crazy.” Ms. Genera states that her thoughts are like “O’Hare airport!” and that she has “no problem keeping up” with the different “planes coming and going.” The patient says that she stopped taking all of her medications about 3 months ago—“That lithium is really hard on me. I don’t like to take it unless I have to.” She has no history of alcohol or other substance use, no history of suicide attempts, and no history of dangerousness toward others.
On mental status exam, Ms. Genera is a neatly dressed, mildly overweight woman who appears slightly older than her stated age. She is cooperative with the clinical interview and asks that her boyfriend step out of the room when she is talking with the doctor. She is speaking quickly and loudly, with appropriate affect. Her thought form is linear. She denies hallucinations and reports no thoughts of self-harm.
Ms. Genera says that she has “Bipolar II, not Bipolar I—I don’t have it that bad. Never have. Yessirree, I am really good right now.” She does not want to be admitted to the hospital, despite her boyfriend’s request, but volunteers that she will go to an ambulatory care appointment with her psychiatrist on the next day.
——1.3 The psychiatrist arranges to speak with Ms. Genera alone during the clinical interview.
——1.4 The psychiatrist respects the patient’s preference not to be admitted to the hospital.
——1.5 The psychiatrist recommends diagnostic tests to occur at the time of the emergency evaluation.
——1.6 The psychiatrist sits with the patient’s boyfriend to offer emotional support and “a listening ear” after the clinical interview with the patient is completed.
——1.7 The psychiatrist documents accurately in the electronic medical record the full set of concerns raised by the patient and her boyfriend.
A resident in internal medicine with a well-established diagnosis of bipolar I disorder volunteers for a clinical trial that will test a new combination of medications and also involve two neuroimaging studies. The resident discusses the trial with his psychiatrist, who discourages the idea, stating that he has been concerned about the resident-patient, given the stresses of training and the severity of his illness. The resident responds, “Hey, Doc—get real! How often can you get $500—plus a brain scan, let alone TWO—free of charge?!” He decides to undergo screening for the clinical trial because he thinks he might benefit medically from an imaging test.
The resident knows that the trial will involve a washout period, so he decides to taper his medications in advance of the “official” enrollment date, 3 weeks away, which coincides with a planned vacation. Without medication, the resident becomes increasingly symptomatic. He has difficulty concentrating, becomes easily upset with team members, and develops progressively more erratic sleep. He was seen standing on the roof of the academic hospital and confided in a roommate that he was “tired of it all.”
Although he originally met criteria for the project, by the time of enrollment he had become too ill to enter the study. The psychiatrist-investigator permitted him to have the baseline neuroimaging study but did not allow the resident to progress to the full clinical trial. The resident returned to his apartment for his weeklong vacation. On the day he was scheduled to return to his training program, he did not turn up.
An 18-year-old male previously diagnosed with bipolar disorder is brought by his best friend to the emergency department of a rural hospital located near a ski area. The best friend reports that the patient “is completely wild—he just won’t stop—he’s going to kill himself on the slopes!”
The patient was first diagnosed when he experienced a “flat out manic” episode at age 13 years; he has been stable and doing well on lithium. He has a psychiatrist and therapist “back home,” although he will not provide their names.
The patient confided to his best friend that he “secretly” stopped his lithium recently, and the best friend states that the patient has been using alcohol. (“He says, ‘I like to get high while I’m high.’ ”) The patient is on vacation with his grandparents, two younger siblings, and the best friend.
The patient shows evidence of intoxication and is irritable but cooperative during the initial interview in the emergency department. His vitals are within normal limits and are stable. No abnormalities are found on physical examination.
While waiting to be seen, the patient appears to “sober up.” He is calm, pleasant, and respectful and thanks his friend and the emergency staff for helping him. He appears embarrassed. No abnormalities are found on mental status examination. The patient refuses a drug or urine test, and he refuses to allow the emergency physician to contact his grandparents or parents. The emergency physician calls a psychiatrist for consultation, which the patient declines.
Laura Weiss Roberts, M.D., M.A., Professor, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA
Dr. Roberts reports: Owner, Investigator: Terra Nova Learning Systems
Srivastava S : Ethical considerations in the treatment of bipolar disorder . Focus ( Fall ); 9(4):461–464. Link , Google Scholar
Roberts LW, Hoop JG : Professionalism and Ethics: Q & A Self-Study Guide for Mental Health Professionals . Washington, DC, American Psychiatric Publishing, 2008 . Google Scholar
Roberts LW, Dyer A : A Concise Guide to Ethics in Mental Health Care . Washington, DC, American Psychiatric Publishing, 2004 . Google Scholar
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Bipolar Disorder
What is bipolar disorder.
Bipolar disorder (formerly called manic-depressive illness or manic depression) is a mental illness that causes unusual shifts in a person’s mood, energy, activity levels, and concentration. These shifts can make it difficult to carry out day-to-day tasks.
There are three types of bipolar disorder. All three types involve clear changes in mood, energy, and activity levels. These moods range from periods of extremely “up,” elated, irritable, or energized behavior (known as manic episodes) to very “down,” sad, indifferent, or hopeless periods (known as depressive episodes). Less severe manic periods are known as hypomanic episodes.
- Bipolar I disorder is defined by manic episodes that last for at least 7 days (nearly every day for most of the day) or by manic symptoms that are so severe that the person needs immediate medical care. Usually, depressive episodes occur as well, typically lasting at least 2 weeks. Episodes of depression with mixed features (having depressive symptoms and manic symptoms at the same time) are also possible. Experiencing four or more episodes of mania or depression within 1 year is called “rapid cycling.”
- Bipolar II disorder is defined by a pattern of depressive episodes and hypomanic episodes. The hypomanic episodes are less severe than the manic episodes in bipolar I disorder.
- Cyclothymic disorder (also called cyclothymia) is defined by recurring hypomanic and depressive symptoms that are not intense enough or do not last long enough to qualify as hypomanic or depressive episodes.
Sometimes a person might experience symptoms of bipolar disorder that do not match the three categories listed above, and this is referred to as “other specified and unspecified bipolar and related disorders.”
Bipolar disorder is often diagnosed during late adolescence (teen years) or early adulthood. Sometimes, bipolar symptoms can appear in children. Although the symptoms may vary over time, bipolar disorder usually requires lifelong treatment. Following a prescribed treatment plan can help people manage their symptoms and improve their quality of life.
What are the signs and symptoms of bipolar disorder?
People with bipolar disorder experience periods of unusually intense emotion and changes in sleep patterns and activity levels, and engage in behaviors that are out of character for them—often without recognizing their likely harmful or undesirable effects. These distinct periods are called mood episodes. Mood episodes are very different from the person’s usual moods and behaviors. During an episode, the symptoms last every day for most of the day. Episodes may also last for longer periods, such as several days or weeks.
Sometimes people have both manic and depressive symptoms in the same episode, and this is called an episode with mixed features. During an episode with mixed features, people may feel very sad, empty, or hopeless while at the same time feeling extremely energized.
A person may have bipolar disorder even if their symptoms are less extreme. For example, some people with bipolar II disorder experience hypomania, a less severe form of mania. During a hypomanic episode, a person may feel very good, be able to get things done, and keep up with day-to-day life. The person may not feel that anything is wrong, but family and friends may recognize changes in mood or activity levels as possible symptoms of bipolar disorder. Without proper treatment, people with hypomania can develop severe mania or depression.
Receiving the right diagnosis and treatment can help people with bipolar disorder lead healthy and active lives. Talking with a health care provider is the first step. The health care provider can complete a physical exam and other necessary medical tests to rule out other possible causes. The health care provider may then conduct a mental health evaluation or provide a referral to a trained mental health care provider, such as a psychiatrist, psychologist, or clinical social worker who has experience in diagnosing and treating bipolar disorder.
Mental health care providers usually diagnose bipolar disorder based on a person’s symptoms, lifetime history, experiences, and, in some cases, family history. Accurate diagnosis in youth is particularly important.
Find tips to help prepare for and get the most out of your visit with your health care provider.
Bipolar disorder and other conditions
Many people with bipolar disorder also have other mental disorders or conditions such as anxiety disorders , attention-deficit/hyperactivity disorder (ADHD) , misuse of drugs or alcohol , or eating disorders. Sometimes people who have severe manic or depressive episodes also have symptoms of psychosis , which may include hallucinations or delusions. The psychotic symptoms tend to match the person’s extreme mood. For example, someone having psychotic symptoms during a depressive episode may falsely believe they are financially ruined, while someone having psychotic symptoms during a manic episode may falsely believe they are famous or have special powers.
Looking at a person’s symptoms over the course of the illness and examining their family history can help a health care provider determine whether the person has bipolar disorder along with another disorder.
What are the risk factors for bipolar disorder?
Researchers are studying possible causes of bipolar disorder. Most agree that there are many factors that are likely to contribute to a person’s chance of having the disorder.
Brain structure and functioning: Some studies show that the brains of people with bipolar disorder differ in certain ways from the brains of people who do not have bipolar disorder or any other mental disorder. Learning more about these brain differences may help scientists understand bipolar disorder and determine which treatments will work best. At this time, health care providers base the diagnosis and treatment plan on a person’s symptoms and history, rather than brain imaging or other diagnostic tests.
Genetics: Some research suggests that people with certain genes are more likely to develop bipolar disorder. Research also shows that people who have a parent or sibling with bipolar disorder have an increased chance of having the disorder themselves. Many genes are involved, and no one gene causes the disorder. Learning more about how genes play a role in bipolar disorder may help researchers develop new treatments.
How is bipolar disorder treated?
Treatment can help many people, including those with the most severe forms of bipolar disorder. An effective treatment plan usually includes a combination of medication and psychotherapy, also called talk therapy.
Bipolar disorder is a lifelong illness. Episodes of mania and depression typically come back over time. Between episodes, many people with bipolar disorder are free of mood changes, but some people may have lingering symptoms. Long-term, continuous treatment can help people manage these symptoms.
Certain medications can help manage symptoms of bipolar disorder. Some people may need to try different medications and work with their health care provider to find the medications that work best.
The most common types of medications that health care providers prescribe include mood stabilizers and atypical antipsychotics. Mood stabilizers such as lithium or valproate can help prevent mood episodes or reduce their severity. Lithium also can decrease the risk of suicide. Health care providers may include medications that target sleep or anxiety as part of the treatment plan.
Although bipolar depression is often treated with antidepressant medication, a mood stabilizer must be taken as well—taking an antidepressant without a mood stabilizer can trigger a manic episode or rapid cycling in a person with bipolar disorder.
Because people with bipolar disorder are more likely to seek help when they are depressed than when they are experiencing mania or hypomania, it is important for health care providers to take a careful medical history to ensure that bipolar disorder is not mistaken for depression.
People taking medication should:
- Talk with their health care provider to understand the risks and benefits of the medication.
- Tell their health care provider about any prescription drugs, over-the-counter medications, or supplements they are already taking.
- Report any concerns about side effects to a health care provider right away. The health care provider may need to change the dose or try a different medication.
- Remember that medication for bipolar disorder must be taken consistently, as prescribed, even when one is feeling well.
It is important to talk to a health care provider before stopping a prescribed medication. Stopping a medication suddenly may lead symptoms to worsen or come back. You can find basic information about medications on NIMH's medications webpage . Read the latest medication warnings, patient medication guides, and information on newly approved medications on the Food and Drug Administration (FDA) website.
Psychotherapy
Psychotherapy, also called talk therapy, can be an effective part of treatment for people with bipolar disorder. Psychotherapy is a term for treatment techniques that aim to help people identify and change troubling emotions, thoughts, and behaviors. This type of therapy can provide support, education, and guidance to people with bipolar disorder and their families.
Cognitive behavioral therapy (CBT) is an important treatment for depression, and CBT adapted for the treatment of insomnia can be especially helpful as part of treatment for bipolar depression.
Treatment may also include newer therapies designed specifically for the treatment of bipolar disorder, including interpersonal and social rhythm therapy (IPSRT) and family-focused therapy.
Learn more about the various types of psychotherapies .
Other treatment options
Some people may find other treatments helpful in managing their bipolar symptoms:
- Electroconvulsive therapy (ECT) is a brain stimulation procedure that can help relieve severe symptoms of bipolar disorder. Health care providers may consider ECT when a person’s illness has not improved after other treatments, or in cases that require rapid response, such as with people who have a high suicide risk or catatonia (a state of unresponsiveness).
- Repetitive transcranial magnetic stimulation (rTMS) is a type of brain stimulation that uses magnetic waves to relieve depression over a series of treatment sessions. Although not as powerful as ECT, rTMS does not require general anesthesia and has a low risk of negative effects on memory and thinking.
- Light therapy is the best evidence-based treatment for seasonal affective disorder (SAD) , and many people with bipolar disorder experience seasonal worsening of depression or SAD in the winter. Light therapy may also be used to treat lesser forms of seasonal worsening of bipolar depression.
Unlike specific psychotherapy and medication treatments that are scientifically proven to improve bipolar disorder symptoms, complementary health approaches for bipolar disorder, such as natural products, are not based on current knowledge or evidence. Learn more on the National Center for Complementary and Integrative Health website .
Finding treatment
- A family health care provider is a good resource and can be the first stop in searching for help. Find tips to help prepare for and get the most out of your visit .
- To find mental health treatment services in your area, call the Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 1-800-662-HELP (4357), visit the SAMHSA online treatment locator , or text your ZIP code to 435748.
- Learn more about finding help on the NIMH website.
If you or someone you know is struggling or having thoughts of suicide, call or text the 988 Suicide & Crisis Lifeline at 988 or chat at 988lifeline.org . In life-threatening situations, call 911.
Coping with bipolar disorder
Living with bipolar disorder can be challenging, but there are ways to help make it easier.
- Work with a health care provider to develop a treatment plan and stick with it. Treatment is the best way to start feeling better.
- Follow the treatment plan as directed. Work with a health care provider to adjust the plan, as needed.
- Structure your activities. Try to have a routine for eating, sleeping, and exercising.
- Try regular, vigorous exercise like jogging, swimming, or bicycling, which can help with depression and anxiety, promote better sleep, and support your heart and brain health.
- Track your moods, activities, and overall health and well-being to help recognize your mood swings.
- Ask trusted friends and family members for help in keeping up with your treatment plan.
- Be patient. Improvement takes time. Staying connected with sources of social support can help.
Long-term, ongoing treatment can help control symptoms and enable you to live a healthy life.
How can I find a clinical trial for bipolar disorder?
Clinical trials are research studies that look at new ways to prevent, detect, or treat diseases and conditions. The goal of clinical trials is to determine if a new test or treatment works and is safe. Although individuals may benefit from being part of a clinical trial, participants should be aware that the primary purpose of a clinical trial is to gain new scientific knowledge so that others may be better helped in the future.
Researchers at NIMH and around the country conduct many studies with patients and healthy volunteers. We have new and better treatment options today because of what clinical trials uncovered years ago. Be part of tomorrow’s medical breakthroughs. Talk to your health care provider about clinical trials, their benefits and risks, and whether one is right for you.
To learn more or find a study, visit:
- NIMH’s Clinical Trials webpage : Information about participating in clinical trials
- Clinicaltrials.gov: Current Studies on Bipolar Disorder : List of clinical trials funded by the National Institutes of Health (NIH) being conducted across the country
- Join a Study: Bipolar Disorder – Adults : List of studies being conducted on the NIH Campus in Bethesda, MD
Where can I learn more about bipolar disorder?
Free brochures and shareable resources.
- Bipolar Disorder : A brochure on bipolar disorder that offers basic information on signs and symptoms, treatment, and finding help. Also available en español .
- Bipolar Disorder in Children and Teens : A brochure on bipolar disorder in children and teens that offers basic information on signs and symptoms, treatment, and finding help. Also available en español .
- Bipolar Disorder in Teens and Young Adults: Know the Signs : An infographic presenting common signs and symptoms of bipolar disorder in teens and young adults. Also available en español .
- Shareable Resources on Bipolar Disorder : Digital resources, including graphics and messages, to help support bipolar disorder awareness and education.
- NIMH Experts Discuss Bipolar Disorder in Adults : Learn the signs and symptoms, risk factors, treatments of bipolar disorder, and the latest NIMH-supported research in this area.
- Mental Health Minute: Bipolar Disorder in Adults : A minute-long video to learn about bipolar disorder in adults.
- NIMH Expert Discusses Bipolar Disorder in Adolescents and Young Adults : A video with an expert who explains the signs, symptoms, and treatments of bipolar disorder.
Research and Statistics
- Journal Articles : This webpage provides information on references and abstracts from MEDLINE/PubMed (National Library of Medicine).
- Bipolar Disorder Statistics : An NIMH webpage that provides information on the prevalence of bipolar disorder among adults and adolescents.
Last Reviewed: February 2024
Unless otherwise specified, the information on our website and in our publications is in the public domain and may be reused or copied without permission. However, you may not reuse or copy images. Please cite the National Institute of Mental Health as the source. Read our copyright policy to learn more about our guidelines for reusing NIMH content.
Bipolar for Psychotherapists and Their Clients pp 95–162 Cite as
Difficult-to-Diagnose Case Studies of Bipolar Demonstrating Wide Variations in Presentations
- C. Raymond Lake 2
- First Online: 06 October 2023
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Seventy case studies help in the recognition of Bipolar across a wide range of severity from successful Bipolar II clients to grandiose, paranoid, and psychotic Bipolar individuals. Mental health workers and families of severe Bipolars are at risk, and recommendations of steps for increased safety are offered. The severely mentally ill are at highest risk for violence against themselves and others.
Psychotic Bipolar killers have been inappropriately found sane and guilty of murder by the legal community.
- Wide variations in bipolar presentations
- Case studies
- Grandiosity
- Political leaders
- Mental health workers
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Lake, C.R. (2023). Difficult-to-Diagnose Case Studies of Bipolar Demonstrating Wide Variations in Presentations. In: Bipolar for Psychotherapists and Their Clients. Springer, Cham. https://doi.org/10.1007/978-3-031-38750-0_4
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Study: Liraglutide safe, effective for weight loss in patients with stable bipolar disorder
by University of Cincinnati
A clinical trial led by University of Cincinnati researchers at the Lindner Center of HOPE found a drug was safe and effective for weight loss for patients with stable bipolar disorder.
The trial results were published in the Journal of Clinical Psychopharmacology .
Susan McElroy, MD, study primary investigator, said many effective bipolar medications have a side effect of weight gain and obesity, and abnormal eating behavior like binge eating is also common in these patients. At the same time, many weight loss drugs have a side effect of destabilizing mental illness, particularly in patients with bipolar disorder .
The trial tested a drug called liraglutide, part of a class of antidiabetic drugs called GLP-1 agonists that include the brand names Ozempic and Wegovy that also are used for weight loss.
"These drugs have some side effects, but their neuropsychiatric profile is benign," said McElroy, the Linda and Harry Fath endowed professor in the Department of Psychiatry & Behavioral Neuroscience in UC's College of Medicine and chief research officer at the Lindner Center of HOPE.
Over 40 weeks, a total of 60 patients with stable bipolar disorder who were obese or overweight were randomized to either receive liraglutide injections or a placebo. Every patient additionally received dietary counseling including recommendations about diet and exercise.
"The most important result was that the drug was efficacious for weight loss in individuals with stable bipolar disorder, and it was safe," McElroy said. "It did not destabilize the illness in any way, and we had no severe medical adverse effects either."
