Familial High Risk (FHR) of Schizophrenia (FHR-SZ) and Bipolar Disorder (FHR-BP) is highly significant in comorbidity with ADHD. A new study of 522 – 7-year olds – shows, that 20.9% of offspring from FHR-SZ and 9.3% of offspring with FHR-BP, also suffers from ADHD. This has important implications for medicinal treatment with ADHD medication due to the increased risk of developing psychosis as a result of ADHD-medication.
It has long been known, that some children with ADHD are at risk of developing psychosis due to ADHD-medication. The reason for this elevated risk has, however not been fully understood. Two new studies, one from National Institute of Mental Helath (NIMH) Moran et al. (2019) and from a Danish longitudinal cohort study Ellersgaard et al (2018) of 7-year olds with a familial high risk of Schizophrenia or Bipolar Disorder, now sheds light on the underlaying causality, due to the neurodevelopmental aspect of both Schizophrenia, Bipolar Disorder and ADHD Owen et al. (2017).
The NIMH study shows that the risk of developing a psychotic episode is 1 in 660 people, with a risk of 0.10% (methylphenidate) and 0.21% (amphetamines). The Danish study shows, that the risk of having Schizophrenia with comorbid ADHD is at 20.9% and the risk of having Bipolar Disorder is at 9.3%.
Combined this tells us, that the risk of developing psychosis due to ADHD-medication is not related to the ADHD.medications, but that it is indeed related to the risk of comorbid Schizophrenia or Bipolar Disorder.
This has major implications for clinical importance, since diagnosis must include rigorous attention to familial high risk of Schizophrenia and Bipolar Disorder when determining the right medicinal treatment regiments, since underlaying conditions such as these, must be addressed prior to prescribing ADHD medication, to avoid serious adverse events, such as psychosis.
Psychopathology in 7-year-old children with familial high risk of developing schizophrenia spectrum psychosis or bipolar disorder – The Danish High Risk and Resilience Study – VIA 7, a population-based cohort study
Ellersgaard D. et al. (2018), Psychopathology in 7-year-old children with familial high risk of developing schizophrenia spectrum psychosis or bipolar disorder – The Danish High Risk and Resilience Study – VIA 7, a population-based cohort study, World Psychiatry. 2018 Jun; 17(2): 210–219. doi: 10.1002/wps.20527 PMCID: PMC598063 PMID: 29856544
PBC – The population-based control group is set as reference
FHR-SZ – children with familial high risk for schizophrenia spectrum psychosis
FHR-BP – children with familial high risk for bipolar disorder
Definitions: […]The idea that disturbances occurring early in brain development contribute to the pathogenesis of schizophrenia, often referred to as the neu- rodevelopmental hypothesis, has become widely accepted. Despite this, the disorder is viewed as being distinct nosologically, and by implication pathophysiologically and clinically, from syndromes such as autism spectrum disorders, attention-deficit/hyperactivity disorder (ADHD) and intellectual disability, which typically present in childhood and are grouped together as “neurodevelopmental disorders”. An alternative view is that neurodevelopmental disorders, including schizophrenia, rather than being etiologically discrete entities, are better conceptualized as lying on an etiological and neurodevelopmental continuum, with the major clinical syndromes reflecting the severity, timing and predomi- nant pattern of abnormal brain development and resulting functional abnormalities. It has also been suggested that, within the neurodeve- lopmental continuum, severe mental illnesses occupy a gradient of decreasing neurodevelopmental impairment as follows: intellectual dis- ability, autism spectrum disorders, ADHD, schizophrenia and bipolar disorder. Recent genomic studies have identified large numbers of specific risk DNA changes and offer a direct and robust test of the predictions of the neurodevelopmental continuum model and gradient hypothesis. These findings are reviewed in detail. They not only support the view that schizophrenia is a disorder whose origins lie in disturbances of brain development, but also that it shares genetic risk and pathogenic mechanisms with the early onset neurodevelopmental disorders (intellectual disability, autism spectrum disorders and ADHD). They also support the idea that these disorders lie on a gradient of severity, implying that they differ to some extent quantitatively as well as qualitatively. These findings have important implications for nosology, clinical practice and research. […] (Owen et al., 2017)
This study aimed to compare the psychopathological profiles of children at familial high risk of schizophrenia spectrum psychosis (FHR‐SZ) or bipolar disorder (FHR‐BP) with population‐based controls. We used Danish nationwide registers to retrieve a cohort of 522 seven‐year‐old children of parents with schizophrenia spectrum psychosis (N=202), bipolar disorder (N=120) or none of these disorders (N=200). Psychopathology was assessed by reports from multiple informants, including children, parents and teachers. Lifetime DSM‐IV diagnoses were ascertained by blinded raters through the Schedule for Affective Disorders and Schizophrenia for School‐Age Children. The dimensional assessment of psychopathology was performed by the Child Behavior Checklist, the Teacher’s Report Form, a modified version of the ADHD‐Rating Scale, the Test Observation Form, and the State‐Trait Anxiety Inventory for Children. Current level of functioning was evaluated using the Children’s Global Assessment Scale (CGAS). The prevalence of lifetime psychiatric diagnoses was significantly higher in both FHR‐SZ children (38.7%, odds ratio, OR=3.5, 95% confidence interval, CI: 2.2‐5.7, p < 0.001) and FHR‐BP children (35.6%, OR=3.1, 95% CI: 1.8‐5.3, p < 0.001) compared with controls (15.2%). FHR‐SZ children displayed significantly more dimensional psychopathology on all scales and subscales compared with controls except for the Anxious subscale of the Test Observation Form. FHR‐BP children showed higher levels of dimensional psychopathology on several scales and subscales compared with controls, but lower levels compared with FHR‐SZ children. Level of functioning was lower in both FHR‐SZ children (CGAS mean score = 68.2; 95% CI: 66.3‐70.2, p < 0.0001) and FHR‐BP children (73.7; 95% CI: 71.2‐76.3, p < 0.05) compared with controls (77.9; 95% CI: 75.9‐79.9). In conclusion, already at the age of seven, FHR‐SZ and FHR‐BP children show a higher prevalence of a broad spectrum of categorical and dimensional psychopathology compared with controls. These results emphasize the need for developing early intervention strategies towards this vulnerable group of children.
