Recognition and Early Intervention on Prodrome in Bipolar Disorders

Recognition and Early Intervention on Prodrome in Bipolar Disorders: a Longitudinal Prospective Study of the Offspring of Parents With Bipolar Disorder

Background and study hypothesis: Many studies including prospective studies have been demonstrated that a long symptomatic prodromal phase exists prior to the onset of full-brown bipolar disorder, lasting for 9-12 years (Egeland et al., 2000). During the prodromal stage, there are three main clusters of syndromes, including hypomania/mania symptoms, depressive symptoms, and signs of attention deficit hyperactivity disorders (Correll et al., 2007; Tillman et al., 2003; Mantere et al., 2008). Of the hypomania/mania symptoms, decreased sleep, elevated mood, irritability, mood lability, increased energy, and psychomotor agitation are present most frequently. The prodromal depressive symptoms are reported to be depressed mood, anhedonia, insomnia, feelings of worthlessness. Among patients with bipolar disorders, 22.5% reported to comorbid with pediatric ADHD. In addition, some symptoms are considered as non-specific such as decreased functioning, anger outburst, social isolation, and anxiety (Egeland et al., 2000). Offspring of parents with bipolar disorders are much likely to present prodromal symptoms compared to offspring of healthy parents. In a 10-year longitudinal study using 55 prodromal symptoms checklist, , Egeland et al.(2002) found that 38% offspring of parents with bipolar disorder were considered as at risk compared to 17% in children of healthy parents. In a 15-year follow-up study, Duffy et al.,(2009) found that 32.7% offspring (aged 8-25 years old) of parents with bipolar disorder met the criteria of major mood episode. Objectives: One primary objective of this study is to prospectively identify the prodromal stage of bipolar disorder. Another primary objective is to conduct a randomized, place-controlled trial of aerobic exercise on people who suffering from prodromal symptoms to the extent of significantly impaired function, with attempt at delaying or preventing the onset of a full-blown bipolar disorder. Design of study and the procedures: The study will consist of two phases: one-week screening period and a randomized, placebo-controlled, 3-month trial. During the screening period, offspring of parents with bipolar disorder will undergo systematically clinical evaluations. The offspring will be evaluated with clinical symptoms assessing scales, neuropsychological tests, magnetic resonance imaging. During the 3-month trial period, the offspring who meet the inclusion criteria will be randomly assigned to receive treatment of aerobic exercise, placebo, or wait-list group. Psychiatrists are scheduled to assess mood, treatment outcome during the 3-month trial. Subjects and treatment It is expected that 120 offspring of parents with bipolar disorder aged between 10-25 years, meeting the inclusion of prodromal stage, will be included in the study. All of the offspring will undertake the Kiddie Sads Present and Lifetime Version (K-SADS-PL), and a 70 checklist items of potential prodromal symptoms suggest by us as well as by Dr. Correll et al. (2007). The parents of these offspring are to have a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders)-defined bipolar disorder (bipolar I or II), confirmed by the Chinese version of Structured Clinical interview for DSM-IV-TR Axis I Disorders patient edition (SCID-I/P) [First et al., 2002]. The offspring are to be recruited through the referrals by their parents who will receive psychiatric services in the Guangzhou psychiatric Hospital. The offspring will be randomly assigned to aerobic exercise and placebo controlled groups. The aerobic exercise would include cycling, jogging,table tennis, and playing badminton for 40 mins at least 3 times a week for 3 months. In each exercise, participants are supposed to exercise to the extent of getting sweaty. In the placebo group, participants will receive general psychoeducation, including delivering knowledge on symptoms, discussion of the suffering mental difficulties, and general coping techniques. Significance: Bipolar disorder is a common, chronic, and recurrent mental disorder. The recognition of prodromal stage of bipolar disorder and the early intervention on it may help delay or prevent the onset of bipolar disorder.

