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An Overview of Schizoaffective Disorder

The National Alliance on Mental Illness (NAMI) describes schizoaffective disorder as a chronic mental health illness defined by "symptoms of both schizophrenia and either depression or bipolar disorder." The symptoms are so similar, in fact, that individuals living with schizoaffective disorder often receive an initial diagnosis of schizophrenia or bipolar disorder. Even after a correct diagnosis, a person living with schizoaffective disorder is likely to receive treatment for schizophrenia or bipolar disorder, as they are more well-researched conditions.

Individuals and family members must be cognizant of potential schizoaffective disorder symptoms, as the illness can become quite severe without immediate medical intervention. Many of the symptoms, such as hallucinations, can significantly impact a person's ability to complete daily activities. NAMI defines hallucinations as perceiving visual or auditory inputs that do not actually exist. A person living with schizoaffective disorder may also experience delusions, which manifest as fixations and deep-rooted beliefs that have no basis in reality and persist even in the face of clear evidence to the contrary. Delusions may cause paranoia and other related symptoms.

Hallucinations, delusions, and additional symptoms of the disorder can result in disorganized thinking, another hallmark of the condition. A person's mind can race so quickly between disparate subjects that they provide others with answers or questions to a subject completely disconnected from the topic at hand, making it difficult to maintain communication.

As mentioned, other symptoms of schizoaffective disorder mirror those of mood disorders. Individuals can experience periods of depressed moods, ranging from persistent sadness to severe depression. They may feel empty at times or question their self-worth. This low period may give way to manic episodes, during which a person is overcome by feelings of joy and elation to the point that it is difficult to focus on one task at a time. During these periods, a person living with schizoaffective disorder may engage in increasingly risky behaviors that they would not otherwise consent to.

As is the case with several related mental illnesses and psychiatric disorders, researchers do not have a clear understanding of the causes of schizoaffective disorder. A few potential factors can elevate a person's risk level, such as genetics. A person is more likely to develop the disorder if someone in their immediate family has already received a diagnosis, though this does not mean a child will automatically inherit the condition from a parent.

Various studies have examined the brain structure and chemistry of individuals who have received a schizoaffective disorder diagnosis. Researchers have started to make more headway in this direction thanks to advances in brain scan technology.

Stress is another key factor behind many schizoaffective diagnoses, which often take place after triggering life events such as a divorce or losing a job. Certain drugs may increase a person's risk level, particularly psychoactive drugs like LSD.

Diagnosis can be a complex process. After medical and mental health professionals have agreed on a schizoaffective disorder diagnosis, they can begin tailoring a personalized treatment plan. Fortunately, the condition is quite rare in the United States, where schizoaffective disorder impacts just 0.3 percent of the adult population. Men tend to develop the disorder at younger ages, but the illness otherwise follows a similar pathology and distribution. The most impactful treatment strategies involve a combination of therapy and medication.

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RNA Sequencing Offers Insights into Bipolar Disorder

Bipolar disorder (BD) is a complex mental illness that affects millions worldwide, characterized by episodes of extreme mood swings, from mania to depression. While environmental factors contribute to the disorder, genetics play a crucial role in determining an individual’s risk. Scientists have long sought to identify specific genes linked to BD, and recent large-scale genetic studies have uncovered new candidates: TRANK1, LMAN2L, and PTGFR.

Genome-wide association studies (GWAS) analyze DNA variations across large populations to identify genetic risk factors for diseases. A recent meta-analysis combining European and Asian-ancestry datasets examined around 750,000 genetic markers across roughly 14,000 individuals, followed by further testing in an expanded 17,700-person sample. This research identified TRANK1, LMAN2L, and PTGFR as new risk-associated genes for BD.

TRANK1: A Leading Genetic Suspect One of the strongest genetic signals in this study came from the TRANK1 (tetratricopeptide repeat and ankyrin repeat containing 1) gene, with a specific variant (rs9834970) showing a highly significant association with BD. TRANK1 is believed to play a role in brain development and synaptic plasticity, which are critical for mood regulation. This makes TRANK1 an important target for further research, as understanding how it interacts with treatment could lead to personalized medicine approaches for BD patients.