Since schizophrenia and bipolar disorder are rare events in the general population, familial high risk studies of children born to parents with schizophrenia (FHR‐SZ) or bipolar disorder (FHR‐BP) are useful in studying trajectories towards these conditions.
The offspring of parents with severe mental disorders have been reported to have elevated rates of not only the disorder of their parents but also a wide range of other mental disorders.
Further, among children with a diagnosis of ADHD, those from the FHR-BP group most often had the predominantly inattentive type, whereas children from the FHR-SZ and control groups most often had the combined or predominantly hyperactive-impulsive type.
Likewise, in the dimensional measures, we only found some evidence of elevated symptoms of ADHD and disruptive behavior disorders in FHR-BP children, in the form of elevated scores on the Inattention subscale and the subscale of oppositional defiant disorder problems of the caregiver version of mADHD-RS.
Detection of inattention in a classroom setting may be more challenging than the observation of hyperactivity and impulsivity, which may explain why the difference between the FHR-BP group and controls only showed a trend towards significance in teachers’ ratings of inattention.
A final cohort of 522 children from 506 families was retrieved from Danish national registers. Of these, 200 FHR‐SZ children, 119 FHR‐BP children and 200 controls participated with some data on psychopathology. We found several significant differences in family characteristics and home environment between the three groups.
The Danish High Risk and Resilience Study ‐ VIA 7 is a nationwide cohort study of 522 seven‐year‐old children. It is the only population‐based, representative familial high risk study, and it is the largest clinical study to date assessing psychopathology in children of parents with schizophrenia and bipolar disorder compared with controls.
We found that FHR‐SZ and FHR‐BP children have an equally higher prevalence of a broad spectrum of lifetime DSM‐IV psychiatric diagnoses – e.g., anxiety disorders, and stress and adjustment disorders – compared with controls.
Further, we found a gradient in levels of unspecific dimensional psychopathology and daily functioning between the groups, with FHR‐SZ children being the most affected and controls being the least affected, whereas FHR‐BP children displayed intermediate levels of psychopathology and functioning.
Specificity of psychopathology in familial high risk children
Our findings of an elevated prevalence of psychiatric diagnoses and dimensional psychopathology in FHR‐SZ and FHR‐BP children are consistent with the results of earlier familial high risk studies.
Overall, both familial high risk groups in our study presented with a broad range, i.e. unspecific, categorical and dimensional psychopathology at this young age. Depressive disorders were rare in both groups, mania was absent, and only two FHR‐SZ children were diagnosed with psychotic disorder not otherwise specified.
We found elevated rates of anxiety disorders as well as stress and adjustment disorders in both familial high risk groups. This is in accordance with earlier reports of anxiety disorders being common in FHR‐BP children. The findings support the first step of the clinical staging model suggested by Duffy et al, implying that anxiety and sleep disorders in childhood, as well as adjustment, mood and substance use disorders in adolescence, could represent early precursors of bipolar disorder in the offspring of parents with that disorder.
Rates of psychopathology in FHR‐BP children have varied substantially in previous studies. This may be attributed to differences in parents’ severity of illness, procedures for assessing offspring diagnoses, and age of the offspring. Parents with bipolar disorder have often been recruited through inpatient and outpatient clinics, whereas they were identified through Danish registers in this study. Therefore, the group of parents in our study was likely to be more heterogeneous in terms of severity of the disorders, which may explain the lower levels of psychopathology in FHR‐BP children compared with other familial high risk studies of bipolar disorder.