The researchers additionally found that liraglutide statistically reduced binge eating behavior based on self-reported data and significantly reduced patients' hemoglobin A1C, a measure of average blood sugar levels used to diagnose and manage prediabetes and diabetes.
McElroy said limitations of the study include its small sample size and a high dropout rate, although more patients on placebo dropped out compared to those taking liraglutide.
"A 40-week study for people with bipolar disorder is a long time, and if there was any sign of their illness destabilizing, we would terminate the study for safety reasons," she said. "More terminations for mood instability on placebo again indicates that we think at least in this population that the drug appeared safe for weight loss."
Other studies have found similar results of safe weight loss with no negative impacts on mental health in patients with schizophrenia. McElroy said she hopes to see more research into this class of drugs for people with mental disorders with or without obesity, in addition to more research in general at the intersection of mental illness and obesity.
"There are many, many studies on obesity with diabetes, obesity with heart disease , but there's very few studies on obesity with mental illness," she said. "It's just an area that is a wide open frontier."
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Case Scenario 1: Patient With Bipolar 1 Disorder Reports New Onset Movements
In this custom video series, experts share overall impressions of a female patient with bipolar 1 disorder who develops new onset movements suggesting tardive dyskinesia and the rationale for intervening with VMAT2 therapy.
EP: 1 . Case Scenario 1: Patient With Bipolar 1 Disorder Reports New Onset Movements
EP: 2 . Case Scenario 2: Patient With Tardive Dyskinesia Prescribed a VMAT2 Inhibitor
EP: 3 . Screening for Tardive Dyskinesia and Intervening With VMAT2 Inhibitors
Ep: 4 . assessing severity of tardive dyskinesia, ep: 5 . managing patients on antipsychotic therapy, ep: 6 . anticholinergic medications and impaired cognition, ep: 7 . vmat2 inhibitors for tardive dyskinesia, ep: 8 . treating tardive dyskinesia with a vmat2 inhibitor, ep: 9 . prevention and early detection of tardive dyskinesia.
EP: 10 . Expert Perspectives on Recognition and Management of Tardive Dyskinesia
Leslie L. Citrome, MD, MPH: Welcome to this Psychiatric Times Case-Based Psych Perspectives, expert perspectives on recognition and management of tardive dyskinesia. I am Dr. Leslie Citrome, clinical professor of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York. And joining me is Dr. Rose Mary Xavier, research scientist and psychiatric nurse practitioner with the University of North Carolina at Chapel Hill. Welcome.
Rose Mary Xavier, PhD, MS, RN, PMHNP-BC: Thank you. I am happy to be here.
Leslie L. Citrome, MD, MPH: I am happy to have this conversation here. It is very clinically relevant to our audience. The goal of our discussion today is to provide an overview of tardive dyskinesia, as well as offer insights into the management of this detrimental disease. Let’s start by reviewing a couple of case scenarios and try to figure this out. The first one is a patient with bipolar 1 disorder who reports new onset of movements. This is a 54-year-old woman who received a diagnosis of bipolar 1 disorder at the age of 32, after requiring hospitalization for an acute manic episode. She was started on lithium at that time. She relapsed at age 41 with a florid manic episode requiring psychiatric hospitalization, resulting in an atypical antipsychotic being added to her regimen. She presents for routine follow-up. Her only concern relates to feedback received from her husband. About 6 months ago, her husband began observing constant movement of both her hands while watching television in the living room. He had not seen these types of movements by her before, and they seemed to be increasing in degree. He also frequently asked her if she was chewing gum or if she had something in her eye. This case tells us something about a woman exposed to a dopamine receptor blocking agent, that is an antipsychotic, who develops abnormal movements after some delay. It did not happen right away, but over time they became noticeable. Dr. Xavier, what is your overall impression?
Rose Mary Xavier, PhD, MS, RN, PMHNP-BC: My impression of this case is focusing on the use of antipsychotic medications for treatment of mood disorders, or disorders other than a primary psychotic disorder. When, just reading through this case, there are several things that stand out. Now she is a 54-year-old female. When we look at the risk factors for development of tardive dyskinesia, there are several things that stand out from the studies that have been published. We know that female sex and that the duration of treatment with antipsychotic medications increase the risk for developing tardive dyskinesia. So here we have a 54-year-old female. She has been diagnosed with bipolar disorder. Even though she was started on treatment with lithium, she relapsed at the age of 41 when an atypical antipsychotic medication was added. That is a 13-year history of treatment with antipsychotic medications. And just thinking about, going back to the training period in recent times, we also think about old generation medications, so the first-generation medications would cause tardive dyskinesia. We do not often hear about atypical antipsychotics, but we have data coming in that show that just because a patient is on an atypical medication, it does not diminish the risk for TD [tardive dyskinesia]. The next thing that comes to us is the type of movements that this patient has had. When you look at the case history, we know it has been about 6 months. She has constant movement of both the hands which is increasing in degree progressively, and she has chewing gum type of moments, as well as there is something in her eyes. So talk about the blepharospasm that could occur with TD. She has 4 different types of moments that have been progressively increasing. So it’s a very interesting case, and I look forward to hearing what your thoughts are.
Leslie L. Citrome, MD, MPH: Well, you have highlighted the important points here. She has had a multi-year exposure to an atypical antipsychotic. Atypical antipsychotics today still block postsynaptic dopamine receptors, and we know that is a key ingredient in perhaps the causation of tardive dyskinesia. And her movements, which appeared over time, are delayed. So tardive dyskinesia, tardive delayed dyskinesia, abnormal movement. It all makes sense that that is what we are going to be thinking about in terms of a drug induced movement disorder with her. And I think you pointed out a very important aspect about our treatments today. Although we use atypical antipsychotics, most of the time, they still incur a risk for tardive dyskinesia. They are better in terms of other drug induced movement disorders dramatically, and we do not see as much drug induced Parkinsonism. For example, that rhythmic tremor that appears right after you start an antipsychotic with the shuffling gait or the rigidity, we see a lot less of that. But there is still this liability for tardive dyskinesia. Epidemiological studies tell us that perhaps the prevalence is a little lower with atypical antipsychotics, but it is certainly not zero. My concern with her though is that she is deriving significant benefit from her regimen currently. It is keeping her stable, euthymic. It is preventing the recurrence of mania, which is really devastating for her. It required hospitalization for example. And we know it is very disruptive to functioning. She needs her medicine. And one of the things we cannot really do is stop the antipsychotic. This is what has kept her stable. We need to look at interventions that will allow us to continue her ongoing treatment for her underlying psychiatric disorder. The option in my mind would be something like a VMAT2 [vesicular monoamine transporter type 2] inhibitor, of which two are approved by the FDA [Food and Drug Administration] for the treatment of tardive dyskinesia, which are added to a person's ongoing regimen. If the patient feels secure with their current long-standing regimen, and I'm comfortable with continuing it, and there is a real concern about relapse, that would be my option. And this ties in with our next case where we are going to talk about a patient with tardive dyskinesia who is prescribed a VMAT2 inhibitor.
Transcript edited for clarity.
Not All That Writhes Is Tardive Dyskinesia
Expert Perspectives on Recognition and Management of Tardive Dyskinesia
Varenicline and Tardive Dyskinesia in Schizophrenia
Patients With Tardive Dyskinesia Feel Unheard, Social Media Listens
Tardive Dyskinesia Facts and Figures
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Bipolar Disorder Symptoms and Traits
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Mania, depression, and in-between episodes
- Types of Symptoms
- Symptom Differences
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- Managing Symptoms
- Next in Bipolar Disorder Guide What Causes Bipolar Disorder?
Bipolar disorder causes periods of dramatically altered mood, behavior, and energy characterized by manic or hypomanic episodes, which are periods of elevated or irritated mood, and depressive episodes, dips in mood and energy, among other symptoms. How bipolar disorder presents can vary from person to person and can differ significantly between women and men.
This article examines the different types of bipolar disorder, how certain factors—including sex—can influence symptoms, and ways to manage the condition.
Antonio_Diaz / Getty Images
Sex & Gender
Verywell Health acknowledges that sex and gender are related concepts, but they are not the same. To reflect our sources accurately, this article uses terms like “female,” “male,” “woman,” and “man” as its sources use them.
Types of Bipolar Disorder Symptoms
When diagnosing bipolar disorder, healthcare providers categorize bipolar disorder cases into three major types :
Cyclothymic
Each type causes mood episodes; however, each has unique characteristics.
When screening for bipolar 1, a healthcare provider will ask if you’ve experienced at least one manic episode a week or more, during which your energy and mood were elevated most of the time for most days, or if the symptoms led to hospitalization. To be diagnosed, symptoms must not be substance induced. During periods of mania, you may:
- Become irritable or agitated
- Engage in more activities or riskier behaviors than usual
- Experience hallucinations, false beliefs, or delusions (in rare and severe cases)
- Experience inflated self-esteem or grandiosity
- Feel elated, like the “center of the world,” or abnormally giddy
- Have rapid and uncontrolled thoughts or talk without staying on topic
- Not require as much sleep or sleep less without feeling tired
Bipolar may also cause hypomanic episodes , which are less severe manic episodes that typically don’t last as long. They’re defined as at least four days of more moderate but disruptive symptoms.
Sometimes—but not always—bipolar 1 also causes depressive episodes in which everything feels “low.” Depressive episodes are characterized by symptoms lasting the majority of the day, most days for 14 days; signs include:
- Difficulty falling asleep, getting up earlier than usual, or sleeping more than usual
- Feelings of sadness; depressed mood
- Feelings of worthlessness or hopelessness
- Forgetfulness, talking slowly, or forgetting what you want to say
- Inability to concentrate
- Lack of energy
- Lack of motivation; loss of interest in activities
- Thoughts of death or suicide
In addition, bipolar 1 causes periods of no symptoms ( euthymic episodes ) as well as “mixed” episodes. As the name suggests, the latter are periods in which you have both depressive and manic symptoms. Some also experience “ rapid cycling ,” which is defined as having four or more mood episodes within a year.
Healthcare providers diagnose bipolar 2 disorder when you have at least one hypomanic episode and one depressive episode. Between these, people return to their baseline mood, behavior, and functions.
Manic episodes aren’t a feature, but the condition causes significant impacts on your social, personal, and professional life. Substance abuse problems are more prevalent with bipolar 2 disorder. As with bipolar 1, some experience rapid cycling.
When you have cyclothymic disorder, you experience frequent and rapid shifts between periods of hypomanic and depressive-like symptoms. Though these mood swings are dramatic, the symptoms are milder and don’t fulfill the criteria for full-blown mood episodes. To be diagnosed, your mood episodes must occur more than half the time over the course of two or more years without ever stopping for more than two months at a time.
Comorbid Conditions and Bipolar Symptoms
Certain mental health conditions are more likely to arise if you have bipolar disorder. These comorbidities (co-occurring conditions) include:
- Generalized anxiety disorder or panic disorder
- Eating, drug, or alcohol use disorders
- Attention hyperactivity stress disorder (ADHD)
These conditions worsen mood episode symptoms, which can also trigger them.
Bipolar Disorder Symptom Differences
Certain health conditions and lifestyle factors can influence the severity of bipolar disorder symptoms. They can trigger mood episodes, make them more severe, and get in the way of treatment. The most common of these include:
- Personal trauma : Traumatic life events, such as a divorce, child abuse, loss of a loved one, or financial problems can trigger or worsen bipolar episodes.
- Stress : Negative stress worsens symptoms and leads to shorter symptom-free periods.
- Sleep disruptions : Though sleep disruptions are features of bipolar disorder, insufficient sleep or interruptions to your sleeping patterns can also trigger or worsen symptoms.
- Substance use disorder : Substance use disorder (SUD) often accompanies bipolar disorder (especially bipolar 2). It can also aggravate symptoms and contribute to manic, hypomanic, and depressive episodes.
- Hormonal shifts : Changes in estrogen can influence this disorder in women, triggering or worsening mood during your menstrual cycle, postnatal period (after childbirth), and menopause.
- Thyroid disorders : Underactive thyroid (hypothyroidism) can cause more severe depressive symptoms and trigger manic episodes.
- Weather changes : Season or weather changes can impact bipolar disorder, and many cases are comorbid with seasonal affective disorder (SAD) .
- Mental health conditions : Anxiety and substance use disorder—which often occur together—can also make symptoms more severe, hinder treatment, and increase the chances of thinking about suicide.
- Health conditions : Obesity , type 2 diabetes, migraine, and cardiovascular diseases also often arise alongside bipolar disorder and can worsen some cases.
Men vs. Women
How bipolar disorder presents can also vary based on the sex assigned at birth. In a study of adults with bipolar 1, women were more likely to experience depressive episodes, whereas men were more likely to have manic episodes.
Other studies found that men had higher rates of rapid cycling and suicidal thoughts. As a result, bipolar disorder in women is more likely to be misdiagnosed as clinical depression.
Teens vs. Adults
There also are differences in how bipolar disorder presents based on age. In most cases, symptom onset occurs between 15 and 25. Though teenagers and adults can have manic, hypomanic, or depressive episodes, there are some differences in how these present.
In a wide-ranging review of the literature, researchers found adolescents are more likely to experience irritability and aggression—rather than giddiness—during manic or hypomanic episodes. In addition, children and teenagers are more likely to experience rapid cycling. Some studies found teenagers were more likely to have depressive episodes as the first sign of bipolar disorder.
Bipolar Disorder Traits and Signs in Other People
If your loved one has bipolar disorder—or if you suspect they do—it’s important to understand the signs someone else is having a mood episode.
Signs of Manic Episodes in Others
There are several signs that someone is having a manic or hypomanic episode. Traits that may be signs in others include:
- The person is unusually energetic, giddy, irritable, or cranky.
- The person talks faster than usual and changes topics more often.
- The person has an abnormally high appetite for food, sex, gambling, substances, alcohol, or other pleasurable activities.
- The person exhibits erratic or unusual behavior.
Signs of Depressive Episodes in Others
If someone is having a depressive episode, signs you may recognize include:
- The person has reduced their level of activity or displays a loss of interest in their favorite activities.
- The person withdraws from family or social events.
- The person speaks or moves more slowly or lacks focus on their tasks.
- The person eats less and experiences noticeable weight changes.
- The person has angry outbursts.
- The person forgets things more frequently or cannot perform daily tasks.
- The person regularly engages in negative self-talk, mentioning feelings of worthlessness or wanting to self-harm or commit suicide.
When to Call 911
If you or a loved one experiences suicidal thoughts, thoughts about hurting themself or others, hallucinations, delusions, or lithium toxicity symptoms, call 911. Lithium toxicity symptoms include nausea, vomiting, dizziness, vision changes, slurred speech, and tremors, among others.
Managing Bipolar Disorder Symptoms
Managing bipolar disorder symptoms can involve medications, psychotherapy and counseling, and lifestyle changes. Because bipolar disorder is a lifelong condition—and because of the risk of medication side effects—the condition requires consistent monitoring.
Medications
Several medications help with both manic and depressive episodes of bipolar disorder and are the frontline treatment option. Healthcare providers prescribe mood stabilizers such as lithium or Depakote (valproic acid) or some atypical antipsychotics such as Seroquel (quetiapine) and Risperdal (risperidone) for manic episodes.
Healthcare providers treat depressive episodes associated with bipolar disorder with combination therapies—often Depakote, lithium, and Seroquel. Your provider may also prescribe selective serotonin reuptake inhibitors (SSRIs) or another antidepressant, Wellbutrin (bupropion), alongside mood stabilizers. These should be taken with caution because SSRIs can worsen manic symptoms or lead to rapid cycling in folks with bipolar disorder.
Depending on any co-occurring conditions, you may be prescribed medications for comorbid sleep problems and anxiety.
Psychotherapy
Your primary healthcare provider may recommend that you (or your loved one) meet with a psychiatrist, psychologist, or mental health counselor for therapy alongside any medication. In psychoeducation therapy, you work with a therapist to learn how to identify, prevent, and treat triggers or factors that make mood episodes worse. Cognitive behavioral therapy involves developing strategies to change your relationship to your condition and cope.
Electroconvulsive Therapy
In rare and severe cases, healthcare providers consider electroconvulsive therapy. In this therapy, electrical shocks delivered to the brain create a kind of controlled seizure. This eases the symptoms of both depressive and manic episodes.
Lifestyle Changes
Specific lifestyle changes are an additional means of managing triggers and symptom severity. These include:
- Adopting a healthy diet rich in nutrients from fresh vegetables and healthy proteins and low in added sugars and salts
- Regular exercise, which improves sleep and eases stress
- Relaxation activities, like meditation or yoga
- Quitting alcohol or avoiding recreational drug use
- Understanding and logging your or your loved one’s symptoms, medications, and potential side effects
Bipolar disorder causes prolonged periods of altered mood, energy, and behavior, known as mood episodes. These are either manic, in which mood and energy are elevated; depressive, marked by sadness and loss of motivation; or mixed, showing attributes of both. The severity and character of bipolar disorder symptoms depend on the type you have and health and personal factors. Treatments for this condition range from medications and therapy to lifestyle changes.
American Psychiatric Association. What are bipolar disorders?
National Institute of Mental Health. Bipolar disorder .
Hossain S, Mainali P, Bhimanadham NN, et al. Medical and psychiatric comorbidities in bipolar disorder: insights from national inpatient population-based study . Cureus . 2019;11(9):e5636. doi:10.7759/cureus.5636
Johnson SL, Cuellar AK, Gershon A. The influence of trauma, life events, and social relationships on bipolar depression . Psychiatr Clin North Am . 2016;39(1):87-94. doi:10.1016/j.psc.2015.09.003
Grzenda A, Veldic M, Jia YF, et al. Differences in perceived life stress in bipolar I and II disorder: implications for future epigenetic quantification . Pers Med Psychiatry . 2022;33-34:100093. doi:10.1016/j.pmip.2022.100093
Gold A, Sylvia L. The role of sleep in bipolar disorder . Nat Sci Sleep . 2016;8:207-214. doi:10.2147/NSS.S85754
Substance Abuse and Mental Health Services Administration. An introduction to bipolar disorder and co-occurring substance abuse disorders .
Perich TA, Roberts G, Frankland A, et al. Clinical characteristics of women with reproductive cycle-associated bipolar disorder symptoms . Aust N Z J Psychiatry . 2017;51(2):161-167. doi:10.1177/0004867416670015
Zhao S, Zhang X, Zhou Y, et al. Comparison of thyroid function in different emotional states of drug-naïve patients with bipolar disorder . BMC Endocr Disord . 2021;21(1):210. doi:10.1186/s12902-021-00869-5
Di Nicola M, Mazza M, Panaccione I, et al. Sensitivity to climate and weather changes in euthymic bipolar subjects: association with suicide attempts . Front Psychiatry . 2020;11:95. doi:10.3389/fpsyt.2020.00095
Bhardwaj S, Sinha D, Pawar A, Mane A. Predominant polarity in bipolar affective disorder and its impact on cognition and quality of life . Indian J Psychiatry . 2023;65(6):641-646. doi:10.4103/indianjpsychiatry.indianjpsychiatry_163_23
Dell'Osso B, Cafaro R, Ketter TA. Has bipolar disorder become a predominantly female gender related condition? Analysis of recently published large sample studies . Int J Bipolar Disord . 2021;9(1):3. doi:10.1186/s40345-020-00207-z
Ryles F, Meyer TD, Adan-Manes J, et al. A systematic review of the frequency and severity of manic symptoms reported in studies that compare phenomenology across children, adolescents and adults with bipolar disorders . Int J Bipolar Disord . 2017;5(1):4. doi:10.1186/s40345-017-0071-y
MedlinePlus. Lithium toxicity .