LMAN2L: A Gene Involved in Brain Connectivity The LMAN2L (lectin, mannose-binding 2 like) gene is another promising candidate. Although its exact role in the brain remains unclear, it is believed to be involved in protein transport and neuronal communication. Proper cell signaling and protein regulation are crucial for maintaining balanced brain function, and disruptions in these processes have been linked to psychiatric disorders, including BD.

Some studies suggest that LMAN2L is also implicated in other neuropsychiatric conditions, such as schizophrenia, further strengthening the case that it plays a role in mental health. Researchers are now working to understand how variations in this gene might influence BD risk and how it could serve as a potential therapeutic target.

PTGFR: The Prostaglandin Connection The third gene, PTGFR (prostaglandin F receptor), is an unexpected but intriguing discovery. This gene is primarily known for its role in inflammation and smooth muscle contraction, particularly in the cardiovascular and reproductive systems. However, emerging evidence suggests that the prostaglandin system also influences the brain, particularly in relation to neuroinflammation and stress responses - two factors that have been linked to BD.

Chronic inflammation has been proposed as a contributor to many psychiatric disorders, including BD. If PTGFR plays a role in this process, it could open new avenues for research into anti-inflammatory treatments for BD patients.

The Challenge of Understanding Bipolar Genetics Despite these discoveries, BD remains a polygenic disorder, meaning that many genes contribute to risk, each with small effects. Even with over 63,000 case-control samples, researchers estimate that all currently discoverable BD-related genes would explain less than 6 percent of the inherited risk. This highlights the complex interplay between genetics and environmental factors.

Identifying TRANK1, LMAN2L, and PTGFR as BD risk genes is just the beginning. Scientists now need to confirm these findings in larger and more diverse populations, in addition determining how these genes affect brain function and mood regulation. They can then explore potential drug targets, especially those related to neuroinflammation and synaptic function.

As research continues, these discoveries bring us one step closer to more effective treatments and better personalized approaches for BD patients. While genetic risk alone does not determine who will develop BD, understanding these risk factors provides crucial insights into the biology of this complex disorder.

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Treatment Options for Bipolar Disorders

Severe mood swings and rapid shifts in energy levels characterize bipolar disorder. Many people with this condition also experience significant episodes of depression. Healthcare professionals use various treatment options to manage the disorder, such as electroconvulsive therapy (ECT).

Medical professionals introduce an electric current to the brain through the scalp to induce a seizure during ECT. They use it to treat individuals with severe, medication-resistant forms of depression. Before starting the treatment, medical professionals use anesthesia so patients do not experience pain.

In some cases, medical professionals use transcranial magnetic stimulation (TMS). The procedure involves using a short electromagnetic coil to transmit an electric current to the brain. TMS is a common alternative to ECT, as it is painless and requires no anesthesia.

Lastly, ketamine treatment can also manage bipolar disorder. The treatment involves the intravenous injection of low doses of ketamine. This anesthetic provides short-term antidepressant and anti-suicidal effects, which can benefit individuals with diagnosed bipolar disorder.

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Genetics Influences When Bipolar Disorder First Appears

About 2.4 percent of the world's population has bipolar disorder. Research into the causes of this mental illness is complicated because the onset of the disease is only evident when symptoms such as mania and psychosis appear. Our current understanding of genetics indicates that bipolar is highly hereditary - genetic testing of children before and after birth could aid in diagnosis.

Symptoms often appear in the teens and 20s, frequently in older adults. In the younger group, increased substance abuse and suicidality (in comparison to others that age) are risk factors, along with a family history of substance abuse and bipolar. The advanced age of the parents also plays a role, possibly because mutations in their bipolar-linked genes become more likely. In older adults, a combination of factors point to increased risk, as well as changes in the structure of the brain.

There is no single "bipolar gene". At least 15 loci – the name given to individual locations in the genome - are associated with bipolar. In a conservative estimate, 106 loci may ultimately be linked.