Differences in psychopathological presentation between the two high risk groups
Even though evidence of the shared genetic risk factors for schizophrenia and bipolar disorder is robust, knowledge concerning common or distinct developmental psychopathology is still lacking.
Our findings showed that FHR‐SZ and FHR‐BP children both present an elevated prevalence of unspecific categorical and dimensional psychopathology, even though FHR‐BP children differed less from controls than did FHR‐SZ children.
Also, FHR‐SZ children consistently displayed elevated levels of behavioral problems across settings, namely at home, at school and during the test session, as rated by several informants.
In contrast, even though parents of FHR‐BP children reported a high prevalence of behavioral and emotional problems compared with controls, teachers reported less deviation from controls and the investigators observed levels of problems equal to those of controls.
Both high risk groups had an elevated prevalence of anxiety as well as stress and adjustment disorders.
FHR‐BP children displayed a significantly elevated prevalence of pervasive developmental disorders compared with controls, whereas the elevated prevalence in FHR‐SZ children did not reach significance.
Only FHR‐SZ children had an elevated prevalence of ADHD and disruptive behavior disorders compared with controls.
Thus, even though both high risk groups show elevated levels of unspecific psychopathology, there are also differences between their psychopathological profiles.
ADHD and disruptive behavior disorders in familial high risk children
We found significantly higher levels of ADHD and disruptive behavior disorders in FHR‐SZ children compared with controls, which is in line with findings of impaired attention and disruptive behaviors in previous studies.
However, earlier studies have reported conflicting results on ADHD and disruptive behavior disorders in FHR‐BP children. In particular, Duffy et al suggested that ADHD only precedes bipolar disorder in offspring of bipolar parents who do not respond to lithium treatment.
We did not find a higher prevalence of diagnoses of ADHD and disruptive behavior disorders in FHR‐BP children at this early age compared with controls. Further, among children with a diagnosis of ADHD, those from the FHR‐BP group most often had the predominantly inattentive type, whereas children from the FHR‐SZ and control groups most often had the combined or predominantly hyperactive‐impulsive type.
Likewise, in the dimensional measures, we only found some evidence of elevated symptoms of ADHD and disruptive behavior disorders in FHR‐BP children, in the form of elevated scores on the Inattention subscale and the subscale of oppositional defiant disorder problems of the caregiver version of mADHD‐RS.
Detection of inattention in a classroom setting may be more challenging than the observation of hyperactivity and impulsivity, which may explain why the difference between the FHR‐BP group and controls only showed a trend towards significance in teachers’ ratings of inattention.
Children from the familial high risk groups displayed significantly more dimensional psychopathology and psychiatric disorders compared with controls.
The finding of high levels of psychopathology at this early age in FHR‐SZ and FHR‐BP children could have implications for school performance, peer relations and other important developmental aspects.
A preventive strategy could be to offer these children and their families special and enhanced attention and support from teachers and health care professionals. Also, our findings highlight the need to strengthen the collaboration between adult and child psychiatry in the treatment of these families.
Furthermore, longitudinal familial high risk studies are needed to identify which psychopathological symptoms predict conversion to severe mental disorders in FHR‐SZ and FHR‐BP children and which resilience factors help these children compensate and protect them from conversion. The next wave of assessment of this cohort at age 11 began in March 2017 and is called the Danish High Risk and Resilience Study ‐ VIA.
Finally, our findings emphasize the need for clinical trials of primary interventions towards this vulnerable group of children to prevent their unspecific psychopathological symptoms from converting into severe mental disorders and to increase their daily level of functioning.
At this stage, we cannot determine whether the signs and symptoms of psychopathology found in these children at familial high risk represent transitory states that they will eventually grow out of or antecedents of more severe disorders.
However, we can assert that some of these children have symptoms which impair their current level of functioning and call for interventions to support their healthy development.
Owen, M. J., & O’Donovan, M. C. (2017). Schizophrenia and the neurodevelopmental continuum: evidence from genomics. World Psychiatry, 16(3), 227-235., doi: 10.1002/wps.20440
Moran L., Ongur D., Hsu J., Castro V., Perlis R., et al., (2019), Psychosis with Methylphenidate or Amphetamine in Patients with ADHD, N Engl J Med 2019; 380:1128-1138
Ellersgaard, D. , Jessica Plessen, K. , Richardt Jepsen, J. , Soeborg Spang, K. , Hemager, N. , Klee Burton, B. , Jerlang Christiani, C. , Gregersen, M. , Søndergaard, A. , Uddin, M. J., Poulsen, G. , Greve, A. , Gantriis, D. , Mors, O. , Nordentoft, M. and Elgaard Thorup, A. A. (2018), Psychopathology in 7‐year‐old children with familial high risk of developing schizophrenia spectrum psychosis or bipolar disorder – The Danish High Risk and Resilience Study ‐ VIA 7, a population‐based cohort study. World Psychiatry, 17: 210-219. doi:10.1002/wps.20527