Marzani G, Neff AP. Bipolar disorders: evaluation and treatment . Am Fam Physician. 2021;103(4):227-239
Bauer IE, Gálvez JF, Hamilton JE, et al. Lifestyle interventions targeting dietary habits and exercise in bipolar disorder: a systematic review . J Psychiatr Res . 2016;74:1-7. doi:10.1016/j.jpsychires.2015.12.006
By Mark Gurarie Mark Gurarie is a freelance writer, editor, and adjunct lecturer of writing composition at George Washington University.
CALM Program
University of California, Berkeley
Healthy Lifestyles for Bipolar Disorder
We are about to launch the largest study ever conducted on how dietary interventions, when added to medication, might help sleep issues for people with bipolar disorder., our goal is to understand not only if the intervention helps, but also a very broad range of the ways in which it may help, including when it helps and when it does not help. we’re looking for people who will help us understand this important set of goals, by sharing their experiences with us through a very broad range of questions, as they try on one of our dietary interventions. this study will involve many, many different questions because we sincerely want to deeply understand each person’s experience during this study. , this study will compare the benefits of two approaches to eating: time-restricted eating and the mediterranean diet. neither food plan is meant to be a diet or a treatment. in this study, we ask you to consume the same amount of food that you normally would and to continue your regular medical care for bipolar disorder. we would assign you to one of these food plans., there are two versions of this study: a local version, and an international version. those who live close to berkeley, ca who might be willing to periodically visit a a locally convenient lab to get blood work done might participate in the local study, while those further from the bay area might participate in our entirely-remote international study..
Time-Restricted Eating
Time restricted eating involves restricting eating to 10 hours per day. to make that happen, people typically avoid eating in the first hour after they wake up and avoid eating in the couple hours before they go to sleep. to do this, you need a standard schedule that works well for you, and we’d work with you to determine that window., tre has been shown to improve sleep and circadian rhythms, and we would like to understand if it has this benefit in bipolar disorder., the mediterranean diet, the mediterranean diet is one of the best studied ways to eat healthfully. it is based on the typical diet in the 16 countries surrounding the mediterranean sea, and it involves eating more fruit, vegetables, whole grains and legumes, and using olive oil in place of less healthy fats., this diet has shown to be significantly beneficial for people with heart disease, diabetes, and a number of other health conditions., we would like to understand if the mediterranean diet has benefits for symptoms of bipolar disorder..
In the study, you would be asked to log your regular eating habits for 2 weeks, while we share tips about healthy sleep and goal-setting with you. Then, we would assign you to follow either Time-Restricted Eating or the Mediterranean Diet. At this point, we would share initial instructions and tips to follow your food plan, and you would continue to receive more tips about healthy eating and sleep throughout the 8 weeks of following the plan. Throughout this time, we’d have you log your food daily, in order to see how the food plans are working for you. Multiple times throughout the study, we would ask you to take paid surveys or interviews so that we can track how things are going.
This study will start in spring 2024. we hope you will be interested in working with us. if you are interested in participating in this study, please fill out the following survey:, please feel free to also join our participant registry to be contacted if you may be a good fit for future studies., collaborators.
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Diagnosis and treatment of patients with bipolar disorder: A review for advanced practice nurses
Ursula mccormick.
1 Medical Services, Centerstone of Indiana, Bloomington, Indiana
Bethany Murray
2 Indiana University School of Nursing, Columbus, Indiana
Brittany McNew
This review article provides an overview of the frequency, burden of illness, diagnosis, and treatment of bipolar disorder (BD) from the perspective of the advanced practice nurses (APNs).
Data sources
PubMed searches were conducted using the following keywords: “bipolar disorder and primary care,” restricted to dates 2000 to present; “bipolar disorder and nurse practitioner”; and “bipolar disorder and clinical nurse specialist.” Selected articles were relevant to adult outpatient care in the United States, with a prioritization of articles written by APNs or published in nursing journals.
Conclusions
BD has a substantial lifetime prevalence in the population at 4%. Because the manic or depressive symptoms of BD tend to be severe and recurrent over a patient's lifetime, the condition is associated with significant burden to the individual, caregivers, and society. Clinician awareness that BD may be present increases the likelihood of successful recognition and appropriate treatment. A number of pharmacological and nonpharmacological treatments are available for acute and maintenance treatments, with the prospect of achieving reduced symptom burden and increased functioning for many patients.
Implications for practice
Awareness of the disease burden, diagnostic issues, and management choices in BD has the potential to enhance outcome in substantial proportions of patients.
Introduction
Bipolar disorder (BD) is a chronic illness associated with severely debilitating symptoms that can have profound effects on both patients and their caregivers (Miller, 2006 ). BD typically begins in adolescence or early adulthood and can have life‐long adverse effects on the patient's mental and physical health, educational and occupational functioning, and interpersonal relationships (Valente & Kennedy, 2010 ). Although not as common as major depressive disorder (MDD), the lifetime prevalence of BD in the United States is substantial (estimated at approximately 4%), with similar rates regardless of race, ethnicity, and gender (Ketter, 2010 ; Merikangas et al., 2007 ). Long‐term outcomes are persistently suboptimal (Geddes & Miklowitz, 2013 ). The economic burden of BD to society is enormous, totaling almost $120 billion in the United States in 2009. These costs include the direct costs of treatment and indirect costs from reduced employment, productivity, and functioning (Dilsaver, 2011 ). Given the burden of illness to the individual and to society, there is an urgent need to improve the care of patients with BD.
There is a growing recognition of the substantial contribution that advanced practice nurses (APNs) such as nurse practitioners (NPs) and clinical nurse specialists (CNSs) can make in the recognition and care of patients with BD (Culpepper, 2010 ; Miller, 2006 ). Most patients with BD present initially to primary care providers, but—through a lack of resources or expertise—many do not receive an adequate evaluation for possible bipolar diagnosis (Manning, 2010 ). Early recognition can lead to earlier initiation of effective therapy, with beneficial effects on both the short‐term outcome and the long‐term course of the illness (Geddes & Miklowitz, 2013 ; Manning, 2010 ). Patients with BD are also likely to have other psychiatric and medical comorbidities, and, therefore, rely on their primary care provider for holistic care (Kilbourne et al., 2004 ; Krishnan, 2005 ). Finally, the importance of collaborative, team‐based care is increasingly recognized in managing BD. APNs, by their training and experience, are well suited to facilitate optimal patient care in collaboration with the other healthcare team members (Bauer et al., 2006 ; Chung et al., 2007 ). An especially important role for APNs within primary care lies in the care of the patient, while specialists manage the bipolar illness. It is essential that these two specialties collaborate in order to stay abreast of each other's current phase of treatment.
This review provides an up‐to‐date discussion of the principles and practices of managing BD in the primary care setting. Our emphasis is on holistic, team‐oriented, multimodal approaches to care, which is compatible with the experience and therapeutic orientation of APNs.
Diagnosis of BD
Definitions in bd.
Patients with BD experience recurrent episodes of pathologic mood states, characterized by manic or depressive symptoms, which are interspersed by periods of relatively normal mood (euthymia; Figure Figure1; 1 ; Vieta & Goikolea, 2005 ). Formal definitions of manic and depressive symptoms are included in the recently updated Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM‐5 ; American Psychiatric Association, 2013 ). Notably, the depressive episodes of BD are defined by the same criteria as MDD in the DSM‐5 , so that distinguishing BD from MDD frequently depends on identifying a history of manic or hypomanic symptoms (Table 1 ).
Mood range and associated mood diagnosis (Vieta & Goikolea, 2005 ).
Diagnostic criteria for BD diagnoses: Overview of DSM‐5
Adapted from DSM‐5 (American Psychiatric Association, 2013 ). Readers are referred to the full DSM‐5 criteria published by the American Psychiatric Association ( 2013 ) for establishing a bipolar diagnosis.
There are two major types of BD. Bipolar I disorder (BD I) is defined by the presence of at least one episode of mania, whereas bipolar II disorder (BD II) is characterized by at least one episode of hypomania and depression. The main distinction between mania and hypomania is the severity of the manic symptoms: mania results in severe functional impairment, it may manifest as psychotic symptoms, and often requires hospitalization; hypomania does not meet these criteria (American Psychiatric Association, 2013 ).
The duration of mood episodes is highly variable, both between patients and in an individual patient over time, but, in general, a hypomanic episode may last days to weeks, a manic episode lasts weeks to months, and a depressive episode may last months to years (Benazzi, 2007 ; Manning, 2010 ; Valente & Kennedy, 2010 ). Although a history of depressive episodes is not required to make a diagnosis of BD I by the DSM‐5 criteria, in practice most patients do experience depressive episodes; however, depressive episodes are required for a diagnosis of BD II. Long‐term studies show that patients with BD, regardless of the subtype, experience symptomatic episodes of depression more frequently and for longer durations than manic or hypomanic episodes (Baldessarini et al., 2010 ; Geddes & Miklowitz, 2013 ; Judd et al., 2003 ; Valente & Kennedy, 2010 ).
While a mood episode may consist solely of manic or depressive symptoms, it may also include a combination of these symptoms. Such episodes are newly defined in DSM‐5 as either a manic or hypomanic episode with mixed features or a depressive episode with mixed features, depending on which symptoms are predominant (American Psychiatric Association, 2013 ; Table 1 ).
Rapid cycling is a term describing the occurrence of at least four mood episodes within 1 year. Identification of rapid cycling is important, because these patients are less responsive to treatment. Rapid cycling should be considered a “red flag” that indicates the need for referral to specialist care.
Diagnostic criteria for BD
Successful assessment and treatment by the healthcare team requires knowledge of the episodic nature of BD. Diagnosis of a full‐blown manic episode may be relatively straightforward. If presenting to primary care, these patients may require immediate referral to specialist hospital care because of the risk of harm to self or others. However, more common in the primary care setting is the presentation of patients with depressive symptoms, who require a differentiation between BD and MDD (Cerimele, Chwastiak, Chan, Harrison, & Unutzer, 2013 ; Sasdelli et al., 2013 ). For this reason, all patients presenting with depressive symptoms should be assessed for a history of manic or hypomanic symptoms (Cerimele et al., 2013 ; Sasdelli et al., 2013 ; Valente & Kennedy, 2010 ).
Use of a bipolar screening tool is a time‐efficient first step in diagnosis, to be followed by a confirmatory clinical interview. The Mood Disorder Questionnaire (MDQ, Table 2 ) and the Composite International Diagnostic Interview, version 3.0 (CIDI 3.0), are commonly used screening tools in which scores above specific cut‐off values raise a suspicion of BD (Hirschfeld et al., 2000 ; Kessler & Ustun, 2004 ). Web‐based and electronic screening tools are also being developed with the aim of greater time efficiency (Gaynes et al., 2010 ; Gill, Chen, Grimes, & Klinkman, 2012 ). A comprehensive recent review of the screening tools in BD is provided by Hoyle, Elliott, and Comer ( 2015 ). While screening tools can help to recognize patients likely to have BD and can improve the efficiency of the clinical interview, it is important to note that case‐finding tools are not infallible and cannot replace the interview.
The Mood Disorder Questionnaire
Adapted from Hirschfeld et al. ( 2000 ).
The clinical interview should aim to establish the following (Manning, 2010 ; Price & Marzani‐Nissen, 2012 ):
- ▪ The presence of past or current episodes of manic or depressive symptoms, as described in DSM‐5
- ▪ The duration and severity of these episodes, including the presence of suicidal or homicidal ideation
- ▪ The impact of mood episodes on functioning in work, social, and family roles
- ▪ The presence of comorbidities (such as substance abuse, personality disorder, and anxiety disorder including posttraumatic stress disorder)
- ▪ The history of treatments administered and the response to treatments
- ▪ The family history.
In cases of continued diagnostic uncertainty, a formal diagnosis of BD may require a consultation with an experienced primary care physician, psychiatrist, psychologist, or APN to confirm the presence of DSM‐5 criteria, as well as to categorize the bipolar subtype that is present. The clinical interview, besides establishing the bipolar diagnosis, represents an important element in treatment planning, by helping to select the optimal medication(s) and the optimal site of treatment—either within primary care or by involving specialist psychiatric support. Finally, continued interviews over the course of treatment will help establish rapport and trust with the patient that encourages communication and enhances treatment adherence (Zolnierek & Dimatteo, 2009 ). Open dialogue between the healthcare worker and patient represents an essential element of patient interviews.
Other elements of the patient interview should include a physical examination and laboratory tests, with the particular aim to exclude disorders that can mimic bipolar symptoms, for example, hypothyroidism or hyperthyroidism, infection, and substance misuse (Krishnan, 2005 ). Psychiatric disorders (e.g., panic disorder, posttraumatic stress disorder) other than MDD can also mimic symptoms of BD and these should be considered in the differential diagnosis (Goldberg, 2010 ).
In establishing a BD diagnosis, it can be very informative to ask family members or close friends to provide a description of the patient's symptoms (with, of course, the patient's consent). Lack of insight is a characteristic of patients with BD, and hypomanic symptoms, in particular, may not be considered a manifestation of the illness by the patient. This is also an opportunity to assess the burden that family or friends may be experiencing as well as their current relationships with the patient (National Collaborating Centre for Mental Health [UK], 2006 ).
Misdiagnosis and underdiagnosis
Because MDD is more common than BD, and because MDD and BD have similar symptoms, it is very common for BD to be misdiagnosed as MDD (Manning, 2010 ; Miller, 2006 ). In one study, over 60% of patients who were eventually diagnosed with BD had previously been misdiagnosed with MDD.
A number of adverse consequences can result from the misdiagnosis and underdiagnosis of BD (Hirschfeld, 2007 ; Manning, 2010 ; McCombs, Ahn, Tencer, & Shi, 2007 ). Most importantly, patients with BD who are misdiagnosed with MDD may be treated with conventional antidepressant monotherapy. Compared with appropriately treated patients, such patients are less likely to respond, are at increased risk of a switch to mania, and may experience an acceleration of mood cycling (Manning, 2010 ; Miller, 2006 ; Sidor & Macqueen, 2011 ; Vieta & Valenti, 2013 ).
Sharing the diagnosis
Discussing the diagnosis with the patient is critical to laying a foundation for effective treatment. The acceptance of a BD diagnosis may be difficult and often occurs over time. The initial diagnosis is frequently provisional, and requires additional observations or confirmatory historical information. It can also be expected that patients will show resistance to the diagnosis, possibly because of the social stigma of having a mental illness. One of the best tools to facilitate acceptance of the diagnosis is motivational interviewing, which is a form of counseling that elicits and strengthens the patient's motivation for change through a process of collaboration and rapport. Motivational interviewing was developed for patients with an alcohol or drug problem, but has been applied more broadly in recent years (Laakso, 2012 ). Having patience and persistence in helping patients to “own” their BD, and take responsibility for managing it, is an important objective in motivational interviewing (Laakso, 2012 ).
Pharmacotherapy
Pharmacological treatment is fundamental for successfully managing patients with BD. For acute episodes, the objective is symptom reduction, with the ultimate goal of full remission. For maintenance treatment, the goal is to prevent the recurrences of mood episodes. Medications used in the treatment of BD include mood stabilizers (e.g., lithium, valproate, lamotrigine, and carbamazepine), atypical antipsychotics, and conventional antidepressants (Geddes & Miklowitz, 2013 ; Hirschfeld, Bowden, & Gitlin, 2002 ). Table 3 lists the medications that are approved by the U.S. Food and Drug Administration (FDA) in treating the different phases of BD.
Medications with FDA indication for treatment of BD
*Also used adjunctively but not FDA indicated.
A, adjunctive to a mood stabilizer; C, combination therapy with another mood stabilizer, antipsychotic, or antidepressant; M, monotherapy; RLAI risperidone long‐acting injectable; X, recommended in guidelines but not FDA indicated.
Mood stabilizers
Lithium was the first agent to be used in the treatment of BD. Although it has many limitations, including a delayed onset of action in the treatment of acute mania, limited efficacy in the treatment of bipolar depression, and a narrow therapeutic window, lithium still has an important role today (Geddes, Burgess, Hawton, Jamison, & Goodwin, 2004 ; Hirschfeld et al., 2002 ). In particular, lithium has shown efficacy in preventing recurrence of manic episodes and it is the only medication correlated with a reduced risk of suicide in BD. A study that reduced the lithium dosage (to increase its tolerability) reported no benefit from using lithium plus optimized personalized treatment when compared to optimized personalized treatment alone (Nierenberg et al., 2013 ).
Sodium valproate is the most commonly used mood stabilizer. It has a more rapid onset of action than lithium for the acute treatment of mania, and was superior to placebo as an acute therapy in the largest study performed to date (Bowden et al., 1994 ), but the evidence for its efficacy as a maintenance treatment for mania is not so robust (Geddes et al., 2010 ; Kessing, Hellmund, Geddes, Goodwin, & Andersen, 2011 ). Placebo‐controlled studies of carbamazepine describe significant efficacy in acute mania (Weisler, Kalali, & Ketter, 2004 ; Weisler et al., 2005 ). In the absence of long‐term controlled studies, a naturalistic study over an average of 10 years reported that carbamazepine is efficacious in most patients (Chen & Lin, 2012 ). Lamotrigine, in contrast to the other mood stabilizers, is more effective for preventing the recurrence of depressive than manic episodes of BD (Vieta & Valenti, 2013 ). Lamotrigine has also been investigated for the treatment of acute bipolar depression, but the evidence for efficacy is less convincing (Geddes, Calabrese, & Goodwin, 2009 ). A study of lamotrigine in acute mania reported no significant difference from placebo (Frye et al., 2000 ).
There are a number of safety and tolerability concerns with mood stabilizers that impact their long‐term use. Lithium requires regular monitoring of blood levels, because the therapeutic window is narrow. Lithium can cause progressive renal insufficiency and thyroid toxicity. After initial assessment of renal and thyroid functions, repeat monitoring of renal and thyroid functions every 6 months is recommended to ensure normal functioning (Price & Heninger, 1994 ). The most common adverse events associated with lithium include tremors as well as gastrointestinal problems such as nausea, vomiting, and diarrhea. Hepatotoxicity is the most common serious adverse event associated with valproate (risk: 1/20,000); other adverse effects include nausea, dizziness, somnolence, lethargy, infection, tinnitus, and cognitive impairment. Monitoring is required for hematologic abnormalities including low platelet count, low white blood count, and, in some cases, bone marrow suppression during valproate therapy (Martinez, Russell, & Hirschfeld, 1998 ). Carbamazepine is associated with reduced tolerability during rapid dose titration and its potential for interaction with other psychiatric and nonpsychiatric medications further limits its use (Grunze et al., 2009 ). Carbamazepine has an FDA boxed warning for agranulocytosis and aplastic anemia and is associated in approximately 10% of patients with the formation of a benign rash. Lamotrigine, which is overall the best‐tolerated medication in this class, can cause a rash like the Stevens–Johnson rash. Lamotrigine has been studied specifically in relation to fetal cleft palate formation; however, the evidence remains unconvincing. Fetal exposure to valproate, carbamazepine, and lithium can be teratogenic (Connolly & Thase, 2011 ; Dodd & Berk, 2004 ; Geddes & Miklowitz, 2013 ; Hirschfeld et al., 2002 ; Tatum, 2006 ).
