The Challenge of Defining Prodromal Symptoms of Schizophrenia and Bipolar Disorders

In this journal, Lambert and colleagues [1] present an excellent critical review of the existing literature regarding the prodromal symptoms of psychotic related disorder (e. g., schizophrenia) and bipolar disorders, illnesses that usually begin during youth and young adulthood and are associated with significant psychosocial impairment. The authors highlighted the importance of identifying the prodromal symptomatology and factors associated with increased risk to develop these disorders and summarized the deficiencies of the current literature. This information is crucial for implementing treatments that may delay and, in the best of cases, prevent the onset of these disorders. Unfortunately, there are few controlled treatment studies for youth at risk for these disorders, particularly for bipolar disorder. Moreover, questions remain regarding for whom, when, which type of treatment and for how long the treatments should be administered. Based on the current literature that is primarily based on adults and on anticipated future studies, the authors made some preliminary recommendations. They recommended evidence-based psychotherapies as the first-line treatment for youth who have not developed and may develop the disorder. This advice is based on several factors including scarcity of data, the difficulty in accurately identifying prodromal symptomatology in youth, and potential side effects from medications. Omega-3 fatty acids that preliminarily appear to be useful as add-on treatments may also be utilized. Treatment with medications usually used for schizophrenia and bipolar disorders was suggested for non-responders and, until future studies, for youth whose prodromal symptoms significantly affect their functioning. However, as the authors pointed out, there are few randomized controlled studies of large samples that address which medications are more useful in preventing the development of these disorders. In addition, the authors recommend management of comorbid disorders and factors associated with increased risk to develop schizophrenia or bipolar disorders using evidence-based treatments.

As a supplement to the authors’ information, the following issues regarding the prodromal literature are important for the identification and the development of appropriate preventative treatments.

1. There are prodromal symptoms that are proximal and symptoms that are more distant to the onset of the disorder. For example, increased subsyndromal manic symptoms close to the onset of BP disorder in offspring of parents with bipolar disorder were closer to the onset of bipolar disorder whereas ongoing mood lability, anxiety and depression were present even 9 years before the onset of bipolar disorder [2]. This is important because the management of an imminent episode may require a different approach such as more aggressive use of pharmacotherapy. Moreover, the presence of proximal symptoms may signify the initial symptoms of the disorder and not prodromal symptoms, which encourages the initiation of evidence-based treatments that have proven beneficial for schizophrenia or bipolar disorders.

2. There are difficulties ascertaining and interpreting prodromal symptoms for schizophrenia and bipolar disorder in youth, particularly in younger children. These problems may be attributable to the following issues:

a) The effects of development on symptom expression (e. g., grandiosity, elation, and formal thought disorders may not manifest the same in younger children as in adolescents or adults), the youth’s trouble expressing her/his own symptoms, and in younger children, the difficulty distinguishing the real from the imaginary. Moreover, some symptoms may be very soft (e. g., “I heard someone calling my name sometimes.”) and untrained clinicians may misinterpret these symptoms as psychosis.

Lambert and colleagues reviewed the scales that are used to evaluate prodromal symptoms for psychosis and bipolar disorder. However, in view of the above issues these scales include symptoms that may be difficult to evaluate in children. For example, the Cognitive-Perceptive Basic Symptoms (COPER) requires only one symptom within the last 3 months from a list of symptoms such as thought interference, unstable ideas of reference, and visual or acoustic perception disturbances [1]. Also, the Late Initial Prodromal State (LIPS) only requires one brief, limited, intermittent psychotic symptom (e. g., hallucinations, formal thought disorder) or at least one attenuated psychotic symptom (e. g., odd beliefs, unusual perceptual experiences) [1]. The number and duration of symptoms required to fulfill the criteria and the quality of the symptoms themselves may increase the number of false positives in children.

b) Psychotic symptoms are prevalent in community samples of youth, particularly in children [3] [4] [5]. For example, the prevalence of psychotic symptoms in childhood and early adolescence was reported to be as high as 25% [3] [4] [5]. In contrast, the prevalence of psychotic symptoms in older adolescents drops to 7.5% [3] [4] and 5% in the adult population [4] [6]. Although there is less information, manic-like episodes seem to be more prevalent in community samples of children than in adolescents and adults [7]. This information suggests that even if the presence of psychotic symptoms, particularly when persistent, is indeed associated with an increased risk to develop psychotic disorders [4] [6] [8], these symptoms may be transitory [3] [4]. Moreover, the predictive validity of single psychotic symptoms assessed in the general population differs markedly from their assessment by trained early recognition teams within clinical settings [9] in which onset and worsening of the symptoms are taken into account [10].

c) It seems that psychotic symptoms are not predictive of a specific disorder and may be a marker of risk for more severe psychopathology in general, not limited to psychosis [3] [4] [5]. In fact, psychotic symptoms are associated with the presence or the risk to develop other disorders, especially mood disorders and anxiety [3] [4] [11] [12]. Youth with elevated manic symptoms are at risk for bipolar disorder, but most have several other psychiatric disorders [13].

d) As the authors noted, the presence of comorbid disorders also affects the clinical presentation of bipolar and schizophrenic disorders because there are often overlapping symptoms. For example, several symptoms of attention deficit hyperactive disorder (ADHD) and oppositional defiant disorder overlap with the symptoms of bipolar disorder and the following symptoms may be misdiagnosed as psychosis:

