with Barbara Pavlova, PhD, Alyson  Zwicker, PhD, Sheri Rempek, MSC, and Rudolf Uher, MD

A family history of mental illness is the strongest known risk factor for psychopathology in children and adolescents. Diagnosis-specific and transdiagnostic aspects of familial risk for mental illness are transmitted through both environmental and genetic channels. Scalable methods of assessment may enable targeted prevention through accurate, early identification of risk for serious forms of mental illness.

In the AACAP October 2020 virtual symposium, “Intergenerational Transmission of Psychopathology and Early Identification of Risk: New Insights from the Study of Child and Adolescent Offspring of Parents Living with Depression, Bipolar Disorder, and Schizophrenia,” moderator Rudolf Uher, MD, led four presenters to examine the mechanisms of transmission of schizophrenia and psychosis and to identify new approaches to early risk identification. The panelists are members of FORBOW (Families Overcoming Risks and Building Opportunities for Well-Being), a research study in Halifax, NS, Canada, that is studying what helps young people develop in a healthy way.

Predicting Anxiety Disorders

Anxiety disorders are common, and their impact is seen not only in educational underachievement, but also in the development of depression, bipolar disorder, harmful substance use, and suicide. “Because anxiety disorders run in families, it is important to know who is at greatest risk so that we can target our interventions to be most effective,” said Barbara Pavlova, PhD, of Dalhousie University, in her presentation on Anxiety in Offspring of Parents with Major Mood Disorders: The Role of Comorbid Anxiety Disorders in Parents and Sex-Specific Parent of Origin Effects.

Not surprisingly, risk factors for anxiety disorder include having a parent with the condition. In addition, having a parent with a mood disorder – such as bipolar disorder or major depressive disorder (MDD) – increases a child’s likelihood of developing one. Mood and anxiety disorders are highly comorbid; according to Dr. Pavlova, as many as three-quarters of individuals with bipolar disorder and MDD have a comorbid anxiety disorder.

Dr. Pavlova’s group sought to establish whether the transgenerational transmission of anxiety is influenced by having a parental mood disorder as well as by the sex of the offspring and the parent. Their study included the children of 221 mothers and 238 fathers (n = 395) aged 5 to 21 years, and they assessed both parents and children for psychiatric disorders using the Schedule for Affective Disorders and Schizophrenia (SADS) and the Structured Clinical Interview for DSM-5 Disorders (SCID) for parents, and the K-SADS and the SCID for children. The assessors of the children were blind to the parents’ diagnosis.

The results showed that anxiety disorder in parents, but not mood disorders, was associated with increased rates of anxiety disorder in their offspring. “The results indicated that anxiety disorders in parents drives the transmission of an anxiety disorder in the offspring, and the odds are increased if both parents have anxiety disorders,” said Dr. Pavlova.

In addition, anxiety disorder in the same-sex parent was associated with increased rates of anxiety disorder in their offspring, while anxiety disorder in the opposite-sex parent did not have the same effect. Intergenerational transmission largely occurs through the same-sex parent.

The study also showed that there is a protective effect against developing anxiety disorder of living with a same-sex, non-anxious parent. However, the same effect does not occur by living with an opposite-sex, non-anxious parent. Based on these results, Dr. Pavlova concluded that the transgenerational transmission of anxiety is at least partially independent of parental mood disorders and likely influenced by learning and modeling. This same-sex, intergenerational modeling effect is also apparent in studies of obesity, physical activity, and suicide, according to Dr. Pavlova.

While acknowledging the importance of a genetic component in psychiatric disorders, “parental modeling matters in children at risk. Living with and learning from a same-sex parent who is not anxious can be protective,” said Dr. Pavlova. She concluded her talk with a preview of research currently underway in her group which demonstrated that behavioral inhibition in a child may be another risk factor for anxiety, especially social anxiety. Overprotective parenting is also emerging as a risk factor for a child developing anxiety disorder. “Helping parents to allow their children to be appropriately courageous is one thing we are focusing on,” concluded Dr. Pavlova.

 

Genetic Risk of Mental Illness

One out of every three offspring of a parent with MDD, bipolar disorder, or schizophrenia will develop a major mood or psychotic disorder themselves. The familial risk is partly diagnosis-specific and partly transdiagnostic. However, assessing an individual’s risk is difficult because of several factors. First, family history is limited because family sizes are generally small and historical information may be incomplete. Moreover, individuals may carry the genetic risk but will not develop the phenotype. In addition, most individuals who develop severe mental illness do not have a family history.