Atypical antipsychotics
The atypical antipsychotics were developed in the modern era of psychopharmacology; all agents in this class have been studied by randomized controlled trials in the treatment of BD (Derry & Moore, 2007 ; Yatham et al., 2013 ). For the treatment of acute bipolar mania, all approved atypical antipsychotics (also called “second‐generation” antipsychotics) demonstrate efficacy and acceptable safety. For acute bipolar depression, however, few atypical antipsychotics have demonstrated efficacy. Only quetiapine (immediate‐release [IR] and extended‐release [XR] formulations) has proven efficacy as monotherapy for treating acute depressive episodes of BD I or BD II (Table 3 ; Calabrese et al., 2005 ; Suppes et al., 2010 ; Thase et al., 2006 ). A fixed‐dose combination of olanzapine and fluoxetine has demonstrated efficacy for treating acute depressive episodes of BD I (Tohen et al., 2003 ) and lurasidone has recently received FDA approval as monotherapy or adjunctive therapy (with either lithium or valproate) in BD I but not BD II (Loebel et al., 2014a , 2014b ).
For the maintenance treatment of BD I, FDA‐approved atypical antipsychotics include aripiprazole, olanzapine, quetiapine (IR and XR), risperidone long‐acting injection (LAI), and ziprasidone; these agents are approved either as monotherapy or as adjunctive therapy in combination with a mood stabilizer. A recent meta‐analysis of trials of the atypical antipsychotics in maintenance treatment concluded that aripiprazole, olanzapine, quetiapine (IR or XR), and risperidone LAI monotherapy were statistically superior to placebo for treating manic or mixed episodes, while quetiapine alone was also significantly effective against recurrence of depressive episodes (Vieta et al., 2011 ).
The safety and tolerability profiles of the atypical antipsychotics have been well characterized in patients with BD. A number of safety issues are associated with these drugs as a class, including sedation/somnolence, metabolic effects (e.g., weight gain, hyperglycemia, and dyslipidemia), and extrapyramidal side effects (EPS). The relative risk of these effects differs between individual atypical antipsychotics. For example, the risk of adverse metabolic effects is reported to be greatest with olanzapine and lowest with ziprasidone, and intermediate with quetiapine and risperidone (Perlis, 2007 ). Adjunctive therapies that include atypical antipsychotics in combination with other agents (usually mood stabilizers) are also associated with a greater risk of adverse events than monotherapies (Smith, Cornelius, Warnock, Tacchi, & Taylor, 2007 ). Given the propensity of atypical antipsychotics to adversely affect weight, lipid levels, and other metabolic parameters, it is important to monitor patients regularly (Hirschfeld et al., 2002 ; The Management of Bipolar Disorder Working Group, 2010 ).
Conventional antidepressants
The proper use of conventional antidepressants is an area of controversy in the treatment of BD (Pacchiarotti et al., 2013 ). The main concern in using antidepressants as monotherapy in patients with bipolar depression is the risk of precipitating a switch to mania/hypomania, which is estimated to occur in between 3% and 15% of cases (Pacchiarotti et al., 2013 ; Tondo, Baldessarini, Vazquez, Lepri, & Visioli, 2013 ; Vazquez, Tondo, & Baldessarini, 2011 ). Another unresolved issue is whether maintenance treatment that includes antidepressants is effective for the prevention of recurrence (Pacchiarotti et al., 2013 ; Vazquez et al., 2011 ). If conventional antidepressants are used, it is recommended to combine them with a mood stabilizer or an atypical antipsychotic, and to taper the antidepressant dose following remission of the episode (Amit & Weizman, 2012 ; Connolly & Thase, 2011 ; Hirschfeld et al., 2002 ; Yatham et al., 2013 ). Contemporary guidelines recommend selective serotonin reuptake inhibitors (SSRIs) or bupropion rather than selective serotonin‐norepinephrine reuptake inhibitors (SNRIs) or tricyclics, as SSRIs and bupropion are less likely to cause manic switch. While full consensus is currently absent, there is wide agreement that antidepressant monotherapy should be avoided in patients with BD I and patients with BD II with two or more concomitant core manic symptoms, while antidepressants should be avoided entirely in patients with rapid cycling or those being treated for a mixed episode (Pacchiarotti et al., 2013 ).
Psychosocial treatments
Psychosocial treatments, including individual psychotherapies as well as educational and supportive group therapies, are increasingly considered an integral part of the treatment of BD (Connolly & Thase, 2011 ; Geddes & Miklowitz, 2013 ). Common components of psychosocial treatments are education about the disease and a focus on treatment adherence and self‐care. Interestingly, among the psychosocial treatments, the strongest evidence for effectiveness is for group psychoeducation of patients and caregivers (Colom et al., 2009 ; Reinares et al., 2008 ). Long‐term benefits of this approach include a reduction in days with symptoms and in days hospitalized (Colom et al., 2009 ).
Two other psychotherapies with evidence to support their effectiveness are BD‐specific cognitive behavioral psychotherapy (Jones et al., 2012 ) and interpersonal and social rhythm therapy (Frank et al., 2005 ). Interpersonal and social rhythm therapy is an intervention designed to increase the regularity of patients’ daily routines, based on the concept that disruption of circadian rhythms is a underlying feature of mood disorders (Frank, Swartz, & Boland, 2007 ). These therapies can help patients improve adherence to their medication, enhance their ability to recognize triggers to mood episodes, and develop strategies for early intervention. Combining BD‐specific adjunctive psychotherapies with pharmacological therapy has been shown to significantly reduce relapse rates (Scott, Colom, & Vieta, 2007 ).
Peer support
BD impacts all aspects of a person's life, causing severe disruption to relationships, employment, and education. Peer support can be very helpful in dealing with the consequences of these effects through sharing of experiences, where patients can discover that others have had similar experiences and can have hope for recovery, stability, and a satisfying life. Support groups, sponsored by national organizations, may be available locally or regionally. There is also a wealth of resources available online (Table 4 ).
Web resources for BD
Major challenges in the management of patients with BD
A number of commonly encountered challenges can contribute to suboptimal outcomes in BD. An awareness of these challenges and the implementation of proactive strategies can help to maximize adherence to care and the benefits of treatment.
Nonadherence
Medication nonadherence is a significant problem in primary care medicine generally, and in patients with BD in particular. Experience from other areas of medicine suggests that nonadherence may be widely unrecognized (Ho, Bryson, & Rumsfeld, 2009 ). Validated scales for gauging nonadherence include the Morisky Adherence Scale, although this is not widely adopted in clinical practice (Morisky, Ang, Krousel‐Wood, & Ward, 2008 ). Reasons for nonadherence among patients with BD include the following: a denial of the diagnosis, especially in those with predominant mania; a lack of belief that the medications being offered are necessary or effective; and a wish to avoid the real or imagined adverse effects of medications (Devulapalli et al., 2010 ). Additional practical factors, including poor access to health care and limited resources to support treatment costs, can also affect adherence (Kardas, Lewek, & Matyjaszczyk, 2013 ).
Nonadherence is probably the most significant factor contributing to poor treatment outcome in BD (Hassan & Lage, 2009 ; Lew, Chang, Rajagopalan, & Knoth, 2006 ), which leads to increased emergency room visits and hospitalization (Hassan & Lage, 2009 ; Lage & Hassan, 2009 ; Lew et al., 2006 ; Rascati et al., 2011 ). Investing more time and resources to work with patients during symptom‐free periods is likely to be cost saving by reducing the utilization of these high‐cost resources (Zeber et al., 2008 ).
Comorbid psychiatric disorders
The complexity in treating patients with BD is increased by the high rates of cooccurring psychiatric disorders, in particular anxiety disorders and substance use disorders (Grant et al., 2005 ; Krishnan, 2005 ). The importance of these cooccurring conditions cannot be overstated; they are associated with both exacerbations of BD and poor treatment outcomes (Grant et al., 2005 ; Kessler et al., 1996 ). Although it may be prudent to refer such patients to specialist care, the first critical step is to make a correct diagnosis and to help these patients to accept the problem and the need for treatment.
Comorbid medical disorders
Patients with BD have an elevated prevalence of medical morbidities, including obesity, diabetes, cardiovascular disease, and hepatitis (Kilbourne et al., 2004 ; Krishnan, 2005 ). A comorbidity of increasingly recognized importance is obstructive sleep apnea (OSA), which causes sleep disturbance that can trigger mood episodes (Soreca, Levenson, Lotz, Frank, & Kupfer, 2012 ). A recent study reported OSA in over 20% of patients with BD, which the authors mention may be an underestimate of the true prevalence (Kelly, Douglas, Denmark, Brasuell, & Lieberman, 2013 ). The authors concluded that unrecognized OSA may play a major role in the mortality and morbidity of BDs. All patients diagnosed with a BD should be screened with an OSA questionnaire.
The burden of medical disorders may be increased by the adverse effects of BD treatment, by cooccurring substance misuse or by decrements in self‐care secondary to BD itself (McIntyre, 2009 ). For example, depression typically deprives patients of the motivation and energy to engage in treatment for chronic medical conditions. Early recognition and treatment of medical disorders in patients with BD has been shown to have a major beneficial effect on all‐cause mortality (Crump, Sundquist, Winkleby, & Sundquist, 2013 ).
Women of childbearing age
Women are at high risk of BD recurrence during pregnancy, especially if medications are discontinued, as well as during the postpartum period. Balancing the risk of medications against the need to prevent a mood episode requires active collaboration between the healthcare providers and the patient (McKenna et al., 2005 ). Teratogenicity is a potential risk with most of the mood stabilizers; lamotrigine may be an exception, but there are no well‐controlled studies in humans to confirm this. Atypical antipsychotics, with the exception of lurasidone, are rated FDA pregnancy category C, meaning that they have not been shown to be either safe or unsafe for use during pregnancy; lurasidone is classed in pregnancy category B based on current data.
Suicide rates in BD are the highest among the psychiatric disorders (Chen & Dilsaver, 1996 ; Tondo, Isacsson, & Baldessarini, 2003 ). The lifetime incidence of at least one suicide attempt was reported in one study to be 29% in patients with BD, compared to 16% for MDD (Chen & Dilsaver, 1996 ). Other studies have reported even higher rates of suicide attempts of 25%–60% during the course of BD, with suicide completion rates of 14%–60% (Sublette et al., 2009). The primary healthcare team should monitor all patients with BD for suicidality, especially those with persistent depressive or mixed‐mood symptoms, and immediately refer any patient at high‐risk for suicide to specialist care (Tondo et al., 2003 ).
Alcohol abuse in patients with BD is associated with further elevation in the risk of suicide, particularly in the presence of concurrent drug use disorders. A study that investigated this association concluded that higher suicide attempt rates in patients with BD I and alcoholism were mostly explained by higher aggression scores, while the higher rates of attempted suicide associated with other drug use disorders appeared to be the result of higher impulsiveness, hostility, and aggression (Sublette et al., 2009). This study, similar to previous reports, found that earlier age of bipolar onset increased the likelihood that alcohol use disorder would be associated with suicide attempts. Effective clinical management of substance use disorders has the potential to reduce the risk of suicidal behavior in these patients with BD.
BD continues to represent a substantial burden to patients, their care providers, and society. Management of BD poses a challenge to all healthcare providers, including the APNs. A suspicion of BD increases the likelihood of successful diagnosis. Emphasis should be placed on accurately identifying manic, hypomanic, and depressive episodes. A number of pharmacological and nonpharmacological treatments are available for acute and maintenance treatments. Healthcare providers should be aware of the efficacy and safety profiles of each of these agents, with the aim to achieve the most effective utilization of the approaches available in the management of patients with BD. An awareness of these aspects in BD—disease burden, diagnostic issues, and management choices—can enhance outcome in substantial proportions of patients. In summary, Table 5 provides a useful overview of the principles to consider when providing care for patients with BD.
Principles of providing care for patients with BD
Red flags indicating need for specialist involvement:
▪ Suicidality
▪ Pregnancy and postpartum
▪ Severe psychiatric comorbidity (e.g., substance dependence, anxiety)
▪ History of treatment resistance (e.g., multiple hospitalizations)
▪ Rapid‐cycling pattern.
Adapted from Culpepper ( 2010 ).
Funding Editorial support was provided by Bill Wolvey of PAREXEL, funded by AstraZeneca.
Disclosure Ursula McCormick has received personal fees from AstraZeneca and Sunovian. Bethany Murray and Brittany McNew report no conflicts of interest.
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Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases
Affiliations.
- 1 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- 2 Unit of Cardiology, Heart and Vascular Division, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
- 3 School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
- 4 Department of Applied Health Science, School of Public Health, Indiana University, Bloomington.
- 5 Department of Psychological and Brain Sciences, Indiana University, Bloomington.
- PMID: 37991787
- PMCID: PMC10851097
- DOI: 10.1001/jamapsychiatry.2023.4294
Importance: Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades. However, the potential risk of cardiovascular disease (CVD) associated with long-term ADHD medication use remains unclear.
Objective: To assess the association between long-term use of ADHD medication and the risk of CVD.
Design, setting, and participants: This case-control study included individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD diagnoses and ADHD medication dispensation were obtained from the Swedish National Inpatient Register and the Swedish Prescribed Drug Register, respectively. Cases included individuals with ADHD and an incident CVD diagnosis (ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease). Incidence density sampling was used to match cases with up to 5 controls without CVD based on age, sex, and calendar time. Cases and controls had the same duration of follow-up.
Exposure: Cumulative duration of ADHD medication use up to 14 years.
Main outcomes and measures: The primary outcome was incident CVD. The association between CVD and cumulative duration of ADHD medication use was measured using adjusted odds ratios (AORs) with 95% CIs.
Results: Of 278 027 individuals with ADHD aged 6 to 64 years, 10 388 with CVD were identified (median [IQR] age, 34.6 [20.0-45.7] years; 6154 males [59.2%]) and matched with 51 672 control participants without CVD (median [IQR] age, 34.6 [19.8-45.6] years; 30 601 males [59.2%]). Median (IQR) follow-up time in both groups was 4.1 (1.9-6.8) years. Longer cumulative duration of ADHD medication use was associated with an increased risk of CVD compared with nonuse (0 to ≤1 year: AOR, 0.99 [95% CI, 0.93-1.06]; 1 to ≤2 years: AOR, 1.09 [95% CI, 1.01-1.18]; 2 to ≤3 years: AOR, 1.15 [95% CI, 1.05-1.25]; 3 to ≤5 years: AOR, 1.27 [95% CI, 1.17-1.39]; and >5 years: AOR, 1.23 [95% CI, 1.12-1.36]). Longer cumulative ADHD medication use was associated with an increased risk of hypertension (eg, 3 to ≤5 years: AOR, 1.72 [95% CI, 1.51-1.97] and >5 years: AOR, 1.80 [95% CI, 1.55-2.08]) and arterial disease (eg, 3 to ≤5 years: AOR, 1.65 [95% CI, 1.11-2.45] and >5 years: AOR, 1.49 [95% CI, 0.96-2.32]). Across the 14-year follow-up, each 1-year increase of ADHD medication use was associated with a 4% increased risk of CVD (AOR, 1.04 [95% CI, 1.03-1.05]), with a larger increase in risk in the first 3 years of cumulative use (AOR, 1.08 [95% CI, 1.04-1.11]) and stable risk over the remaining follow-up. Similar patterns were observed in children and youth (aged <25 years) and adults (aged ≥25 years).
Conclusions and relevance: This case-control study found that long-term exposure to ADHD medications was associated with an increased risk of CVDs, especially hypertension and arterial disease. These findings highlight the importance of carefully weighing potential benefits and risks when making treatment decisions about long-term ADHD medication use. Clinicians should regularly and consistently monitor cardiovascular signs and symptoms throughout the course of treatment.
Publication types
- Attention Deficit Disorder with Hyperactivity* / epidemiology
- Cardiovascular Diseases* / epidemiology
- Case-Control Studies
- Hypertension*
- Risk Assessment
- Open access
- Published: 22 November 2023
Endophenotype trait domains for advancing gene discovery in autism spectrum disorder
- Matthew W. Mosconi ORCID: orcid.org/0000-0002-1981-6777 1 , 2 ,
- Cassandra J. Stevens 1 , 2 ,
- Kathryn E. Unruh 1 ,
- Robin Shafer 1 &
- Jed T. Elison 3 , 4
Journal of Neurodevelopmental Disorders volume 15 , Article number: 41 ( 2023 ) Cite this article
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A Correction to this article was published on 28 February 2024
This article has been updated
Autism spectrum disorder (ASD) is associated with a diverse range of etiological processes, including both genetic and non-genetic causes. For a plurality of individuals with ASD, it is likely that the primary causes involve multiple common inherited variants that individually account for only small levels of variation in phenotypic outcomes. This genetic landscape creates a major challenge for detecting small but important pathogenic effects associated with ASD. To address similar challenges, separate fields of medicine have identified endophenotypes, or discrete, quantitative traits that reflect genetic likelihood for a particular clinical condition and leveraged the study of these traits to map polygenic mechanisms and advance more personalized therapeutic strategies for complex diseases. Endophenotypes represent a distinct class of biomarkers useful for understanding genetic contributions to psychiatric and developmental disorders because they are embedded within the causal chain between genotype and clinical phenotype, and they are more proximal to the action of the gene(s) than behavioral traits. Despite their demonstrated power for guiding new understanding of complex genetic structures of clinical conditions, few endophenotypes associated with ASD have been identified and integrated into family genetic studies. In this review, we argue that advancing knowledge of the complex pathogenic processes that contribute to ASD can be accelerated by refocusing attention toward identifying endophenotypic traits reflective of inherited mechanisms. This pivot requires renewed emphasis on study designs with measurement of familial co-variation including infant sibling studies, family trio and quad designs, and analysis of monozygotic and dizygotic twin concordance for select trait dimensions. We also emphasize that clarification of endophenotypic traits necessarily will involve integration of transdiagnostic approaches as candidate traits likely reflect liability for multiple clinical conditions and often are agnostic to diagnostic boundaries. Multiple candidate endophenotypes associated with ASD likelihood are described, and we propose a new focus on the analysis of “endophenotype trait domains” (ETDs), or traits measured across multiple levels (e.g., molecular, cellular, neural system, neuropsychological) along the causal pathway from genes to behavior. To inform our central argument for research efforts toward ETD discovery, we first provide a brief review of the concept of endophenotypes and their application to psychiatry. Next, we highlight key criteria for determining the value of candidate endophenotypes, including unique considerations for the study of ASD. Descriptions of different study designs for assessing endophenotypes in ASD research then are offered, including analysis of how select patterns of results may help prioritize candidate traits in future research. We also present multiple candidate ETDs that collectively cover a breadth of clinical phenomena associated with ASD, including social, language/communication, cognitive control, and sensorimotor processes. These ETDs are described because they represent promising targets for gene discovery related to clinical autistic traits, and they serve as models for analysis of separate candidate domains that may inform understanding of inherited etiological processes associated with ASD as well as overlapping neurodevelopmental disorders.