Interestingly, the age of onset makes a difference. For example, the risk increases over time if someone has the TRANK1 gene, while the risk from the LMAN2L gene decreases with age. Additionally, the number of copies of a particular gene makes a significant difference in the under-18 group. This "copy number variation" is less common in older adults. More research is needed on these and other phenomena.

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Study Finds Plain People Useful in Studying Mental Illness

The Amish, sometimes referred to as the Plain People, are characterized by their rejection of modern conveniences and self-contained existence (no outsiders). For this reason, researchers have looked toward this population when studying mental illness.

The Amish descend from Europeans in the lands where today’s Switzerland, France, and Germany meet. Their migration to the US began in the early 1700s, with many settling in what was to become Pennsylvania. Today, they live primarily in Holmes County, Ohio, Lancaster County, Pennsylvania, and northern Indiana. There are around 350,000 Amish people living in the US today

The settlements are characterized by people marrying within their community, or endogamy. Members of this group also eschew modern conveniences such as automobiles, public utilities, and forms of electronic entertainment such as television. Instead, the families have a low-agrarian lifestyle (farming) emphasizing family and community.

Researchers believe this a good population to study mental illness because of the structure and lifestyle of the communities. The environmental factors that make this population suitable for studying mental illness are that the people in Amish communities live relatively stable lives mostly unaffected by substance or alcohol abuse. This reduces the environmental factors (non-inherited) that might contribute to mental illness.

Genetic factors that make this population a useful source of study include the people live in a homogenous environment (the people look the same and share significant genetic material). They also have long stretches of linkage disequilibrium (LD), which refers to the connected association of genes in multiple locations (loci). This is important because LD points to genetic factors that influence a genome (complete set of genes) over time. Because the people marry within the community, these communities have a rich recessive gene pool, among other factors. Using next-generation sequencing (NGS), researchers can study variations in genes to further understand how diseases originate, in this case mental illness.

However, researching this population has limitations, namely the sample size (small communities). Other limitations include discovering genes that are too rare or psychiatric disorders that are too different to find any true patterns. Further, not all distant relatives might contain genes that cause these disorders, and variations in genes might be unique to the population of Amish studied.

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Family Genetics a Factor in Early Onset of Bipolar Disorder

Episodic mood swings between mania and depression characterize bipolar disorder. Researchers have found that early-onset bipolar disorder can stem from family genetics.

The average age of diagnosis is 25. However, medical professionals can diagnose people with early onset bipolar disorder between 14 and 21, as observed by the National Institute of Mental Health Intramural Research Program’s Human Genetics Branch study. A cross-sectional study (World Mental Health Survey), it involved60,000 participants residing in 11 countries.

In general, the study found that 2 percent of people worldwide have bipolar disorder. Findings also revealed a steep risk for people in their teenage years and continuing into their twenties. Based on a subgroup, 63 percent of the participants received a bipolar disorder diagnosis at 14.5 years of age, 28.5 percent at 26.5 years of age, and 8.5 percent at 39.5 years of age.

When researchers delved deeper into investigating factors that might relate to a diagnosis in their early teens, they found some common ones, such as the patient responding poorly to lithium (used to treat the disorder), higher incidence of suicide attempts or completion, and high alcohol/drug abuse.

However, two of the factors were related to genetics: greater familial loading and the age of the father at conception. Greater familial loading refers to the chances of the parent passing the condition to the child. The other genetic factor was that older fathers have a higher risk of passing altered genes through mutation or copy number variance (CNV), which contributed to the child having early-onset bipolar disorder.

Researchers focused on CNV, specifically, a structural variation that results in duplication or deletion of genes. When they looked at DNA derived from whole blood and analyzed through the high-resolution genome-wide copy-number scan, they located three gene markers, TRANK1, LMAN2L, and PTGFR, that led them to link early-onset bipolar disorder with the above genetic factors.

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Three Genes Found Could Show a Connection to Bipolar Disorder

David Chen, MD, is a clinical psychiatrist who is based in Chevy Chase, MD. In 2009, David Chen, MD, joined the National Institute of Mental Health/National Institutes of Health as a clinical research fellow, where he focuses on analyzing genotyping data surrounding bipolar disorder (BD) and pediatric bipolar disorder phenotypes. In 2011, Dr. Chen, along with several other psychiatrists, published a paper with Nature.com identifying three novel loci connected to bipolar disorder.