“Therefore, to help individuals assess their risk for mental illness, molecular genetic information is increasingly available and affordable, and it is possible to collect genetic information just from a saliva sample,” said Alyson  Zwicker, PhD, of Dalhousie University, in her presentation on Family History, Polygenic Risk, and Developmental Psychopathology Leading to Major Mood and Psychotic Disorders.

However, for most people, the disorder is not the effect of a single gene, but rather results from several common genetic variants. Variants that are individually weakly related to psychopathology can be combined into scores that are more strongly associated. “We test whether polygenic scores derived from genome-wide association studies can predict the risk of mood and psychotic disorders and whether they improve prediction over family history,” she added.

In ongoing research, Dr. Zwicker uses genotype and clinical assessment data collected from thousands of children, many of whom have parents with mood and psychotic disorders. Her group constructed polygenic scores indexing children’s genetic predisposition to schizophrenia, bipolar disorder, MDD, ADHD, anxiety disorder, and neuroticism.

Specifically, the team collected genotypes and prospective clinical assessment data from 1,638 children and youth, including 439 offspring of parents with MDD, 704 offspring of parents with bipolar disorder, 62 offspring of parents with schizophrenia, and 394 offspring of control parents with no disorders. The majority of these participants have been followed up through ages 12 to 24 years, and 293 developed MDD, bipolar disorder, or psychosis.

“Results showed that higher polygenic scores for all six phenotypes were positively associated with family high-risk status,” said Dr. Zwicker. Each polygenic score was significantly associated with its corresponding disorder in offspring. But there are associations between a polygenic score for one disorder with a phenotype for another disorder, which suggests a shared genetic etiology between the two phenotypes. For example, the diagnosis of MDD among offspring was significantly predicted by polygenic scores for anxiety, schizophrenia, and neuroticism. The diagnosis of bipolar disorder among offspring was predicted by the polygenic score for schizophrenia. Interestingly, the polygenic score for neuroticism made a unique contribution to predicting onsets of severe mental illness.

Dr. Zwicker concluded that common genetic variations associated with psychopathology can be captured using polygenic scores, which are associated with a range of psychiatric phenotypes. Polygenic scores may complement family history in the prediction of risk for major mood and psychotic disorders and may be used in the future with other clinical information. While information provided by genetic scores overlaps with family history, genetic scores also add unique predictive information.

Professional Takeaways

  • The transgenerational transmission of anxiety is at least partially independent of parental mood disorders and likely influenced by learning and modeling.
  • Pending research demonstrates that behavioral inhibition in a child may be another risk factor for anxiety, especially social anxiety – with overprotective parenting as an emerging risk factor.
  • Speech patterns in healthy youth resemble the speech of their parents with a mental illness.
  • Individuals with antecedents are 10-fold more likely to develop a major disorder than those with no antecedents (Anxiety was the risk factor with the greatest predictive ability, with psychotic symptoms second.)
  • Mental illness is predictable.  The robust relationship between childhood antecedents and adolescent onsets suggests that early transdiagnostic identification of risk for serious forms of mental illness may identify individuals who could benefit from targeted prevention.

Speech Patterns Can Predict Mental Illness

Speech rhythm, prosody, and content reflect cognitive processes and psychopathology. “We look for subtle features related to rate, rhythm, tone, and content to obtain information about a person’s mental state,” said Sheri Rempek, MSC, Nova Scotia Health Authority, in her presentation, Familial Risk for Major Mood Disorders Reflected in the Speech of Children and Adolescents. “These features, looked at in detail,  may be useful in detecting subtle indicators of risk before the onset of mental illness.”

Although there are no available objective measures for classifying speech features, there are certain patterns that are related to specific psychiatric disorders:

  • Depression
    • slow rate, long pauses, reduced pitch range, low volume, glottal features
    • rumination, more negative words, first person pronouns
  • Bipolar disorder
    • mania – high speech rate, high pitch variation, and less coherence
  • Schizophrenia
    • atypical rate, less cohesion and coherence, neologisms

Rempek’s group examined whether audio recordings of naturalistic speech may detect signs of familial risk for mental illness, including MDD, bipolar disorder, and schizophrenia. They obtained 7 minutes of audio recordings of natural speech following neutral, positive, and negative prompts from 310 youth aged 9 to 19 (mean = 14) years, including offspring of parents with MDD, bipolar disorder, or schizophrenia, as well as control offspring of parents with no major mental illness. The recordings were divided into sentence-length segments. Raters blind to parent diagnosis rated each segment for richness of content, coherence, person reference (self, relationship, other), and sentiment (negative, neutral, positive).