Autism spectrum disorder (ASD) is both clinically and etiologically diverse. Rare inherited and de novo pathogenic variants each have been repeatedly implicated and account for up to 20% of cases [ 1 , 2 ]. For a plurality of individuals with ASD, however, it is believed that the primary causes include gene-gene and gene-environment interactions that involve multiple common inherited variants and non-linear complex genetics [ 3 , 4 ]. Consistent with this hypothesis, > 1000 different genes show associations with ASD, and the majority of variants implicated each confer only small effects [ 5 ]. These findings suggest that many different pathogenic processes contribute to ASD, and that additive or multiplicative genetic effects play prominent roles in the development of autism. This polygenic landscape also suggests significant etiological heterogeneity among autistic individuals, indicating studies of large numbers of individuals will be necessary to help parse the many distinct causal pathways involved. Large, multi-site research networks and data sharing consortia have been leveraged to establish a growing number of candidate genes and greater understanding of their downstream molecular consequences in relation to ASD [ 6 , 7 , 8 , 9 ]. Despite these efforts, diagnostic yield from genetic testing in ASD remains low and etiological processes for most autistic individuals remain unexplained [ 10 , 11 ]. Additional approaches are needed to increase resolution for detecting small but significant genetic effects and advance more individualized identification and therapeutic strategies.
One approach to gene discovery that has proven valuable in separate fields of medicine is the identification of condition-related biological traits that can be used to decompose complex clinical phenotypes into less genetically complex trait structures. Endophenotypes, or discrete, quantitative traits that reflect genetic likelihood for a particular clinical condition, have been used to identify polygenic mechanisms of complex conditions and advance more personalized therapeutic strategies for heart disease [ 12 , 13 ], obesity [ 14 , 15 ], diabetes [ 16 ], and osteoporosis [ 17 , 18 ]. Endophenotypes represent a distinct class of biomarkers useful for understanding genetic contributions to clinical entities because they are (A) embedded within the causal chain between genotype and clinical phenotype, (B) closer to the action of the gene(s) than the constellation of clinical phenotypes that define a diagnosis, and (C) quantitative and therefore capable of showing greater sensitivity to additive causal processes than categorical outcomes, such as affectation status. Despite their demonstrated power for guiding new understanding of complex genetic structures of clinical conditions, few endophenotypes associated with ASD have been identified and integrated into family genetic studies.
In this paper, we argue that understanding the complex pathogenic processes that contribute to ASD can be accelerated by refocusing attention toward identifying endophenotypic traits reflective of inherited mechanisms. This pivot requires renewed emphasis on study designs integrating measurement of familial co-variation including infant sibling studies, family trio and quad designs, and analysis of monozygotic and dizygotic twin concordance for select trait dimensions. Given that most, if not all behavioral traits associated with ASD also are implicated in separate behaviorally defined disorders (e.g., repetitive sensorimotor mannerisms are common in intellectual and developmental disability; difficulties with modulating eye contact during interaction also have been demonstrated in multiple anxiety disorders) and show wide variation in neurotypical development, it is likely that endophenotypic traits associated with ASD will cut across diagnostic boundaries, and transdiagnostic designs will be critical.
Multiple candidate endophenotypes associated with ASD likelihood are described herein, though the intent is not to provide a comprehensive review (for more systematic reviews, see [ 19 , 20 ]), but instead to focus on promising targets for accelerating progress in understanding etiological processes associated with traits involved in ASD. Toward this goal, we propose a new focus on the analysis of “endophenotype trait domains” (ETDs), or traits measured across multiple levels along the causal pathway from genes to behavior. To elucidate ETDs, “dense-phenotyping” approaches will be integral to establishing within-individual associations between traits across molecular, cellular, circuit, system, and behavioral levels, as has been done in separate fields of medicine and areas of psychiatry (see Fig. 1 ). For example, the Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) is an on-going, multi-site, transdiagnostic study focused on identifying quantitative traits, measured across multiple levels of analysis, that are associated with psychosis and co-segregate in patients and their first-degree relatives. Studying > 1000 patients affected by psychiatric disorders associated with psychosis (e.g., schizophrenia, bipolar disorder), this network has leveraged broad phenotyping, including measurement of sensory, motor, behavioral, and psychiatric traits, and dense phenotyping strategies, utilizing multiple measures of target domains including genetic, immunological, electrophysiological, oculomotor, functional and structural MR imaging, cognitive, and clinical assays, to derive data-driven “biotypes”, or biologically distinct subgroups of patients [ 21 ]. Initial principal components analysis and k-means clustering were used to first derive latent factors across behavioral, cognitive, and brain levels, and then to identify clusters of more biologically homogeneous subtypes. Subsequent work has shown that these biotypes differ on separate external validation characteristics, including brain morphometry, and that affected and unaffected family members co-segregate into similar biotypes implicating high levels of familiality. Similar approaches have been advanced in separate fields of medicine, but no known efforts such as these have been conducted to understand biotypes based on ETDs for neurodevelopmental conditions, including autism.
Levels of analysis for mapping etiological pathways associated with behavioral and clinical traits. This schematic shows different layers or functional units of analysis that can be evaluated to clarify linkages between genotype and clinical phenotype. Endophenotypic traits closer to the level of genotype are expected to be more closely associated with inherited variation given their relatively simpler genetic architecture compared to behavioral traits, as evidenced above by the reduced complexity (i.e., number of genes or letters) at the higher levels (e.g., cells, circuits/networks). Multiple levels of analysis are depicted, though separate intermediate levels are not included for ease of presentation (e.g., proteomic). Based on this model, analysis of traits closer to genotypes will provide greater sensitivity to inherited variations than assessments of behavior or complex clusters of clinical symptoms. Analysis of traits across multiple levels, or establishment of endophenotypic trait domains (ETDs), also is proposed to offer unique opportunities for understanding etiological pathways contributing to discrete traits associated with ASD. Important environmental and developmental factors also are proposed to modify trait associations across levels and over time
The concept of ETDs is drawn from the NIMH Research Domain Criteria (RDoC) that focuses on the analysis of domains of behavior from molecular to self-report levels [ 22 ], but extends this idea to focus on traits that represent key intermediary processes between genetic causes and select behavioral or clinical dimensions. Here, we emphasize the importance of quantitative trait outcomes rather than categorical diagnoses. This emphasis is critical in the context of considerable evidence that ASD, similar to other psychiatric disorders defined behaviorally by DSM, represent heterogeneous clusters of individuals showing both shared and distinct quantitative deviations from typical or normative profiles of functioning rather than any discovered entity grounded in nature or biology [ 23 ]. By mapping endophenotypes across multiple levels and across the full range of neurodiversity, ETDs may provide important insights into pathways of inherited traits that contribute to clinical vulnerabilities and maladaptive developmental functioning. Illustrative examples of how this concept can be applied to understand mechanistic pathways associated with ASD are provided.
To inform our central argument for research efforts toward ETD discovery, we first provide a brief review of the concept of endophenotypes and their application to psychiatry. Next, we highlight key criteria for determining the value of candidate endophenotypes, including unique considerations for the study of ASD and neurodevelopmental disorders more broadly. Descriptions of different study designs for assessing endophenotypes in ASD research then are offered, including analysis of how select patterns of results may help prioritize candidate traits in future research. We then present multiple candidate ETDs that collectively cover a breadth of clinical phenomena associated with ASD, including social, language/communication, cognitive control, and sensorimotor processes. These ETDs are described because they represent promising targets for gene discovery related to clinical traits associated with ASD, and they serve as models for analysis of separate candidate domains that may inform understanding of inherited etiological processes contributing to ASD or associated neurodevelopmental traits.
Endophenotypes in psychiatry and their application to ASD
The endophenotype concept was first introduced in insect biology to describe “microscopic and internal traits” that contrast “exophenotypes”, or behaviors that are directly observable [ 24 ]. Gottesman and Shields [ 25 ] initially brought the concept to psychiatry asserting that endophenotypes could provide greater sensitivity to inherited risk factors for psychopathology because they are “a measurable trait that is not observable by the unaided eye… and that lies more proximal to the underlying genetics of a disorder than the clinical phenotype” [ 26 ]. Endophenotypes thus represent a unique class of biomarkers that is necessarily influenced by the genetic factors that confer susceptibility to a particular clinical condition [ 27 , 28 ]. Consistent with this broader definition, Gould and Gottesman [ 28 ] proposed key criteria for evaluating the viability of biomarkers as endophenotypic traits. Briefly, the authors indicated that a candidate endophenotype should be (1) associated with condition-specific traits as demonstrated by its presence in affected individuals and covariation with primary trait dimensions in the population, (2) associated with clinical severity within affected individuals, (3) familial, meaning it shows decreasing levels of severity from affected individuals to unaffected family members to unaffected population controls, (4) heritable, and (5) reliably measured and reproducible [ 26 , 29 ]. Original definitions of endophenotypes also indicated that they should be “state-independent and detectable regardless of whether an individual is acutely ill or in remission”, though recent amendments to these criteria have been proposed to include traits that are observed “prior to the manifestation of features that define a given condition/disorder” that “may or may not persist through development” [ 30 ]. Evidence suggests that the familial traits most predictive of autistic outcomes may in fact be deviations previously considered associated features (e.g., motor control features, attention impairments), rather than (or in addition to) core social-communication or repetitive behavior features that appear to show less predictive value early in ontogeny [ 31 ]. Moreover, Mous and colleagues [ 32 ] found that attention-deficit/hyperactivity disorder (ADHD) and motor coordination traits in both siblings with family history of autism with ASD (FH + ) and without ASD (FH − ), strongly predicted ASD trait severity of their autistic sibling and categorical recurrence of ASD within participants’ families (i.e., accounting for ~ 50% of variance). These results suggest that genetic variation underlying non-specific neurodevelopmental traits may represent background ASD susceptibilities that are inherited and non-specific and may confer additive genetic risk alongside variants conferring specific ASD liability (e.g., BAP and subclinical ASD features in parents). These non-specific traits may be detectable earlier than other ASD-related behaviors and serve as critical early targets for intervention. Together, these results suggest that expanding our endophenotype definition to account for a broader range of traits and their developmental variance is crucial.
Several factors have impeded progress in identifying endophenotypic traits useful for gene discovery in ASD. First, studies aimed at understanding the genetics of ASD are inherently constrained by their reliance on categorical definitions that do not have a strong grounding in biology. The diagnostic standards developed by DSM task forces and the gold-standard assessment tools used to inform ASD classifications each primarily were intended to guide reliable, differential diagnoses based on behavioral observation. Historical beliefs that behaviorally defined categories would structure research that could eventually illuminate distinct pathogenic processes for select disorders have not been borne out, likely reflecting the high level of clinical overlap across diagnostic categories and the profound heterogeneity within categories. This realization was explicitly acknowledged by the American Psychological Association prior to publication of DSM-5 when they indicated “historical aspiration of achieving diagnostic homogeneity by progressive subtyping within disorder categories no longer is sensible” ([ 33 ], p. 12). It is not surprising then that separate behaviorally defined neurodevelopmental disorder categories (e.g., ASD, ADHD, and obsessive-compulsive disorder, or OCD) each show considerable etiological heterogeneity and overlapping genetic backgrounds [ 34 , 35 , 36 ]. Case-control designs that rely on categorical determinations for participant selection also do not capture the full range of trait variation useful for understanding additive genetic effects as demonstrated by population studies showing that defining and associated characteristics of ASD each are normally distributed within the non-autistic population and overlap considerably among autistic and non-autistic individuals [ 37 , 38 ]. These data indicate transdiagnostic or population-based designs consistent with broader efforts in psychiatry (e.g., the Research Domain Criteria structure of NIMH; Hierarchical Taxonomy of Psychopathology consortium) should be emphasized in the pursuit of identifying familial genetic factors contributing to traits associated with ASD [ 39 ].
Translation of the endophenotype concept to ASD also is made difficult by the developmental variance seen in both clinical and biological traits across the life span. Clinical signs of ASD emerge within the first years of life (or perhaps earlier) and evolve in non-linear ways, suggesting endophenotypic traits may differ quantitatively as a function of the age or developmental level at which individuals are studied. In support of this hypothesis, multiple studies have shown that some behavioral differences seen in young siblings of autistic individuals relative to non-autistic peers are not predictive of eventual affectation status [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. These findings implicate developmental compensations that mask trait expression at later ages among unaffected first-degree relatives [ 49 ]. Further, evidence of “normalization” of key behavioral deficits in later childhood or adulthood among autistic individuals and their unaffected relatives [ 50 , 51 , 52 , 53 ] suggests that mapping growth trajectories of endophenotypic traits will be critical for establishing trait markers sensitive to gene variation and changes in expression over time.
Additional support for a developmental perspective comes from studies showing characteristics reflecting ASD likelihood in infancy are not direct phenocopies of the defining features measured in children or adults implicating qualitative differences in trait expression. For example, recent studies of sibling concordance have indicated that trait dimensions often considered co-occurring conditions may present as the earliest indicators of ASD for some individuals (e.g., motor coordination and behavioral control impairments [ 32 ]). These data highlight the importance of analyzing developmental traits beyond core ASD features using a “broad” phenotyping strategy in which diverse traits and their neurodevelopmental and molecular substrates are analyzed. This strategy also demands multivariate analytic approaches in which interactions between different trait domains can be examined. Co-occurring specifiers introduced in DSM 5 (e.g., accompanying intellectual or language impairment) offer a useful set of traits that should be considered as they each individually may represent a top-down starting point for identifying biological processes that collectively contribute to neurodevelopmental disorders including ASD (e.g., accompanying language or intellectual impairment). The question of why these associated traits may co-segregate with core autistic traits in some but not other individuals may be best answered by clarifying the etiologic pathways that underpin discrete traits rather than the more complex (and variable) constellation of clinical behaviors.
Sex differences in both etiological processes and clinical outcomes for autistic individuals also are important considerations in the study of autism genetics. ASD disproportionately impacts males relative to females, and there is considerable evidence that males and females with ASD differ clinically [ 54 , 55 ], at the level of structural and functional brain development [ 56 , 57 , 58 ], and genetically [ 54 , 59 ]. Infant sibling studies have shown that at least some early indicators of ASD hold predictive power for males but not for females [ 60 ], suggesting that candidate traits useful for mapping individual pathophysiologies may differ as a function of sex. In contrast, Burrows et al. [ 61 ] recently utilized a data-driven approach to derive behavioral factors and map their early childhood trajectories among infant siblings. Results identified similar sex ratios in infants identified in a “high concern” cluster based on both social-communication and restricted behavior dimensions. Similarly, findings form the Baby Siblings Research Consortium suggest that out of ~1800 toddlers, sex differences in cognitive performance and repetitive behaviors are observed across siblings with a family history of autism (FH) and children with no family history of autism (nFH), suggesting that some early emerging sex differences in cognitive and behavioral development do not appear to be ASD-specific but instead reflect sex-dependent variation in developmental processes that may or may not be altered in ASD [ 62 ]. These findings highlight the critical need to adjust for sex-specific biases across trait development for establishing new endophenotypes predictive of autistic trait expression. Inclusion of autistic females in ASD research has been increasingly emphasized in recent years, though this subpopulation remains understudied and still constitutes only a small minority of individuals included in ASD research. There is a strong need for systematic comparisons of trait variation in males and females in the search for ETDs.
Factors affecting the sensitivity of candidate endophenotypes to genotypes of interest
The genetic landscape of many heritable diseases is defined by complex, non-linear, and polygenic architectures that will not map cleanly onto models developed to predict categorical outcomes (e.g., affectation status) that include highly complex clinical pictures and a diverse range of individuals. While monogenic syndromes show tight genotype-phenotype relationships, complex conditions such as ASD involve high levels of polygenicity, environmental influences, and stochastic events that collectively contribute to diverse behavioral and developmental variation. Defining models that are sensitive to the complex polygenic processes associated with ASD will require identification of dimensional traits that co-vary with additive and non-linear likelihood elements across the affected and unaffected population [ 63 ]. By prioritizing dimensional traits sensitive to the full range of expression of candidate genes, power can be maximized for detecting important effects of low penetrant genes that may be accounting for important variation in autistic traits.
The extent to which resolution for identifying pathogenic mechanisms is increased depends on multiple features of candidate traits, including their proximity to the action of the gene. Endophenotypic traits constitute “bridges” linking molecular, cellular, and system-level mechanisms and clinical dimensions. Their associations with genetic variation will be stronger if their relative location on these “bridges” is closer to genetic origins. In principle, endophenotypic traits closer to molecular processes that scaffold brain development will show greater power for informing mechanistic models than more downstream traits that vary as a function of epigenetic processes, environmental factors, and stochastic influences. For example, while the most common endophenotypes studied in psychiatry tend to come from cognitive psychology and take a behavior first, “top down” approach to ETD discovery, cognitive traits often have highly complex genetic architectures themselves, suggesting that their added value relative to measurement of behavior may be limited. It also has been argued that some candidate endophenotypes, including electrophysiological traits, also have shown little power for advancing gene discovery in psychiatric conditions because they have such complex genetic architectures themselves, and thus their study will require very large samples (i.e., tens of thousands) [ 64 ]. In contrast, assays of molecular structure or function including transcript- or blood-based traits may offer increased power as they likely will be more directly influenced by the genotype of interest. Mapping ETDs beginning with more molecular traits, or using a “bottom-up” approach, may provide important traction for understanding simpler genetic structures related to discrete trait outcomes. The relationships between molecular traits and the signs and symptoms of ASD often are unclear; however, suggesting that integration of endophenotypes across multiple units of analysis (e.g., transcript, brain function, cognitive processing) will be integral to mapping causal pathways.
Endophenotypic traits also will provide greater power for elucidating genotypes of interest if they are highly translatable across species and model systems. Analyses of preclinical model systems allow for more direct interrogation of cellular and molecular processes and can therefore facilitate more detailed descriptions of the pathways linking genetic substrates and behavioral traits. This consideration is especially important in studies of ASD given that defining symptoms are complex and not easily translatable across primate and more primitive species. For example, translation of the social behavioral difficulties experienced by autistic individuals to model systems is difficult given the complexity of these behaviors and limited conservation of social brain network functions across species. Backwards translation of traits that may be more ontogenetically primitive, including sensory and motor processes, as well as traits measured similarly across species, such as brain structural and functional connectivity, may provide critical insights into the genetic, molecular, and cellular bases of autistic traits. This hypothesis has been supported by studies of “endophenotype ranking values (ERV)” applied to traits associated with separate psychiatric diagnoses [ 27 , 65 ]. The ERV provides a quantitative ranking system based on estimates of standardized genetic covariance of candidate traits with clinical outcomes. ERV studies have indicated that endophenotypes closer to gene action and translatable across species may show the greatest potential to guide a more mechanistic understanding of complex behavioral dimensions [ 27 , 66 ].
Study designs and considerations for identifying endophenotypes
Endophenotypic traits are distinct from other biomarker classes because they represent inherited, additive effects related to development of select traits or disease processes. Based on this premise, candidate traits should show high levels of familiality, meaning they both co-segregate within families and track with clinical traits across affected and unaffected family members. To assess the familiality of candidate traits, multiple different family study designs may be leveraged. Integration of findings across these separate designs is important given that each approach is characterized by unique sets of strengths and limitations.