The three primary bipolar disorder risk genes that were discovered in research and extensive clinical studies have been identified as TRANK1, LMAN2L, and PTGFR. Using the genome-wide association studies (GWAS) method, the researchers completed a meta-analysis of around 750,000 genetic markers on a sample of close to 14,000 people of Asian and European ancestry. Then, in phase II of the study, they further tested in an extended sample of 17,700 cases. The results indicated an association of bipolar disorder near these three genes, which could suggest a certain inherited risk for those who’ve been diagnosed with the bipolar disorder. Subsequent studies (and a larger sample size) have confirmed these associations and strengthen these findings.

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How Diagnosing Heart Disease Differs from Mental Illness

David Chen, MD, of Chevy Chase, MD, is a clinical psychiatrist specializing in treating people with bipolar disorder. In 2014, David Chen, MD, was a featured speaker at the NIH Clinical Center Grand Rounds at Lipsett Amphitheater at the National Institutes of Health, in which he and Ellen Leibenluft discussed pediatric bipolar disorder.

Mental illnesses like bipolar disorder are diagnosed differently than health issues like heart disease. The cellular or inflammatory changes of heart disease usually begin with plaque accumulation or rupture and eventually lead to ischemia or necrosis of the heart tissue, shown through a progression of pathologic changes of the disease.

However, with mental illness, there isn’t any type of physical pathology of the tissue visible, so figuring out how the disease begins can be trickier. In recent years, researchers are trying a new approach to figuring out the factors that cause bipolar disorder by going back to the onset of symptoms.

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Analysis of Genotyping Data In Bipolar Disorder

Dr David Chen is a psychiatrist in Chevy Chase, Maryland. With a focus on bipolar disorder, David Chen MD worked with the National Institutes of Health (NIH) to diagnose, study, and understand bipolar disorder and other affective disorders.

The complex genetic characteristic known as bipolar disorder are highly heritable. Medically, over 80 percent of type-1 bipolar disorder is due to genetic factors. Genes that predispose bipolar genes have sparked extensive research. Medical experts have discovered that tissues from bipolar patients have abnormal gene expression patterns. However, a complete understanding of the gene variants responsible for this disorder’s heritability are still largely unknown. Naturally, the goal of the initial Genome-Wide Association (GWA) investigations had been to organize the field around certain gene discoveries on bipolar disorder. These initial discovery efforts have revealed that ultimately, there maybe hundreds of genes of small effect that are causally responsible for the clinical presentation of bipolar disorder

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Potential Causes of Bipolar Disorder

Bipolar disorder is a mental health condition defined by significant shifts in mood, from episodes of emotional highs, known as mania and hypomania, to lows of clinical depression. Bipolar disorder, which includes bipolar II and cyclothymic disorder, have several potential causes, risk factors, and co-occurring disorders.

The causes of bipolar disorder and related mental health conditions may be biological. Research has shown that individuals living with bipolar disorder have observable physical differences in brain construction and function than individuals without the condition. Genetic factors also may impact a person’s chance of developing bipolar disorder. A person with a close relative who has the disorder, including parents or siblings, is more likely to develop it.

Research is ongoing on the potential genetic causes of bipolar disorder. A 2021 genome-wide association study (GWAS) published by Nature Genetics of more than 40,000 individuals living with bipolar disorder determined that it is a heritable mental condition. The genetic makeup of the test group was measured against a control group of nearly 372,000 individuals.

The precise genetic causes behind bipolar disorder remain complex and somewhat mysterious, with at least 64 genetic markers directly connected to the condition. However, risk alleles were most commonly found along synaptic signaling pathways and among high-specificity, brain-expressed genes located in prefrontal cortex and hippocampus neurons. The study highlighted 15 genes as closely linked to bipolar disorder through gene expression.