The features present in the speech of at-risk youth reflect the unique characteristics of their speech and not language ability. Offspring of parents with MDD provided less rich content in response to neutral prompts but rich content in response to negative prompts. Offspring of parents with bipolar disorder made fewer self-referential statements in response to positive prompts and spoke with more extreme positive and negative sentiment in response to positive and negative prompts, respectively. Children of parents with schizophrenia spoke with lower coherence and less rich speech content.

“Acoustic analysis provides a novel method to objectively measure risk for and presence of mental illness,” concluded Rempek. Speech patterns in healthy youth resemble the speech of their parents with a mental illness. In a similar study in which clinicians measured acoustic features related to speech, they were able to predict risk of developing a mental illness over a 2-year period with 73% accuracy.1  Future studies conducted by Rempek’s group will explore automated analysis of speech audio and examine the validity of speech characteristics in prospectively predicting the onset of mental illness.

 

Can We Prevent Mental Illness?

“The earlier we invest in our human development, the more return we get for our investment,” said Rudolf Uher, MD, of Dalhousie University, in his presentation, Early Transdiagnostic Identification of Risk for Major Mood and Psychotic Disorders. Mental illness is a leading cause of disability, now overtaking cardiovascular disease and cancer as factors responsible for the loss to global productivity. All three of these conditions start early in life, are common, and are chronic.

Prevention is best targeted to those deemed at higher risk and thus having greater need than the general population, according to Dr. Uher. “Certain mental states have been identified as indicators of risk or prodromes of schizophrenia and bipolar disorder, but we’re finding that these at-risk mental states are already impaired to a degree similar to those with definite disorders,” he said. “Can we identify risk earlier, at a stage well before the prodrome where the impairment is not yet entrenched?” he asked. Poor functional outcomes among individuals with at-risk mental states suggest a need for earlier risk identification and intervention.

Major mood and psychotic disorders share a typical age at onset in late adolescence or early adulthood and are jointly referred to as severe mental illness. “The familial risk of mental illness to offspring where one parent is affected is approximately 33% and if both parents are affected, approximately 50% and these numbers may be underestimated,” said Dr. Uher.

He and his group developed an early transdiagnostic risk identification procedure based on familial risk (mental illness in parents) and psychopathological antecedents (risk factors) including:

  • affective lability, or sudden mood changes that are unpredictable, as seen in parents with mood disorders
  • anxiety, the tendencies toward worry and avoidance that precede and predict depression and bipolar disorder
  • psychotic symptoms, which may be common in childhood and predictive of severe mental illness 5-10 years later
  • basic symptoms, defined as loss of function or the presence of unusual perceptive experiences that typically start in adolescence and predict the risk of psychotic illness

They tested this procedure in a cohort of 536 youth aged 9 to 24 years, including offspring of parents with MDD, bipolar disorder, and schizophrenia. Severe mental illness in parents along with each of the antecedents significantly predicted mental illness onsets over an average of 4 years of follow-up. Over 1,400 person-years of follow-up of youth believed to be at significant risk of onset of major mood or psychotic disorders, they recorded 43 new onsets of major mood and psychotic disorders (33 onsets of MDD, 8 onsets of bipolar disorder, 2 onsets of schizophrenia) at a mean age of 17 years. Of these onsets, 41 occurred in those with one or more antecedent.

Dr. Uher estimated that individuals with antecedents are 10-fold more likely to develop a major disorder than those with no antecedents. Anxiety was the risk factor with the greatest predictive ability, with psychotic symptoms second. “The risk of severe mental illness increases almost exponentially with the number of antecedents identified,” said Dr. Uher. For someone with all four antecedents, the risk is more than 20% per year, he added.

According to Dr. Uher, mental illness is predictable.  The robust relationship between childhood antecedents and adolescent onsets suggests that early transdiagnostic identification of risk for serious forms of mental illness may identify individuals who could benefit from targeted prevention.

 

References
Last Updated: Nov 23, 2020