Family studies represent a broad class of methodologies aimed at determining the extent to which discrete traits differ between unaffected relatives and population controls and co-vary across related family members. The underlying assumption of family study designs aimed at identifying candidate endophenotypes is that traits with strong patterns of inheritance should be more similar across first-degree relatives compared to distant relatives and unrelated population controls. According to Gottesman and Gould’s [ 28 ] criteria, strong candidate endophenotypes are evidenced by profiles in which the greatest deviations are seen in individuals with a particular condition relative to population controls, but family members show intermediate levels of deviation from controls in the same direction as seen for affected individuals. Both family trio (biological mother, biological father, and autistic offspring) and quad studies (biological parents, affected, and unaffected siblings) will be important for identifying endophenotypes associated with ASD, and initial family studies already have documented cognitive [ 67 ], behavioral [ 68 ], and brain differences [ 69 ] that covary across affected individuals and their biological parents.
Infant sibling designs represent an important family study approach useful for clarifying endophenotypic traits associated with early development in ASD. Based on the high heritability of ASD and findings that ASD recurrence among siblings (13–20% [ 70 , 71 ]) is considerably higher than base rates in the general population (1–2% [ 72 ]), analysis of infant siblings of previously diagnosed children provides important power for identifying both diagnostic predictors and traits associated with ASD that track in family members. Beginning with Bryson et al.’s [ 73 ] initial report documenting social and attentional differences in 12-, but not 6-month-old infants with familial history of ASD who later were diagnosed with ASD, infant sibling designs have identified multiple early emerging markers that can be identified years before the age at which children typically are diagnosed [ 73 , 74 ]. These studies also have identified candidate traits that track in affected (FH + ) and unaffected (FH − ) siblings, suggesting that they may reflect inherited genetic influences associated with ASD. Traits that are deviant in both FH + and FH − infant siblings relative to same-age nFH population control infants reflect an important class of familial biomarkers that can guide new knowledge of inherited genetic substructures related to liability for autistic traits. Findings that distinguish FH siblings and nFH peers, regardless of diagnostic status, may reflect familial genetics while stepwise patterns of effects (e.g., FH + > FH − > nFH) may indicate key familial traits that confer susceptibility but only lead to ASD when sufficiently severe, through interaction with separate liabilities, or when exacerbated in the context of developmental or stochastic effects. Familial traits detectable in infancy also may be particularly important for defining endophenotypes because they are less likely to be impacted by compensatory behavioral or brain processes in unaffected relatives. For example, behavioral differences in unaffected first-degree relatives of autistic individuals may not be as severe or detectable in later childhood or adulthood due to compensatory processes used to mask perceived challenges, or atypical maturational trajectories that converge with neurotypical patterns later in development [ 75 , 76 ].
Additional examples of the power of family study designs for advancing gene discovery related to neurodevelopmental disorders can be found in adult psychiatry. For example, as described above, BSNIP takes a unique approach to family genetic research by developing hypothesis-driven and data-driven endophenotypes associated with psychosis that cut across diagnostic boundaries, deriving multi-level endophenotype factors that separate biologically separable clusters of patients, or “biotypes” [ 77 , 78 ]. These biotypes do not align with diagnostic categories of DSM but are characterized by greater homogeneity of neural features and higher levels of intra-familial trait aggregation than DSM diagnostic categories [ 78 ]. Analyses of these biotypes in family genetic studies offer significant promise for gene discovery, and greater power than case-control studies using classification strategies that have less grounding in biology. Analogous approaches have yet to be leveraged in ASD, but such strategies could greatly increase power for detecting the additive, complex genetic substructures that contribute to autistic traits for the majority of affected individuals.
While family studies are central in the search for endophenotypic traits useful for defining etiological mechanisms associated with familial ASD (as opposed to ASD caused by de novo variants or environmental factors), their limitations also should be considered in the context of research aimed at understanding heritable influences. Family study methods provide only necessary, but not sufficient evidence that select traits are inherited. More specifically, family study designs are not capable of quantifying the impacts of shared environments and are thus not able to directly inform estimates of heritability. Family designs that focus on traits already shown to be highly heritable or less likely to be strongly influenced by social modeling or other environmental influences (e.g., social determinants of health such as socio-economic status or educational quality) may provide greater leverage in advancing endophenotype discovery.
Trait heritability is best demonstrated through twin studies examining concordance in monozygotic (MZ) and dizygotic (DZ) twins raised in the same family environments. Based on the assumption that MZ twins share approximately double the proportion of genetic material as DZ twins, greater similarity (i.e., concordance) between MZ relative to DZ pairs on select traits serves as an index of variation attributable to genetic inheritance rather than shared environment. Large-scale twin studies offer rich information on the heritability of individual traits that may directly guide analyses of candidate endophenotypes for clinical conditions or dimensions and guide interpretation of studies examining autistic individuals and their unaffected family members. For example, basic attentional and sensorimotor traits implicated in ASD each show high levels of heritability based on population twin studies and thus offer strong candidates for endophenotype discovery (e.g., [ 79 , 80 ]). Importantly though, a series of twin studies examining eye-tracking data also has documented high levels of heritability in more complex processes including visual exploration during processing of social [ 80 ] and non-social scenes, as well as executive functions such as visual disengagement [ 81 ] and behavioral response inhibition [ 82 ]. Each of these behaviors has been implicated in ASD through either case-control or family study designs, suggesting that they may represent promising endophenotypes sensitive to inherited variation. Studies focused on the familial co-segregation of strongly heritable traits in ASD optimize the strengths of both family and twin designs for endophenotype discovery [ 79 , 80 , 81 , 82 ].
Twin studies have proven invaluable for developing new knowledge on the heritability of ASD and autistic traits. For example, twin studies consistently have indicated that ASD represents perhaps the most heritable behaviorally defined condition identified in the DSM [ 83 , 84 , 85 ]. They also have highlighted several key considerations in the analysis of trait inheritance patterns associated with ASD. First, heritability estimates show significant variation across studies (37–90%; [ 86 , 87 , 88 , 89 ]) due to multiple features, including the complexity of genotype-environment interactions, and the strong influence of measurement differences on the classification of individuals. For example, Colvert et al. [ 88 ] found that additive genetic effects explained 76–95% of diagnostic covariance when classifications were based on the Developmental and Well-Being Assessment and Autism Diagnostic Observation Schedule, but only 56% of covariance when classification was based on the Autism Diagnostic Interview–Revised (ADI-R). Second, evidence that trait concordance may be substantially lower in autistic relative to non-autistic twins implicates greater sensitivity to stochastic influences during development. Conducting the first known quantitative analysis of twin-twin severity of autistic traits, Castelbaum and Constantino [ 90 ] documented high levels of diagnostic concordance (96%) but low levels of autistic trait concordance across three different samples of autistic MZ twins ( R 2 < 0.1). Trait concordance was high in non-autistic population control MZ twins ( R 2 = 0.6) indicating that trait heritability estimates from non-autistic twins may not be directly translatable to ASD populations, and that environmental influences on trait outcomes and development may be profound.
In summary, family and twin studies each provide critical, complementary information for establishing endophenotypic traits associated with ASD. While family designs, including trio, quad, and infant sibling methods, each can yield important new insights into traits that “run in families”, they are not able to directly index heritability of candidate traits. Instead, heritability estimates from twin studies are important for understanding inheritance patterns and parsing environmental and genetic contributions to trait outcomes. Twin studies also are limited by difficulties ascertaining sufficient samples of autistic twins and evidence that heritability estimates from non-autistic twins may not be directly applicable to autistic twins. Large-scale twin studies that characterize carefully selected continuously distributed traits in the general population represent a promising future direction. More specifically, focus on analyses of early emerging heritable traits less influenced by stochastic or environmental processes will be important for identifying endophenotypic traits sensitive to inherited genetic processes.
Candidate endophenotypes and trait domains associated with ASD
The majority of traits examined in family studies of ASD have been measured at the behavioral level. It is important to note that endophenotypes originally were differentiated from behavioral traits based on their “internal” and “unobservable” qualities allowing them to be objectively measured and suggesting they lie more proximal to gene action [ 26 , 91 , 92 ]. Based on this premise, it has been argued that familial behavioral traits should be considered separately as intermediate phenotypes [ 92 ]. This distinction is important in the context of findings that behavioral and cognitive dimensions studied as familial traits in ASD also have highly complex genetic architectures, suggesting their added value in advancing knowledge of pathogenic processes relative to clinical symptoms may be limited [ 27 , 92 , 93 ].
Despite these caveats, we propose that familial behavioral traits are important to integrate in family genetic studies because they can be leveraged to focus the search for associated “internal” traits closer to genetic substructures. Studies of core autistic traits represent important examples of how understanding familial behavioral phenotypes may guide the search for endophenotypic traits. For example, considerable evidence shows that first-degree relatives of autistic individuals present mild traits qualitatively similar to those found in their autistic family members, justifying the definition of a “broader autism phenotype” (BAP) characterized by social aloofness, pragmatic communication difficulties, and a rigid personality style [ 94 , 95 ]). Notably, a stepwise pattern of BAP trait loading has emerged for multiplex, simplex, and adoptive parents of autistic children [ 96 , 97 ] indicating that trait burden reflects an aggregation of ASD-related genetic liability, and that dosage of genetic influences is greater in families with recurring ASD [ 98 , 99 ]. Consistent with this hypothesis, Lyall et al. [ 100 ] documented that child ASD risk is increased by 85% when both parents show elevated autistic traits. Collectively, these findings provide strong support that analysis of BAP traits across family members holds significant power for determining familial ASD processes and informing genetic models [ 94 , 95 , 98 , 99 , 100 ].
In principle, identifying endophenotypic traits associated with BAP behaviors and those features closer to molecular and neurodevelopmental mechanisms contributing to ASD will increase resolution for detecting etiological pathways. This process of mapping ETDs by linking behavioral traits back to their genetic origins aims to define the full chains of causality contributing to traits that may collectively constitute ASD. To illustrate how this approach may enhance resolution for detecting genetic substructures, we integrate findings from case-control and family designs assessing the neurodevelopmental substrates of multiple behavioral traits associated with ASD. Our list of candidate ETDs is not intended to be exhaustive. Instead, we focus on discrete behaviors that are highly quantitative, have been studied across multiple levels, and also have shown promise for clarifying etiological processes based on studies of their heritability, familiality in ASD, underlying biology, and potential for back-translation to model systems (see Table 1 ).
Social gaze
Social impairments have served as the pathognomic features of ASD since Kanner’s original case studies [ 154 ]. They include a broad class of behavioral issues ranging from differences in basic attentional allocation to social information to more complex cognitive difficulties in the processing of social cues and development of social relationships (e.g., [ 101 , 155 ]). The complex nature of many social behaviors that are impacted in ASD highlights challenges in establishing their underlying biology and therefore identifying endophenotypic traits. Quantitative studies of social attention have served to deconstruct complex behaviors into simpler cognitive processes that offer more potential for back-translation to preclinical models and may represent simpler genetic substructures than complex social phenotypes. For example, social gaze toward faces represents a highly quantitative biomarker that appears to show familial patterns. Importantly, eye tracking of social gaze can be done in studies of wide ranges of ages as demonstrated by multiple studies documenting non-linear changes in social gaze as early as the first weeks of life through adulthood (e.g., [ 101 ]). Leveraging similar measurement approaches, foundational work from Jones and Klin indicated that infants later diagnosed with ASD show declining rates of gaze shifts toward the eye regions of others between 2 and 6 months resulting in reduced overall attention to faces relative to neurotypical peers [ 102 ]. These findings are consistent with separate studies documenting reduced attention to faces in autistic adolescents and adults [ 103 , 104 ]. Reduced eye gaze is strongly associated with the severity of autistic traits suggesting that this highly quantitative trait may represent a key endophenotype related to liability for autistic traits or ASD affectation.
Family studies provide support for social gaze as a useful endophenotypic trait associated with ASD. Studying non-autistic twins, Constantino et al. [ 79 ] demonstrated high levels of heritability for infant gaze to eye and mouth regions. MZ twins also showed high concordance of the duration and direction of saccadic eye movements when viewing social scenes, consistent with separate studies documenting high levels of heritability for social gaze in more complex social environments [ 80 ]. Social gaze differences also appear to be strongly familial in ASD [ 80 ]. Atypical social gaze is seen in parents [ 105 ] and siblings of autistic individuals [ 51 ], and parents with BAP characteristics show decreased gaze toward social stimuli in complex scenes relative to population controls and parents of autistic individuals who do not show BAP features [ 105 , 106 ]. These findings suggest that atypical social gaze is associated with core autism behavioral traits in unaffected family members and may serve as a quantitative link between social traits of ASD and their inherited biological underpinnings.
Quantitative EEG/ERP studies of social gaze in ASD offer insights into the neural substrates of social gaze phenotypes. The N170 peaks 150–200 ms after stimulus onset and is sensitive to the visual presentation of social stimuli including faces [ 156 ]. During viewing of faces, the N170 is thought to index early structural encoding of facial features and face categorization [ 157 , 158 ]. In non-autistic individuals, the latency of the N170 ERP is shorter to faces than to houses or other objects [ 120 ] suggesting increased automaticity of percept processing. The N170 to faces also typically is right lateralized implicating hemispheric specialization for processing facial information [ 159 ]. Delayed N170 latencies have been consistently documented in autistic individuals compared to non-autistic controls (e.g., [ 120 , 121 ]), and they appear to be associated with reduced memory for faces [ 160 ]. Both autistic individuals and their unaffected siblings also demonstrate a reduced difference in amplitudes between inverted and upright faces compared to controls suggesting reduced specialization of neural processing of facial information that is familial [ 122 ]. Parents [ 123 ] and infant siblings of autistic individuals show diminished right lateralization of N170 amplitudes associated with more severe social-communication impairments and sensory symptoms further indicating that developmental specialization of select social brain networks represents a familial neural endophenotype associated with core autistic characteristics [ 124 ].
While a myriad of MRI studies have identified structural and functional brain alterations [ 104 , 161 , 162 ] associated with atypical social gaze in ASD implicating prefrontal and temporo-parietal circuits as well as amygdala nuclei (for reviews, see [ 163 , 164 ]), only a small number of MRI studies have examined neural correlates of social gaze in unaffected family members. During face viewing, parents of autistic individuals irrespective of BAP status demonstrated increased functional activation of the fusiform face area and amygdala [ 126 ] suggesting that increased activation in these regions associated with social gaze processing reflects ASD-familial status; however, parents with the BAP showed more severe hyper-activation of right fusiform gyrus than parents without the BAP and controls. Consistent with this findings, both autistic individuals and their unaffected siblings show reduced frontal (i.e., left superior frontal gyrus; right middle, left posterior, left dorsomedial PFC) and temporal (i.e., temporal pole, fusiform face area) activation during face viewing relative to controls [ 125 ] indicating alterations of neurodevelopmental processes supporting the functional specialization of brain networks involved in facial processing represent strong candidate endophenotypes for elucidating familial and perhaps inherited trait processes.
Multiple separate preclinical studies also have been conducted to understand cellular, physiological, and molecular genetic mechanisms of different social traits associated with ASD. Current challenges in back-translation of ASD-related social differences include limits to mimicking complex social behaviors in model systems such as the rodent models that often are used in genetic knock-out (KO) studies. Despite these challenges, studies of non-human primates have provided some insight into cellular and molecular processes associated with social gaze behavior. Chen and colleagues found that non-human primates with TALEN-edited MECP2 mutations exhibited a preference for social over nonsocial stimuli and looked to conspecific faces exhibiting aggressive and submissive expressions for shorter durations than neutral expressions [ 138 ]. Based on findings implicating maternal immune system activation in autistic liability, non-human primate maternal immune activation models have also been studied to understand basic physiology of social gaze and relationships with autistic traits. During viewing of facial images of conspecifics, offspring of maternal immune activation models showed multiple gaze differences relative to control animals, including longer latencies to fixate on the eyes, fewer fixations directed at the eyes, and less fixation time on the eyes [ 139 ]. Studies of non-human primates defining cellular and synaptic processes supporting social gaze also may be integrated to clarify cellular and molecular mechanisms of social gaze differences in ASD and their genetic underpinnings. Non-human primate studies have documented selective firing of lateral interparietal neurons during social gaze and gaze shift behavior [ 165 ] and increased firing of amygdalar cells during viewing of eyes and direct eye contact [ 166 ].
In contrast to non-human primate studies, mouse genetic studies allow for interrogation of gene-specific effects and downstream molecular and electrophysiological traits. Yet, they are limited in the extent to which behavioral phenotypes can be translated to inform understanding of complex social traits in humans given limited homology of brain and behavior between humans and rodents. For example, common behavioral assays for rodent models of social traits in ASD include nose-to-nose sniffing, pushing or crawling, time spent in a chamber with (or at a partition next to) another mouse versus alone, partner preference, and social transmission of food preference [ 167 ]. Most of these behaviors do not closely mirror naturalistic social behavior in humans; however, social approach, withdrawal, and recognition are cross-species social behaviors that may be more easily translatable from rodent models to humans. Multiple mouse models of autism have documented reduced social approach relative to wild-type (WT) mice, suggesting multiple gene variants associated with ASD may contribute directly to diminished interest in or increased resistance to social interaction [ 140 , 141 ]. Findings that the selective GABA B enantiomer R-Baclofen reverses deficits in social approach in BTBR mice [ 142 ] and mice with 16p11.2 microdeletions [ 143 ] suggest that atypical GABA signaling may underpin social approach differences in some autistic individuals, though R-Baclofen has shown variable effects on social difficulties in autistic individuals. Integration of these preclinical studies therefore offers important traction for understanding molecular and cellular processes that may contribute to social impairment in autistic individuals, though these studies also highlight the significant challenges in translating model system findings regarding the pathophysiology of social difficulties to humans.
Together, data across behavioral, cognitive, and brain system levels suggest that social gaze traits and their neural substrates comprise a promising ETD linked to the pathognomonic features of ASD. Separate social behavioral traits associated with ASD also warrant further study. For example, atypical functional activations of fusiform gyrus, superior temporal sulcus, middle frontal gyrus, and amygdala during biological motion processing have been identified in both autistic individuals and their unaffected siblings, including compensatory activations seen specifically in unaffected siblings [ 49 ]. The extent to which biological motion processing differences and associated alterations in functional brain development relate to differences in social gaze or represent a unique ETD in ASD remains unclear. Histological analyses of cellular features and gene expression in targeted brain regions of autistic individuals and their family members also will be important for determining the molecular substrates of familial social gaze differences.
Language and communication
Autistic individuals show a range of language and communication challenges including reduced receptive and expressive language abilities as well as difficulties in pragmatic forms of communication [ 168 ]. Differences in the suprasegmental aspects of speech, including prosody (e.g., intonation, rate, and rhythm of speech) also are common. Atypical intonation, rate, and rhythm of speech appear to be familial, suggesting they represent promising targets for establishing endophenotypes useful for understanding genetic pathways associated with autistic traits and liability [ 20 , 168 , 169 ].
Meta-analytic data indicate that autistic individuals exhibit higher mean pitch, greater pitch variability, and longer voice duration relative to controls [ 107 ]. These features have been highly reliable for distinguishing autistic from non-autistic individuals [ 107 , 108 ]. Differences in suprasegmental components of speech among autistic individuals are also evident in tonal languages which use pitch to convey not only pragmatic information, but also word meaning [ 170 ]. For example, Cantonese speaking autistic children and adults show less robust prosodic encoding compared to controls, suggesting that difficulties processing suprasegmental features of speech in ASD persist into adulthood despite years of experience with a tonal language [ 170 ].