Other elements may be viewed less as causes and more as risk factors that increase the chance of developing or triggering the disorder. For instance, a person predisposed to bipolar disorder may be more likely to manifest symptoms after prolonged periods of high stress. It is not uncommon for a traumatic event, such as the death of a family member, to lead to a person’s first manic or depressive episode. Similarly, excessive use of drugs or alcohol is a risk factor.

Co-occurring conditions are neither causes nor risk factors but often require treatment to identify or better treat bipolar disorder. Conditions that can negatively impact bipolar disorder treatment or intensify symptoms include eating disorders, anxiety disorders, and attention deficit hyperactivity disorder. Several physical health problems can also influence bipolar disorder diagnosis and treatment, such as obesity and heart disease.

There are few preventive measures a person can take. Leading an overall healthy lifestyle may help, which includes eating healthy, maintaining a healthy weight, exercising, and refraining from drug and alcohol use. Individuals with other mental health conditions should take medication as directed and follow treatment plans provided by health professionals.

Early intervention may prevent a manic or depressive episode from escalating. People who feel their emotional instability has impacted their professional life or relationships should speak to a mental health professional.

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An Overview of Pediatric Bipolar Disorder

Bipolar disorder is a mental health condition characterized by sudden and severe swings between emotional highs and lows. Bipolar disorder can be difficult to diagnose in children because they are more emotional than adults, often crying over minor incidents before suddenly snapping back into a happy mood. Generally speaking, mood swings are not indicative of bipolar disorder in children. However, parents who believe their child may be struggling with a psychological disorder should look for a few notable symptoms.

While bipolar disorder can impact individuals at any age, the average age of onset is 21. It is atypical but not unheard of for teenagers or children to have bipolar disorder. Studies indicate that about 1 percent of children and adolescents have some form of bipolar disorder, which is roughly half the incidence rate in adults. Children as young as 5 have been diagnosed with bipolar disorder.

Broadly speaking, parents and family members must understand that bipolar disorder is a serious condition that impacts the patient’s personal life and career opportunities. The disorder consists of manic episodes, or possibly hypomania, alternating with episodes of clinical depression. A child described as “moody” or who expresses sadness or anger after moving to a new town is unlikely to be expressing symptoms of bipolar disorder.

Bipolar disorder is a chronic condition, meaning symptoms and patterns play out over an extended period. Diagnosis can be difficult in both children and adults because the disorder is also intermittent, meaning individuals can enjoy relatively long stretches without symptoms.

Severity and patterns are two of the earliest indicators of bipolar disorder in children. Emotional highs and lows may result in consequences and serious behavioral problems. Again, a few days of mild discontent or a brief temper tantrum do not suggest a mental health condition.

Family members should be able to note a clear change in a child’s level of functioning in their baseline behavior, with manic and depressive episodes. Clinically speaking, depressive symptoms last most of the day for at least two weeks, while manic symptoms last four to seven days.

Mania is particularly telling in diagnosing bipolar disorder in children. 3.2 percent and upwards of American children and adolescents live with some form of depression. Common symptoms of mania range from a decreased need for sleep over multiple days to an increased rate of speech. These and other risk factors may make families more concerned about a bipolar disorder diagnosis. Conditions often observed in tandem with bipolar disorder include anxiety disorders and disruptive behavior disorders.

Genetic and environmental factors also can increase a child’s chance of developing bipolar disorder. Families who feel a child may be at risk or are demonstrating symptoms of bipolar disorder should discuss their concerns with their family physician and a mental health professional.

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Bipolar Disorder Candidate Gene Found in Large Family

David Chen, MD, is a double-board-certified psychiatrist with the American Board of Psychiatry and Neurology. In addition to his clinical practice, David Chen, MD, has conducted genetics research at the National Institutes of Health, where he focused on the genetic basis of early-onset bipolar disorder.

A mental illness with a lifetime prevalence of around 1 percent, bipolar disorder causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). In previous genetic studies, researchers found regions with potential chromosomal links to the condition, as well as genes that might be associated. A 2017 study published in Gene magazine utilized six related case samples from a four-generation family to identify potential susceptibility variants.