• Developmental delays causing idiosyncratic descriptions of thinking and perceptions

• Dissociation/derealization/flashbacks

• Obsessions in obsessive compulsive disorder without insight

• Illusions (amplified by anxiety)

• Communication/language disorders

• Perceptions at sleep onset or awakening

• Imaginary friends

• Audible thoughts

• Seeing / hearing loved one who recently died

The above information emphasizes that it is critically important to train clinicians and researchers to use age appropriate techniques to evaluate whether “symptoms” of mood disorders or psychosis are indicative of pathology or are developmentally appropriate, including the differentiation of true psychotic phenomena vs. imaginary playmates and fantasy figures. Clinicians and researchers should also carefully assess disorganized thinking, determine whether the symptoms are persistent, what the child thinks about the symptoms, whether the symptoms affect their behavior (e. g., acting out the hallucinations or delusions), and whether there are symptoms of other disorders such as major depression or bipolar disorders. Also, it is important to take into account the context in which these symptoms occur (e. g., parental beliefs), especially because children are more susceptible to cultural/family influences.

The identification of factors associated with increased risk of developing bipolar disorder or schizophrenia (e. g., family history of schizophrenia or bipolar disorders, presence of subsyndromal manic symptoms, persistent thought disorder) can eventually be used to build risk calculators that can be used across settings to predict who is at risk to develop each of these disorders and to help implement preventative treatments [14]. These calculators are currently in use in medicine to inform treatment. For example, factors associated with increased risk for a myocardial infarction such as increased weight, high cholesterol, lack of exercise, smoking, etc. are entered into a calculator and based on the score, the physician may decide whether to administer medications to lower the risk for myocardial infarction (e. g., cholesterol-lowering medications).

The facts and recommendations described by Lambert and colleagues in this journal and the above information are vital for the development of treatments to prevent or delay the onset of schizophrenia and bipolar disorder as well as for treatment of the prodromal symptoms themselves because they significantly affect the youth’s psychosocial functioning and increase the risk for other problems such as suicidality, behavior problems, and substance abuse. Finally, educating youth and families about the meaning and implications of the prodromal symptoms and their treatment is essential because even for youth with acute symptoms, the acceptance of and adherence to treatment are low.

• References

• 1 Lambert M, Niehaus V, Correll CU. Pharmacotherapy in children and adolescents at clinical-high risk for psychosis and bipolar disorder. Pharmacopsychiatry 2016; 49: 229–244
• 2 Hafeman D, Merranko J, Axelson D. Toward the definition of a bipolar prodrome: dimensional predictors of bipolar spectrum disorders in at-risk youths. Am J Psychiatry Published online 2016 Feb 19:appiajp201515040414. [Epub ahead of print]
• 3 Kelleher I, Keeley H, Corcoran P. et al. Clinicopathological significance of psychotic symptoms in non-psychotic young people: evidence from four population-based studies. Br J Psychiatry 2012; 201: 26-32
• 4 Kelleher I, Connor D, Clarke MC. et al. Prevalence of psychotic symptoms in childhood and adolescence: a systematic review and meta-analysis of population-based studies. Psychol Med 2012; 9: 1-7
• 5 Murray K, Jones G. PB. Psychotic symptoms in young people without psychotic illness: mechanisms and meaning. Brit J Psychiatry 2012; 201: 4-6
• 6 van Os J, Linscott RJ, Myin-Germeys I. et al. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis-proneness-persistence-impairment model of psychotic disorder. Psychol Med 2008; 8: 1-17
• 7 Stringaris A, Santosh P, Leibenluft E. et al. Youth meeting symptom and impairment criteria for mania-like episodes lasting less than four days: an epidemiological enquiry. J Child Psychol Psychiatry 2010; 51: 31-38
• 8 Poulton R, Caspi A, Moffitt TE. et al. Children’s self-reported psychotic symptoms and adult schizophreniform disorder: a 15-year longitudinal study. Arch Gen Psychiatry 2000; 57: 179-195
• 9 Fusar-Poli P, Schultze-Lutter F, Cappucciati M. et al. The dark side of the moon: meta-analytical impact of recruitment strategies on risk enrichment in the clinical high risk state for psychosis. Schizophr Bull 2016; 42: 732-743
• 10 Schultze-Lutter F, Michel C, Ruhrmann S. et al. Prevalence and clinical significance of DSM-5–attenuated psychosis syndrome in adolescents and young adults in the general population: the Bern Epidemiological At-Risk (BEAR) study. Schizophr Bull 2014; 40: 1499-1508
• 11 Ulloa RE, Birmaher B, Axelson D. et al. Psychosis in a pediatric mood and anxiety disorders clinic: phenomenology and correlates. J Am Acad Child Adolesc Psychiatry 2000; 39: 337-345
• 12 Birmaher B, Brent D. Practice parameter for the assessment and treatment of children and adolescents With depressive disorders. J Am Acad Child Adolesc Psychiatry 2007; 1503-1526
• 13 Findling RL, Youngstrom EA, Fristad MA. et al. Characteristics of children with elevated symptoms of mania: the Longitudinal Assessment of Manic Symptoms (LAMS) study. Journal of Clinical Psychiatry 2010; 71: 1664-1672
• 14 Cannon TD, Yu C, Addington J. et al. An individualized risk calculator for research in prodromal psychosis. Am J Psychiatry 2016; DOI: 10.1176/appi.ajp.2016.15070890. [Epub ahead of print]