Measuring non-speech vocalizations also is important for understanding language and communication development across the lifespan in autism. For example, infant siblings of autistic children show differences in vocal properties that emerge early in ontogeny, including atypical prosody during crying in infancy [ 42 , 46 ]. At 6 months, pain cries from FH infants are higher and more variable in pitch than those of nFH peers [ 46 ]. Similarly, Esposito and colleagues found that cries of 15-month-old FH toddlers showed higher frequencies [ 42 ] and were shorter in duration than nFH toddlers [ 42 , 109 ]. Importantly, FH + infants had higher fundamental frequencies than FH − infants, who had higher fundamental frequencies than nFH infants (FH + > FH − > nFH) [ 42 ]. Parents of autistic children show some overlap with their offspring in suprasegmental speech, including greater variability in frequency driven specifically by mothers showing high levels of BAP features [ 108 ]. These findings suggest differences in suprasegmental aspects of speech that may represent endophenotypic traits in a select subset of families and therefore may serve as important targets for parsing etiological heterogeneity [ 171 , 172 ]. Large-scale quantitative family studies assessing interactions of maternal autistic traits and suprasegmental aspects of speech hold promise for understanding inherited genetic processes contributing to ASD in select clusters of families.
Suprasegmental features of speech represent important targets for studies of endophenotypes because relevant measures also can be translated to neuroimaging environments and across species. Studies of neurophysiological processes associated with speech differences in ASD have provided important information on candidate endophenotypic traits. The frequency following response (FFR) is an early auditory-evoked potential which marks how sounds at the frequency of natural speech and their harmonics are encoded in relevant cortical pathways [ 173 , 174 , 175 ]. The degree to which frequency of the stimulus is reflected in the FFR indexes the integrity of the auditory pathway for encoding early features of acoustic stimuli [ 175 ]. Importantly, FFR responses can be leveraged across the lifespan to understand neural processing of sound, especially since this neurophysiological measurement is a customary practice in newborn hearing screening. Autistic individuals show less stable FFR responses to speech sounds relative to non-autistic peers suggesting greater levels of variability in processing auditory speech information [ 127 ]. Differences in the neural processing of sounds may underlie difficulties monitoring, adjusting, or matching aspects of speech like tone, rate, and rhythm, which may in turn affect higher-order features of language like prosody and pragmatics. Additionally, during a task of vocal production with dynamic auditory feedback, autistic individuals and their parents showed reduced auditory P1 amplitudes relative to age-matched controls, reflecting less robust detection of changes in pitch during auditory feedback [ 128 ]. Diminished ability for feedforward vocal control in contexts requiring audio-vocal integration may be a mechanism of prosodic differences in ASD and may also be reflective of disrupted neuromotor control of speech.
Back-translation of language and communication traits into preclinical models represents a major challenge given the unique language and communication abilities of humans and non-human primates. Still, analysis of suprasegmental speech offers some opportunity for translational research that may be informative for understanding genetic and molecular substrates of impairments in ASD. For example, differences in the acoustic properties of pup vocalizations can be measured in rodent species and appear to be selectively disrupted by KO of multiple ASD-related genes. More specifically, higher peak frequencies and reduced modulatory abilities of vocalizations have been demonstrated in mouse models of ASD [ 144 ], including higher peak frequencies and reduced modulatory abilities in SHANK3 KO, mirroring results found in autistic individuals [ 145 ]. Separate non-human primate models of ASD may be leveraged to characterize qualities of vocalizations associated with ASD to help bridge pre-clinical rodent findings to brain system, neuropsychological, and behavioral level communication traits associated with ASD.
Language-related endophenotypes separate from suprasegmental speech characteristics also exist (e.g., pragmatic communication features, expressive vocabulary). Fewer studies have examined the familiality and neural substrates of these distinct language and communication traits owing to multiple considerations, including their relative complexity (e.g., pragmatic communication) and limited suitability for imaging environments sensitive to oromotor movements (e.g., functional MRI). Studies of language-related endophenotypes also are hindered by difficulties assessing the full range of language impairments in ASD, including both non-speaking and fluent individuals. Assessment of neurophysiology may be particularly challenging with autistic individuals who show severe impairments in processing or expressing language, as these individuals may not process instructions or task demands. Similarly, individuals with severe expressive language disability may show limited ability to respond to task demands, or rates of echolalia that may make it difficult to obtain adequate naturalistic language samples [ 176 ]. The growing use of augmentative and alternative communication (AAC) strategies may also introduce questions of comparability between expressive language in written and spoken modalities. These challenges have contributed to a dearth of studies including the full range of language traits in studies of ASD, confounding progress in determining etiological processes. There is a critical need to develop strategies to integrate individuals who are minimally- or non-speaking and, where possible and appropriate, utilize compound tasks that involve both direct measurement of language and simultaneous tracking of biobehavioral indices (e.g., imaging, neurophysiology, eye tracking, oromotor movements).
Cognitive control
Executive functions represent a diverse range of cognitive abilities supporting the regulation of thought and action, including the abilities to inhibit dominant responses, update working memory representations, and flexibly shift behavior or cognitive strategies in response to changes in environmental demands. Consistent with their diversity, the genetic substrates of executive abilities are complex. Executive functions show high levels of heritability involving a common genetic “factor” as evidenced in the analysis of twin concordance (e.g., [ 177 ]). While these data implicate common, likely polygenic processes contributing to high levels of heritability for executive functions, different executive abilities also appear to be modified by separable genetic influences that contribute to diverse estimates of heritability for individual functions [ 177 , 178 ]. These results are consistent with studies documenting modest covariation of different executive abilities and the overarching conceptualization that executive processing is a multi-dimensional set of cognitive operations [ 179 , 180 ]. The genetic structures of executive abilities also appear to show complex interactions with general cognitive abilities, showing both covariation and high levels of heritability that are distinct from genetic influences on IQ, processing speed, and visuospatial abilities [ 177 , 178 ]. These findings collectively indicate that while executive abilities involve multiple diverse functions, heritability is high and trait inheritance likely reflects common pathways that also can be modified by separable genetic influences that shape individual executive outcomes.
Despite findings that executive functions are among the most heritable psychological traits [ 177 ], and that they are consistently disrupted in autistic individuals [ 181 ], their familiality in ASD seldom has been examined. Behavioral rigidity, perhaps the most common trait characteristic of family members of autistic individuals [ 97 ], appears to involve alterations of executive processing, including reduced abilities to flexibly shift cognitive strategies and to inhibit prepotent behavioral responses [ 67 ]. For example, prior work by our group and others has demonstrated that reduced cognitive flexibility and behavioral response inhibition in autistic individuals each are associated with more severe clinically rated RRBs, including a strong need for sameness in the environment and in routines (i.e., insistence on sameness) and compulsions [ 110 , 111 , 112 ]. These findings together implicate cognitive inflexibility and reduced behavioral response inhibition as important cognitive trait markers associated with behavioral rigidity.
Similar cognitive traits have been implicated in unaffected family members. Reduced behavioral flexibility, characterized by a strong insistence on sameness and intense preoccupations, appears to co-segregate in families of autistic probands [ 182 , 183 , 184 ]. Studying a probabilistic reversal learning test in which individuals must shift a response selection away from a previously reinforced item after reinforcement contingencies have changed, Schmitt et al. [ 67 ] documented that unaffected parents of autistic individuals show an increased rate of regressing back to previously reinforced stimuli, or “regressive errors”, similar to findings from a previous study of autistic individuals performing the same reversal learning task [ 110 ]. These findings were consistent with prior studies documenting reduced cognitive flexibility on tests of set shifting in autistic individuals and unaffected first-degree relatives [ 113 , 114 , 115 ] but also extended this work to show that increased rates of regressive errors were specific to parents showing high levels of BAP features and their autistic children [ 67 ]. These results suggest that cognitive control traits are familial and that they may contribute to or interact with core autistic traits to increase ASD likelihood of affectation. These findings are particularly promising for defining multi-factorial endophenotypes (BAP features and cognitive control impairments) that may co-segregate and be useful for establishing more homogeneous subgroups, or biotypes, for family genetic research. Results also may help explain prior findings that some unaffected family members show relatively intact cognitive flexibility as subsets of families with an autistic family member but without parental BAP traits may have relatively preserved cognitive flexibility [ 185 , 186 ]. Analyses of inhibitory control abilities among this same sample of autistic individuals and their parents showed increased error rates in parents and autistic individuals relative to age-matched controls, though deficits appeared to be independent of parental BAP status [ 67 ]. Together, these findings suggest that cognitive flexibility and inhibitory control impairments each may represent important familial endophenotypes associated with RRBs in probands and behavioral rigidity in parents, and that their analysis could help parse etiologic heterogeneity by identifying more cognitively homogeneous subsets of families.
Tests of cognitive flexibility (probabilistic reversal learning) and inhibitory control (stop signal and antisaccade) constitute important measures for ETD studies because each can be adapted to neuroimaging environments to examine underlying brain functions (e.g., [ 129 , 187 , 188 ]). Reversal learning is supported by neural systems including middle frontal gyrus, posterior parietal cortex, striatum, and midbrain nuclei [ 189 ]. Using fMRI, D’Cruz et al. [ 129 ] documented reduced activation in both prefrontal cortex and ventral striatum in autistic individuals relative to controls during trials in which participants needed to shift their response set. Reduced activation in frontal cortex implicates problems in decision-making and response planning, while atypical activation of ventral striatum suggests limited processing of reinforcement cues, as has been demonstrated more broadly in ASD [ 190 , 191 ]. These processes, and their integration, are essential for flexible behavior. Alterations in these systems may therefore contribute to a rigid adherence to preferred behavioral patterns in autistic individuals.
Cognitive/behavioral flexibility also is a promising target for studies of ETDs in ASD because of the potential for back-translation to model systems. Probabilistic reversal learning tests in particular have proven to be highly translational strategies for studying neurophysiologic, cellular, and molecular mechanisms of cognitive/behavioral rigidity across species. For example, using a probabilistic reversal learning paradigm similar to that described above in clinical studies of autistic individuals, Ragozzino and colleagues have conducted a series of studies documenting elevated rates of errors in multiple mouse models of ASD [e.g., BTBR mice, mice reared in conditions of high maternal stress or maternal exposure to a selective serotonin reuptake inhibitor (SSRI)] [ 146 , 147 ]. They also have demonstrated rescue of reversal learning deficits in mouse models with administration of an adenosine A 2a receptor agonist and a 5HT 2a receptor antagonist in dorsomedial striatum implicating selective receptor targets for drug development as well as gene expression studies focused on cognitive/behavioral rigidity in ASD [ 146 , 147 , 148 , 149 ].
Studies of inhibitory control show similar potential for translation across behavioral and imaging environments in ASD studies and for back-translation in lower-order species. Using tests of antisaccades, or the ability to consistently suppress prepotent oculomotor responses, multiple fMRI studies have detailed neural networks supporting top-down control of reactive behaviors, including frontal and parietal eye fields, anterior cingulate cortex, middle frontal gyrus, and dorsal striatum [ 187 ]. Increased rates of antisaccade errors have been repeatedly documented in autistic individuals [ 130 , 131 , 187 , 192 , 193 ]. and their unaffected first-degree relatives [ 111 ], and shown to be associated with reduced activations across frontal and parietal eye fields [ 132 ] that are important for generating motor plans [ 194 ]. Atypical activation of anterior cingulate also has been observed during antisaccades in ASD, suggesting deficits in response monitoring processes central to modifying behavior in response to external contingencies [ 130 , 131 ]. Antisaccade tests frequently have been examined in non-human primates to determine the cellular processes that support inhibitory control (e.g., [ 195 , 196 ]), and separate tests of behavioral response inhibition have been developed to examine these processes in rodent models (e.g., [ 197 ]). Parallel human and model system studies similar to those examining cognitive flexibility described above may help elucidate distinct genetic and molecular processes contributing to familial deficits of inhibitory control in ASD.
Sensorimotor control
Sensorimotor functions frequently are impaired in ASD affecting a range of behaviors and effector systems including oculomotor, vestibulo-motor, and skeletomotor processes [ 116 , 198 , 199 ]. Sensorimotor impairments in ASD also emerge early in development, perhaps earlier than primary social-communication and cognitive/behavioral traits [ 200 , 201 , 202 , 203 , 204 , 205 , 206 , 207 ]. Sensorimotor behaviors represent highly promising targets for endophenotype research because they can be decomposed into quantitative motor control processes subserved by discrete neural systems. For example, while a broad range of sensorimotor behaviors have been shown to be affected in ASD (e.g., [ 198 , 199 , 208 ]), converging evidence indicates a reduced ability to integrate multi-sensory feedback to guide ongoing behaviors resulting in increased variability and regularity of motor output [ 116 , 209 , 210 , 211 ]. Brain systems supporting sensory feedback control during motor behavior have been well-delineated via non-human primate, human lesion, and basic neuroimaging studies and include temporo-parietal and occipital circuits involved in sensory processing and integration, premotor and primary motor cortices involved in planning and executing motor commands sent to the periphery, and cerebellar circuits involved in modulating motor commands to motor cortex based on sensory feedback error information relayed via cortical-pontine circuits (e.g., [ 212 , 213 , 214 ]). Cortical and cerebellar circuits involved in sensory feedback control of motor behavior each have been implicated in ASD via anatomical MRI studies [ 215 ] and post-mortem brain studies [ 216 , 217 , 218 , 219 ]. These results highlight the strong promise of investigating sensorimotor behavioral dysfunctions across motor control, brain system, and cellular levels for mapping ETD pathways associated with ASD.
Multiple sensorimotor behaviors, including sensory feedback guided precision manual motor behaviors and sensorimotor sequence learning, each show high levels of heritability in twin studies [ 220 ]. Analyses of the neural substrates of these sensorimotor behaviors also show strong inherited genetic contributions. More specifically, structural features of unimodal (sensory/motor) cortical regions show reduced variability and increased heritability relative to structural characteristics of heteromodal association networks involved in more complex cognitive operations [ 221 ]. These findings together provide evidence that the study of sensorimotor traits and their neurodevelopmental substrates may offer significant leverage for identifying ETDs associated with inherited autistic traits [ 220 , 221 , 222 ].
The hypothesis that sensorimotor traits represent promising candidate endophenotypes is supported by studies showing that sensorimotor impairments in ASD also may manifest in first-degree family members. Examining multiple oculomotor behaviors, we previously documented that impairments seen in autistic individuals also were present in their unaffected biological parents and siblings, including reduced accuracies of saccadic eye movements, reduced smooth pursuit eye movement velocity during closed-loop phases, lateralized reductions of smooth pursuit eye movement velocity during the open-loop phase (i.e., the initial period of smooth pursuit that precedes the availability of sensory feedback input due to afferent delays), and atypical lateralization of procedural learning of saccadic eye movements [ 119 ]. Each of these oculomotor differences parallels findings from prior studies of autistic probands [ 223 , 224 , 225 , 226 ] suggesting oculomotor abnormalities may track in families of autistic individuals. Studies of infant siblings of autistic children also highlight strong familial patterns consistent with the hypothesis that different sensorimotor abilities may represent promising endophenotypes. Infant sibling studies using standardized tests of fine and gross motor developmental abilities have indicated that motor skills are predictive of language outcomes [ 62 , 201 , 227 ] and autistic traits in FH infants [ 205 , 228 , 229 , 230 ]. A stepwise pattern has been documented in which sensorimotor impairments are more severe in FH + siblings relative to FH − siblings who show differences compared to controls [ 62 , 205 ]. It should be noted that infant sibling studies of sensorimotor behaviors also have yielded inconsistent results owing to multiple factors, including variance related to the abilities tested, diversity of the measures used to test early sensorimotor development, and developmental heterogeneity across the samples studied. Studies using behavioral coding or wearable sensors suggest that more consistent patterns of familiality may be detectable with quantitative measures relative to standardized behavioral assessments that aggregate categorical items (e.g., Mullen Scales of Early Learning). For example, stepwise patterns were seen in infant siblings (FH + > FH − > nFH; [ 117 ]), and during postural control, familial patterns were evident that varied according to whether FH siblings were diagnosed with ASD or language delay (FH + < FH − with language delay < FH − without language delay = controls; [ 118 ]). Together, these findings offer strong support that separate sensorimotor behaviors may serve as endophenotypic traits representing early emerging inherited factors associated with autistic traits and related developmental issues (e.g., language delay). Separate sensorimotor behaviors do not show familial patterns (e.g., quantity of movement [ 231 ]) indicating that only a circumscribed set of sensorimotor behaviors will offer power as endophenotypic traits indexing heritable pathways associated with ASD.
The multiple familial oculomotor differences identified in studies of autistic individuals and first-degree relatives each implicate separate neurophysiological processes. The accuracy of saccadic eye movements, or rapid, ballistic shifts in eye gaze, is guided by frontal and parietal eye fields and modulated on a trial-to-trial basis by cerebellar-brainstem circuits that act to reactively adjust output precision according to error feedback information [ 232 ]. Smooth pursuit eye movements include both closed- and open-loop phases separated by the extent to which sensory feedback is available to guide output precision. Reduced accuracy of closed-loop pursuit suggests atypical processing of error feedback information in cerebellum as well as prefrontal cortex and frontal eye field circuits involved in planning motor behavior. Consistent with these findings, multiple studies have documented atypical activation of premotor and motor cortex during motor behavior [ 133 ] and cerebellar-cortical functional connectivity during visuomotor behavior [ 133 , 134 ] in autistic individuals. These sensorimotor data implicate familiality of atypical neural functioning within systems supporting motor planning, sensory feedback guided motor behavior. Findings of reduced lateralized dominance during open-loop smooth pursuit eye movements in autistic individuals and their first-degree relatives [ 119 , 233 ] also are consistent with findings of atypical functional lateralization of motor circuits in autistic individuals during rest [ 135 ], reduced lateralized hand dominance [ 135 ], and results showing reduced lateralization of ERP N170 components during facial processing [ 234 ], to suggest reduced hemispheric specialization of functional brain networks may be a familial endophenotypic trait affecting multiple developmental abilities in autism. Analyses of how different sensorimotor endophenotypes co-vary across family members are needed to determine whether they represent separate ETDs associated with distinct genetic substructures [ 119 , 133 , 135 , 232 , 233 , 234 ].
Sensorimotor behaviors also offer important advantages in the search for endophenotypes based on their translational nature. Motor control systems are largely preserved across different species allowing for direct back-translation. Oculomotor systems have been studied extensively in non-human primates advancing resolution of the circuits and cellular processes contributing to distinct behaviors. For example, Takagi et al. [ 136 ] documented that ablation of posterior cerebellar vermis impairs feedback mechanisms supporting saccade accuracy. Recovery of function is seen in primates, though persistent deficits modulating accuracy across repeated events/trials are evident, highlighting a critical role in error feedback correction that also is seen in autistic individuals implicating cerebellar modulation of brainstem circuits [ 137 ]. Subsequent analyses show that olivary climbing fibers synapsing with cerebellar Purkinje cells are necessary for feedback learning and may act as a crucial circuit for interrogation of ASD-related sensorimotor impairment [ 235 ].