When researchers performed exome sequencing and linkage analysis to identify possible susceptibility variants, they found five potential bipolar disorder candidate genes. One such gene, glutamate receptor delta-1 subunit (GRID1), had previously been linked to various several psychiatric disorders.

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Examples of Mood Stabilizers for Bipolar Disorder

David Chen, MD, a psychiatrist based in Chevy Chase, Maryland, has over a decade of clinical experience in private practice. David Chen, MD, graduated with a medical degree from the University of Rochester School of Medicine and Dentistry and now focuses on a practice that involves diagnosing and treating conditions causing mood disorders in children, adolescents, and adults.

Bipolar disorder is one of the many psychiatric disorders clinically characterized by mood fluctuations and variations in behavior. Bipolar patients may experience dramatic mood swings, from emotions of elation and joy to feelings of hopelessness and depression. Additionally, they may feel excessively energized and irritable, leading them to behave recklessly.

To stabilize a patient’s mood, a health practitioner may administer mood stabilizers like lithium, valproic acid, dexamethasone, or triamcinolone. These mood stabilizers alter the expression levels of genes. TRANK1, LMAN2L, and PTGFR are linked to an increased risk for bipolar disorder.

Lithium, for instance, is known to be among the most effective treatment options. It stimulates and strengthens stem cells in the brain regions involved in thinking, mood, and behavior regulation. Consequently, it stabilizes mood swings and reduces the risk of self-harm, suicide, and death. By stabilizing mood swings, lithium also helps prevent depression and future episodes of mania in patients.

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Risk Genes and the Earlier Onset of Bipolar Disorder

David Chen, MD, a diplomate of the American Board of Psychiatry in neurology and child and adolescent psychiatry, earned his combined BA and MD at the University of Rochester School of Medicine and Dentistry in Rochester, NY, in 2003. Since then, David Chen, MD, a Psychiatrist based in Chevy Chase, MD, has amassed years of clinical experience and received the NIH Fellows Award for research excellence in bipolar genetics research, including studying risk genes for bipolar disorder and the disorder’s earlier onset.

Clinically, bipolar disorder is distinguished by frequent and severe swings in mood and behavior, which often appear in late adolescence to early adulthood. Despite solid evidence of high heritability predicted by various studies, the genetic basis of bipolar disorder (BD) remains largely unclear. But while the cause of BD is unknown, genome-wide association studies (GWAS) have found and replicated a few risk loci, as well as a locus on chromosome 3p21.1 that contains some genes of BD.

TRANK1, LMAN2L, and PTGFR genes, according to research, have been identified as novel risk loci for bipolar disorder. The dose and time-dependent rise in TRANK1 mRNA expression in response to valproic acid treatment offer an independent line of support, indicating that the causal variant(s) in TRANK1 cause a loss of function. Relatedly, LMAN2L is thought to regulate a subset of glycoprotein export from the endoplasmic reticulum and may also be a regulator of ERGIC-53. On the other hand, The prostaglandin F receptor, a member of the G-protein-coupled receptor family, is encoded by PTGFR on chromosome 1p31.1.

Regarding its earlier onset, research indicates that BD begins with cellular or inflammatory alterations and may be influenced by pathological changes and the underlying pathophysiology of the disease. Recognizing the significance of earlier onset BP is crucial not only clinically, but also in the ongoing discovery of BP genetics. In addition, determining family loading and other possible factors like advanced parental age during a clinical interview might prove crucial in this discovery. A better understanding of the biology and pathophysiology of bipolar disorder may result in future advances in its treatment and translation.

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A psychiatrist and researcher based in Chevy Chase, MD, Dr. David Chen has spent much of his career researching the role that genetics plays in conditions such as bipolar disorder. David Chen, MD, has worked for various organizations, and his research has appeared in a number of publications, including Molecular Psychiatry.

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A psychiatrist in Chevy Chase, MD, Dr. David Chen has served as the clinical supervisor of the George Washington University Department of Psychiatry since 2018. When he isn’t working, David Chen, MD, practices Wing Chun kung fu.