Background and study hypothesis: Bipolar disorder is one of the most common recurrent mental illnesses, with a lifetime prevalence of 3.9%, causing physical as well as mental disabilities. Nearly 40% of people with bipolar disorder experience at least one attempt of suicide, and around 10% end up with suicide completed. The mean age of onset for bipolar disorder is 20 years old, and the peak age of onset is between 15 and 19 years. Evidence shows that the first symptom could present in child as early as 3 years old, however, getting a proper diagnosis and treatment for bipolar disorder is delayed for 16.3 years in those presenting the first psychiatric symptom between 3-15 years, and for 9.9 years in those presenting the first psychiatric symptom between 16-25 years. Such a delay compromises largely the treatment as well as functional outcome of bipolar disorders. Many studies including prospective studies have been demonstrated that a long symptomatic prodromal phase exists prior to the onset of full-brown bipolar disorder, lasting for 9-12 years. During the prodromal stage, there are three main clusters of syndromes, including hypomania/mania symptoms, depressive symptoms, and signs of attention deficit hyperactivity disorders. Of the hypomania/mania symptoms, decreased sleep, elevated mood, irritability, mood lability, increased energy, and psychomotor agitation are present most frequently. The prodromal depressive symptoms are reported to be depressed mood, anhedonia, insomnia, feelings of worthlessness. Among patients with bipolar disorders, 22.5% reported to comorbid with pediatric ADHD. In addition, some symptoms are considered as non-specific such as decreased functioning, anger outburst, social isolation, and anxiety. Offspring of parents with bipolar disorders are much likely to present prodromal symptoms compared to offspring of healthy parents. In a 10-year longitudinal study using 55 prodromal symptoms checklist, , Egeland et al., found that 38% offspring of parents with bipolar disorder were considered as at risk compared to 17% in children of healthy parents. In a 15-year follow-up study, Duffy et al., found that 32.7% offspring (aged 8-25 years old) of parents with bipolar disorder met the criteria of major mood episode. Objectives: One primary objective of this study is to prospectively identify the prodromal stage of bipolar disorder. Another primary objective is to conduct a randomized, place-controlled trial of aerobic exercise on people who suffering from prodromal symptoms to the extent of significantly impaired function, with attempt at delaying or preventing the onset of a full-blown bipolar disorder. Design of study and the procedures: The study will consist of two phases: one-week screening period and a randomized, placebo-controlled, 3-month trial. During the screening period, offspring of parents with bipolar disorder will undergo systematically clinical evaluations. The offspring will be evaluated with clinical symptoms assessing scales, neuropsychological tests, magnetic resonance imaging. During the 3-month trial period, the offspring who meet the inclusion criteria will be randomly assigned to receive treatment of aerobic exercise, placebo, or wait-list group. Psychiatrists are scheduled to assess mood and treatment outcome during the 3-month trial. Subjects and treatment: It is expected that 120 offspring of parents with bipolar disorder aged between 10-25 years, meeting the inclusion of prodromal stage, will be included in the study. All of the offspring will undertake the Kiddie Sads Present and Lifetime Version (K-SADS-PL), and a 70 checklist items of potential prodromal symptoms suggested by us as well as by Dr. Correll and his colleagues. The parents of these offspring are to have a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders)-defined bipolar disorder (bipolar I or II), confirmed by the Chinese version of Structured Clinical interview for DSM-IV-TR Axis I Disorders patient edition (SCID-I/P). The offspring are to be recruited through the referrals by their parents who will receive psychiatric services in the Guangzhou psychiatric Hospital. The offspring will be randomly assigned to aerobic exercise and placebo controlled group. The aerobic exercise would include cycling, jogging, table tennis,and playing badminton for 40 mins at least 3 times a week for 3 months. In each exercise, participants are supposed to exercise to the extent of getting sweaty. In the placebo group, participants will receive general psychoeducation, including delivering knowledge on symptoms, discussion of suffering mental difficulties, and general coping techniques. Significance: Bipolar disorder is a common, chronic, and recurrent mental disorder. The recognition of prodromal stage of bipolar disorder and the early intervention on it may help delay or prevent the onset of bipolar disorder.

Prodromal Symptoms, bipolar disorder, Neuropsychological Tests, Magnetic Resonance Imaging, Treatment Outcome, aerobic exercise, psychotherapy

including delivering knowledge on symptoms, discussion of suffering mental difficulties, and general coping techniques

The aerobic exercise would include cycling, jogging, table tennis,and playing badminton for 40 mins at least 3 times per week for 3 months. In each exercise, participants are supposed to exercise to the extent of getting sweaty

Clinical Global Impressions (CGI) Scale is used to assess the patient's global functioning prior to and after initiating a study medication. The CGI provides an overall clinician-determined summary measure, taking into account all available information, including a knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function

Global Assessment Scale is a numeric scale (1 through 100) used by mental health clinicians to rate the general functioning of children

Neuropsychological performance is valuated with the MATRICS Consensus Cognitive Battery (MCCB), Test of Nonverbal Intelligence, Third Edition (TONI-3), and STROOP task. The MATRICS Consensus Cognitive Battery (MCCB), developed by the National Institute of Mental Health (NIMH) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative, has been recommended as the standard battery for clinical trials of cognition-enhancing interventions for schizophrenia as well as bipolar disorders. TONI-3 is used as language free intelligence measure which also helps in the assessment of aptitude, abstract reasoning and problem solving.

Functional magnetic resonance imaging or functional MRI (fMRI) is an magnetic resonance imaging procedure that measures brain activity by detecting associated changes in blood flow.

The instrument consists of 70 items assessing different sorts of symptoms, based on the researchers' clinical experiences and the current literature.

The instrument consists of 70 items assessing different sorts of symptoms, based on the researchers' clinical experiences and the current literature.

Inclusion Criteria: have at least one biological parent diagnosed as bipolar disorder (bipolar I or II) have at least one of the following syndromes i) two or more DSM-IV defined hypomania/mania symptoms, lasting for at least 4 days; ii) two or more DSM defined major depressive symptoms, lasting for 1 week; iii) at least one of the psychotic symptoms, lasting at least 10 min for each manifestation, and 2-7 manifestations a week for at least 3 months, including: ideas of reference; odd ideas, odd belief, unusual perceptual experiences, bizarre thought or speech, Grandiosity, suspicious ideas, paranoid idea, odd mannerisms, hallucination, disorganized/catatonic behavior; iv)two or more of the DSM-IV defined Attention deficit hyperactivity disorder (ADHD)symptoms; and there must be clear evidence of clinically significant impairment in social, academic, or occupational functioning due to ADHD symptoms Exclusion Criteria: DSM-IV defined Axis I disorders; Serious general medical illness; mental retardation; was/is treated with antipsychotic drugs; unable to complete neuropsychological tests due to physical conditions; in pregnancy and lactation; was taking thyroxine therapy in the last three months or is taking hormone therapy

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