Multiple mouse genetic models of ASD also show sensorimotor deficits, including deficits of coordination and increases in movement variability offering important leads for clarifying molecular mechanisms associated with sensorimotor and perhaps downstream behavioral differences in ASD [ 150 , 236 ]. Another mouse model of ASD via valproic acid exposure produced selective cell loss in motor cortex and cerebellum, with a greater degree of cell loss in males than females. In addition, both male and female mice exhibited motor deficits that were associated with Purkinje cell loss in crus I of cerebellum [ 151 ]. Findings that rescue of cerebellar Purkinje cell function through the mTOR pathway also indicate that understanding of the molecular, cellular, and neurophysiological bases of sensorimotor impairments may guide new therapeutic strategies targeting familial risk mechanisms of ASD [ 152 , 153 ].
Multiple promising endophenotypes associated with key behavioral traits in ASD, including social, communication/language, cognitive, and sensorimotor behaviors, have been identified. Their analysis across multiple levels holds promise for identifying ETDs that may elucidate pathways of ASD inheritance. Analysis of ETDs is aided by focus on discrete, quantitative, and heritable traits that also are capable of being readily back-translated to model systems for interrogating cellular and molecular processes. The ETDs described above are not intended to be exhaustive, but instead serve as important targets for dense phenotyping family studies as has been done for separate psychiatric traits and clinical populations (e.g., [ 237 , 238 , 239 ]). Analyses of separate behaviors implicated in ASD (e.g., attention, sleep disturbances), and ETDs within the same individuals and across species will be imperative for mapping causal chains related to separate clinical traits in ASD.
Bottom-up approaches for parsing etiological heterogeneity in ASD
The ETDs described above each were developed based on descriptions of behavioral traits associated with ASD. While we propose that “top-down” mapping of ETDs starting with behavioral traits will accelerate progress in understanding inherited pathways, it also is likely that significant advances will be generated using a “bottom-up” approach in which traits with simpler genetic structures serve as the starting point for connecting genes to behavior. This approach involves developing ETDs that leverage known genetic/molecular targets, blood-based, neurophysiological, or cellular traits to understand neurobiological processes contributing to select behavioral outcomes [ 240 , 241 ]. Multiple candidates have been implicated based on their associations with autistic traits and ability to provide mechanistic insights, including increased extra-axial fluid [ 242 , 243 , 244 ], atypical melatonin [ 245 ], and immune system dysfunctions [ 246 ]. Studies are needed to determine the familiality of these traits and the extent to which they may offer power for more direct linkage with pathogenic variants.
Analysis of serotonergic (5HT) function represents an illustrative example of how an endophenotype-first approach may provide traction for gene discovery in ASD. Elevated whole-blood 5HT (WB5HT), or hyperserotonemia, represents perhaps the most replicated biomarker associated with ASD. It is evident in more than 25% of autistic individuals, tracks in unaffected family members [ 247 , 248 ], and is highly heritable [ 249 ]. Despite WB5HT being a more molecular trait than the behaviors described above, mechanisms of hyperserotonemia remain complex and not well understood. It is possible that hyperserotonemia in ASD reflects atypicalities in synthesis within the intestines, abnormal uptake into platelet, or differences in 5HT release related to receptor expression or function [ 249 , 250 , 251 ]. One candidate mechanism that has been well studied is 5HT 2a receptor function in platelet aggregation. The vast majority (99%) of blood 5HT is stored in platelets [ 251 ], and 5HT 2a receptor enhances platelet aggregation [ 252 ] and is correlated with WB5HT levels [ 251 , 253 ]. While findings regarding 5HT 2a receptors in platelets have not been consistent in ASD studies [ 254 , 255 ], hyperserotonemic first-degree relatives of autistic children show lower densities of 5HT 2 receptors in platelets in comparison to normoserotonemic relatives [ 251 ]. Further, PET and SPECT studies have indicated that individuals with ASD and parents in multiplex families show lower 5HT 2 density and binding in cortex that may be negatively correlated with platelet 5HT [ 253 ]. While associations between 5HT 2a binding, WB5HT, and discrete behavioral traits in ASD have been largely inconsistent, these results suggest that WB5HT and 5HT 2a receptor density and function could serve as important candidate traits for taking an endophenotype-first approach to characterize genetic substructures in subsets of families, and is highly heritable [ 249 ]. Despite WB5HT being a more molecular trait than the behaviors described above, mechanisms of hyperserotonemia remain complex and not well understood. It is possible that hyperserotonemia in ASD reflects atypicalities in synthesis within the intestines, abnormal uptake into platelet, or differences in 5HT release related to receptor expression or function [ 249 , 250 , 251 ]. One candidate mechanism that has been well studied is 5HT 2a receptor function in platelet aggregation. The vast majority (~ 99%) of blood 5HT is stored in platelets [ 251 ], and 5HT 2a receptor enhances platelet aggregation [ 252 ] and is correlated with WB5HT levels [ 251 , 253 ]. While findings regarding 5HT 2a receptors in platelets have not been consistent in ASD studies [ 254 , 255 ], hyperserotonemic first-degree relatives of autistic children show lower densities of 5HT 2a 5HT 2 receptors in platelets in comparison to normoserotonemic relatives [ 251 ]. Further, PET and SPECT studies have indicated that individuals with ASD and parents in multiplex families (i.e., families with more than one autistic child) show lower 5HT 2a 5HT 2 density and binding in cortex that may be negatively correlated with platelet 5HT [ 253 ]. While associations between 5HT 2a binding, WB5HT, and discrete behavioral traits in ASD have been largely inconsistent, these results suggest that WB5HT and 5HT 2a receptor density and function could serve as important candidate traits for mapping ETDs to characterize genetic substructures of select traits in subsets of families.
Increased total brain volume is perhaps the most replicated finding from MRI studies of autistic individuals [ 256 , 257 , 258 ]. Brain enlargement also has been documented down to infancy [ 259 , 260 ] with altered growth trajectories observed across the lifespan [ 256 ] involving multiple brain regions and subcortical structures and both gray and white matter [ 257 , 260 , 261 , 262 , 263 ]. Importantly, head circumference, an index of total brain volume, has been found to be heritable [ 19 ]. Further, first-degree family members of individuals with ASD and macrocephaly show increased head circumference relative to family members of individuals with ASD who are not macrocephalic [ 240 , 264 ], suggesting that co-segregation of autistic traits and macrocephaly may represent separate inherited polygenic backgrounds or biotypes. While increased head circumference has been a consistent finding, associations with clinical and behavioral traits have been inconsistent as studies have documented relationships with social-communication severity, restricted, repetitive behaviors, uneven cognitive development, and language outcomes [ 265 , 266 , 267 , 268 ], though these results have varied as a function of the age of individuals studied, their severity, clinical outcome measures, and brain regions studied [ 19 , 269 ]. These “inconsistencies” are not surprising given the wide range of mechanisms that could underpin generalized brain overgrowth, and studies focused on select subregions or subcortical structures have found strong and somewhat consistent relationships with different clinical behaviors (e.g., [ 267 , 268 , 270 ]). Developmental variations also appear to strongly impact the nature and direction of these relationships [ 161 ].
Further, separate mechanisms may contribute to brain enlargement, and the extent to which they may be related to overlapping or distinct phenotypic patterns remains unclear. For example, germline mutations in PTEN, a tumor-suppressing gene, have been linked to conditions of tissue overgrowth in Cowden and Bannayan-Riley Ruvalcaba syndromes [ 271 ] and macrocephaly in some individuals with ASD. More specifically, 10–20% of autistic individuals with macrocephaly show PTEN mutations [ 271 , 272 , 273 ], and macrocephaly also is seen in non-autistic family members of these probands, but only selectively in family members who also have PTEN [ 272 ]. These findings are important in potentially understanding downstream molecular signaling mechanisms (e.g., mTOR) that may contribute to risk for autistic traits and macrocephaly, and for guiding imaging and neuropsychological studies to map ETDs useful for indexing etiological processes associated with autistic traits in populations with macrocephaly. Importantly, associations between macrocephaly, autistic traits, and PTEN mutations also inform powerful approaches for interrogating select trait pathways in model systems. For example, happloinsufficient mice with PTEN mutations also show brain overgrowth and some social and behavioral traits associated with ASD [ 274 ]. Similarly, selective deletion of PTEN in the hippocampus and layers III and V of cerebral cortex lead to macrocephaly in mice as well as atypical social behaviors, sensory hyperreactivity, and neuronal hypertrophy [ 275 ]. It remains unclear if molecular signaling and neurodevelopmental pathways impacted by PTEN mutations may overlap with those affecting some autistic individuals with macrocephaly but without known genetic causes. Studies of PTEN mutations provide a promising illustration of how endophenotype research may benefit from studies examining relationships between the many known genetic variants associated with autistic traits and candidate endophenotypes. Knowledge of the functional significance of known genetic risk variants also may be leveraged to generate new endophenotypes.
Transdiagnostic considerations
While the focus of this review has been on ETDs associated with ASD, the endophenotype approach derives power from measuring traits that are continuously distributed in the population and agnostic to diagnostic status or categorical distinctions. This conceptual shift is critical in the context of repeated findings that the vast majority of variants associated with ASD also are associated with multiple separate psychiatric and neurodevelopmental disorders (e.g., [ 34 , 276 ]). In support of this proposal, multiple studies have shown that copy number variants (CNVs) associated with ASD and other neuropsychiatric disorders (e.g., schizophrenia, ADHD) also converge on common patterns of functional and structural brain differences. Moreau et al. [ 277 ] identified signatures of functional connectivity differences associated with both 16p11.2 and 22q11.2 CNVs that both transcended clinical diagnosis (ASD, ADHD, schizophrenia) and also were seen in select cases without known associated variants. Studies of brain morphometry have shown similar overlap across different CNVs and subsets of individuals without known genetic causes for their diagnosis (i.e., idiopathic cases), suggesting that understanding of the neurodevelopmental processes affected by pathogenic CNVs may inform understanding of broader subgroups of neurodevelopmental traits [ 278 ]. Importantly, because these CNVs and associated clinical traits are present across diagnostic categories, they strongly suggest that transdiagnostic strategies will be crucial for understanding pathogenicity.
Historically, endophenotype criteria have stipulated that ETDs must be disorder-specific, but research in psychiatry has yielded strong evidence of phenotypic overlap at multiple levels of analysis. Population studies of non-clinical samples have indicated that, in many instances, self-endorsed clinical symptoms show similar levels of heterogeneity within diagnostic categories as between diagnostic categories [ 279 ]. Consistent with this hypothesis, the vast majority of (if not all) traits associated with ASD also are implicated in separate developmental conditions (e.g., atypical social gaze is seen in non-clinical populations as well as social phobia and schizophrenia; repetitive behaviors are seen in non-clinical populations, intellectual developmental disability and OCD). ETD discovery will be most powerful if focused on the full range of trait variation, including clinical and subclinical variation [ 280 ]. By measuring the full range of endophenotypic trait variation, we will have more power to identify associations with dimensional behavioral traits and neurodivergent trajectories without the constraints of categorical designations that do not appear to be directly linked to discrete biologies.
Summary and conclusions
It is our position that understanding the complex pathogenic processes associated with ASD can be accelerated by shifting away from traditional case–control designs for gene discovery and instead prioritizing transdiagnostic studies that integrate dimensional endophenotypes for participant stratification. One method for leveraging candidate endophenotypes to understand mechanisms of ASD inheritance is developing ETDs, or associated endophenotypes that cut across functional units of analysis. Similar approaches (e.g., see above descriptions of the BSNIP studies) have proven powerful for identifying more biologically homogeneous subgroups of individuals, but have not yet been leveraged to understand traits associated with neurodevelopmental disorders including ASD. The quest for ETDs involved in ASD should focus on traits that are discrete, quantitative, familial, closer to gene action than behavioral traits, and translational. The dimensional and condition-agnostic nature of ETDs may accelerate gene discovery and advance understanding of heritable, polygenic processes contributing to neurodevelopmental impairments.
Availability of data and materials
Not applicable.
Change history
28 february 2024.
A Correction to this paper has been published: https://doi.org/10.1186/s11689-024-09523-2
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Acknowledgements
The authors are thankful to families participating in ASD research, past, present, and future, who continue to make family study and endophenotype research possible.
This work was supported by R01 MH112734 (MWM), U54 HD090216 (MWM, KEU, RS), P20 GM103418 (KEU, RS), and R01 MH115046 (JTE).
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Mosconi, M.W., Stevens, C.J., Unruh, K.E. et al. Endophenotype trait domains for advancing gene discovery in autism spectrum disorder. J Neurodevelop Disord 15 , 41 (2023). https://doi.org/10.1186/s11689-023-09511-y
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CASE STUDY Gary (bipolar disorder) Case Study Details. Gary is a 19-year-old who withdrew from college after experiencing a manic episode during which he was brought to the attention of the Campus Police ("I took the responsibility to pull multiple fire alarms in my dorm to ensure that they worked, given the life or death nature of fires"). ...
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Gus Alva, MD, DFAPA: Psychiatric Times presents this roundtable on the management of bipolar disorder, a phenomenal dialogue allowing clinicals a perspective regarding current trends and where we may be headed in the future. This is an interesting case, as we take a look at this 23-year-old female who first comes in to see her psychiatrist with moderate depressive symptoms.
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 ...
studies. Case reports and small observations studies or randomized controlled trials of fewer than 50 patients were excluded. Modern definitions of bipolar disorder In the 1970s, the International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders reflected the prototypes of mania
Presents a case report of a 30-year-old married Caucasian woman, presented to our university clinic seeking a new psychiatrist to manage her bipolar illness. She had moved to the Southeast due to her husband's job relocation three months ago, and had few social contacts in her new city. She reported emerging from the depths of a severe major depressive episode one year ago and since then had ...
The terms "soft bipolar" or "bipolar spectrum" were first proposed by Akiskal and Mallya ( 4) to describe psychopathological states that could not be easily diagnosed. It has been reported that soft bipolar cases may be prevalent up to 5.1%-23.7% ( 5 ). Cyclothymia and unspecified type of bipolar disorder are suggested to be present ...
Bipolar disorder is a mood disorder characterized by a history of mania, hypomania, or mixed episodes along with mood episode recurrences over time (American Psychiatric Association, 2000). A manic episode includes an elevated or irritable mood lasting at least one week, along with increases in the speed of thoughts, distractibility, speech ...
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Introduction. Bipolar disorder is one of the common psychiatric disorders with an episodic instability in the mood, behavior, and insight ().It has a significant impact on individual performance, reduces the quality of life (), and amplifies suicide risk ().Fortunately, with advances in the treatment of psychiatric illnesses, including bipolar disorder, many of these patients are able to live ...
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Here, we present a case of bipolar disorder emerging in late life with no clear organic causes. This case highlights the importance of a broad differential diagnosis when approaching new-onset manic symptoms among geriatric patients. 2. Case report. Mr. K, a 59-year-old retired ethnic Taiwanese man who had graduated from elementary school, was ...
Case 1. Ms. Genera is a 36-year-old woman with bipolar II disorder, first diagnosed in college, who is brought to the psychiatric emergency room by her boyfriend of 5 years. He is hoping that she will be admitted to the hospital "before she goes all-the-way manic.". He reports that she "almost lost her job last time!".
The Impact of Mood Stabilizers on Suicide in Bipolar Disorder: A Comparative Analysis. Frederick K. Goodwin and S. Nassir Ghaemi. CNS Spectrums. Published online: 7 November 2014. Chapter. Molecular imaging of bipolar illness. John O. Brooks , Po W. Wang and Terence A. Ketter. Understanding Neuropsychiatric Disorders.
Bipolar disorder (formerly called manic-depressive illness or manic depression) is a mental illness that causes unusual shifts in a person's mood, energy, activity levels, and concentration. These shifts can make it difficult to carry out day-to-day tasks. There are three types of bipolar disorder. All three types involve clear changes in ...
Seventy case studies help in the recognition of Bipolar across a wide range of severity from successful Bipolar II clients to grandiose, paranoid, and psychotic Bipolar individuals. ... There is little question that high levels of creativity often accompany a diagnosis of Bipolar Disorder. Such is the case with singer/songwriter Kurt Cobain ...
Abstract. When a patient suffering from bipolar II disorder is misdiagnosed as experiencing unipolar depression, the recommended treatment of the latter may precipitate a hypomanic or manic ...
Decreased need for sleep. 3. More talkative than usual or pressure to keep talking. 4. Flight of ideas or subjective experience that thoughts are racing. 5. Distractability, i.e. attention too ...
Case Report on Bipolar Affective Disorder: Mania with Psychotic Symptoms Kounassegarane Deepika AbstrAct Bipolar affective disorder (BPAD) is a major psychiatric disorder all around the world, which is mainly characterized by frequent and recurrent episodes of mania, hypomania, and depression. A majority of complete etiology or pathogenesis of ...
Early-onset Bipolar Disorder. Studies have shown that bipolar disorder usually begins with an index episode of depression: positive family history (Pavuluri, Birmaher, & Naylor, 2005), clinical severity, psychotic symptoms, and psychomotor retardation are well documented predictors of bipolarity.Approximately 20% of youths with a first major depressive episode will develop a manic episode.
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The first one is a patient with bipolar 1 disorder who reports new onset of movements. This is a 54-year-old woman who received a diagnosis of bipolar 1 disorder at the age of 32, after requiring hospitalization for an acute manic episode. She was started on lithium at that time. She relapsed at age 41 with a florid manic episode requiring ...
Personal trauma: Traumatic life events, such as a divorce, child abuse, loss of a loved one, or financial problems can trigger or worsen bipolar episodes.; Stress: Negative stress worsens symptoms and leads to shorter symptom-free periods.; Sleep disruptions: Though sleep disruptions are features of bipolar disorder, insufficient sleep or interruptions to your sleeping patterns can also ...
Healthy Lifestyles for Bipolar Disorder. We are about to launch the largest study ever conducted on how dietary interventions, when added to medication, might help sleep issues for people with bipolar disorder. Our goal is to understand not only if the intervention helps, but also a very broad range of the ways in which it may help, including ...
Introduction. Bipolar disorder (BD) is a chronic illness associated with severely debilitating symptoms that can have profound effects on both patients and their caregivers (Miller, 2006).BD typically begins in adolescence or early adulthood and can have life‐long adverse effects on the patient's mental and physical health, educational and occupational functioning, and interpersonal ...
How can the healthcare team address Sarah's substance abuse issues in the context of her bipolar disorder? Addressing substance abuse in the context of bipolar disorder involves integrated treatment approaches. Collaborate efforts between psychiatric and addiction specialists, along with support groups, can help manage dual diagnoses.
Design, setting, and participants: This case-control study included individuals in Sweden aged 6 to 64 years who received an incident diagnosis of ADHD or ADHD medication dispensation between January 1, 2007, and December 31, 2020. Data on ADHD and CVD diagnoses and ADHD medication dispensation were obtained from the Swedish National Inpatient ...
Autism spectrum disorder (ASD) is both clinically and etiologically diverse. Rare inherited and de novo pathogenic variants each have been repeatedly implicated and account for up to 20% of cases [1, 2].For a plurality of individuals with ASD, however, it is believed that the primary causes include gene-gene and gene-environment interactions that involve multiple common inherited variants and ...