Early Intervention Strategies for Bipolar Disorder: Clinical Dilemmas and Directions
Early-onset parental bipolar disorder is the most important single risk factor for the development of bipolar disorder in offspring.
Early intervention in bipolar disorder (BPD) is "gaining momentum" as a way of averting potentially irreversible harm from the disease, as the early phases may be more responsive than later stages to treatments and may also require less aggressive therapies.1
"Most psychiatric conditions, including BPD, are late manifestations of brain disease," according to Eduardo Vieta, MD, PhD, professor of psychiatry at the University of Barcelona, Spain.
"What we see at the time of diagnosis that is actually brought to us by the patient or a relative or family member may sometimes be late in the disease process," he told Psychiatry Advisor.
Dr Vieta and colleagues, who authored a review article1 on early intervention in BPD, use the term "at-risk stage" to refer to the set of risk factors and prodromal symptoms that, if identified and treated, can inform psychiatric treatments at an earlier stage of the disease.
However, the at-risk date "is pleomorphic and nonspecific and has the potential to evolve into diverse formed phenotypes or no disorder," the authors note.
BPD is a "multifactorial disease that is influenced by environmental factors, some of which might be used as targets of early intervention strategies since they can be potentially modified,"1 the authors write.
Environmental Risk Factors
The authors point to several life events that might raise the risk for a mood disorder. For example, lifetime sexual abuse seems to be related to a more difficult course of BPD. Antidepressants, which can sometimes induce (hypo)manic symptoms, may also be a risk factor.2,3 Substance abuse disorder, smoking, and even maternal smoking can increase the risk in offspring.1
Biological Risk Factors
Family history of BPD is "one of the more solid risk factors for [BPD]" and is a "primary threshold from universal to indicated prevention strategies,"1 the authors write.
Longitudinal studies have shown that offspring of early-BPD probands were at increased risk for BPD,4,5 and that lithium nonresponsiveness in parents was associated with poorer premorbid functioning, more chronic course, and higher prevalence of psychotic disorder in their offspring.6
In addition, neurodevelopmental factors, such as child developmental delay or premorbid cognitive ability, may play a role, although children with high academic attainment may be at even greater risk for BPD.1
The index (hypo)manic episode in bipolar offspring, as well as community cohorts, is often preceded by other affective or nonaffective symptoms, which may be considered as early symptoms of BPD and may help predict future BPD onset. These potentially include depression, subjective sleep problems, and childhood anxiety disorder.1 Subthreshold (hypo)manic symptoms have emerged as a "key predictor" of the development of (hypo)mania, even after adjusting for risk factors associated with psychopathology, such as parental psychiatric morbidity.7,8
Several "dimensional factors" that may have predictive value include significant symptoms of anxiety/depression, affective lability, subsyndromal manic symptoms, sensitivity, hyperalertness, anxiety, and somatic complaints during the preschool period, as well as increased mood/energy fluctuations, tearfulness, sleep disturbances, and fearfulness during school years.1 There is a relationship between the diagnosis of psychotic depression and a switch to (hypo)mania.
However, early-onset parental BPD is the "most important single risk factor" for developing BPD, and in addition, subsyndromal manic symptoms are the "most consistent" prodromal factor. In the presence of ongoing mood lability or irritability, anxiety, and depression, "there is increased likelihood that this youth will develop [BPD]," although "the onset and severity of these symptoms are heterogeneous."1
Screening Tools in Predicting BPD
The authors note that reliable screening tests and screening criteria to assess prodromal symptoms are "still lacking." However, a combination of self-reports and clinical semistructured interviews might "be a more accurate approach for clinical decision making than the use of a single scale."1
Subsyndromal manic symptoms should be assessed by trained professionals, "as subsyndromal symptoms are difficult to ascertain when assessing children or if comorbid disorders are present." Parental reporting provides the greatest validity, regardless of whether the parent has a diagnosis of a mood disorder.
The authors recommend the Early Phase Inventory for Bipolar Disorders criteria9 and the Bipolar Prodrome Syndrome Scale (based on the At Risk for Mania Syndrome criteria)10 as "promising screening tools."
The Potential Role of Biomarkers
Biological and behavioral biomarkers "hold promise as objective and useful tools for identifying patients at higher risk of developing BPD," although biomarkers and staging have "not yet had an impact on the official classificatory systems for mental disorders," the authors write.
They list several types of biomarkers, including neuroimaging, peripheral, and behavioral (derived from the ability to track behavioral data through mobile devices), as potentially useful. The latter, in particular, can be achieved through "big data, such as geolocation, activity, Internet use, calls, and payments" that can be analyzed to provide algorithms to use through machine learning techniques as sources for risk surveillance and early personalized interventions.11-14
Early Treatment Strategies
"[T]here are critical ethical issues pertaining to preventive interventions in at-risk individuals," the authors observe, suggesting that potential benefits should be balanced against risks for pre-onset interventions.
A recent literature review15 called the notion of early intervention into question for these reasons and concluded that the "unpredictable nature of [BPD] creates substantial difficulties when determining an optimal therapeutic target for early intervention."
Moreover, it is challenging to identify "appropriate populations and apposite times for early intervention strategies."15
Clinicians therefore face a dilemma when they encounter patients with potential signs of a BPD prodrome.
"We want to advocate early intervention, but also we need to be very careful because we do not want to medicalize or give treatment with potential adverse effects to a person who does not actually have the condition, but at the same time, we need to intervene early if we want to prevent consequences which, by the time the patient comes to us, they are already suffering from," Dr Vieta said.
Awareness of risk factors facilitates early intervention, typically beginning with lifestyle changes rather than pharmacotherapy.
"Physical exercise is helpful with heart disease and blood pressure and also good for mental conditions, encouraging neurogenesis and neuroplasticity," he said.
Psychoeducation plays a role. "It is very important that at-risk people learn how to deal with stressful situations and avoid them if possible," Dr Vieta said.
In addition, patients "should avoid drastic lifestyles, such as taking on a job that necessitates being up all night for several nights, or being awake until very late drinking at parties. These are risk factors for vulnerable people," he emphasized.
He noted that taking drugs is "bad for anyone," but in many people, "the drugs have a more limited harm. However, in people with warning signs of bipolarity or psychosis, taking certain drugs such as marijuana, which has the potential to induce psychosis, can be particularly harmful."
Family-focused therapy, which combines psychoeducation with training in communication and problem-solving skills, has been associated with longer affective stability and milder symptoms in youth at high familial risk for BPD or with BPD and other psychiatric disorders.16 Multifamily psychoeducational psychotherapy and interpersonal and social rhythm therapy, as well as some online psychosocial interventions, have shown promise.17,18
There is a lack of empirical evidence to demonstrate the efficacy of psychotropic medications for bipolar prodrome, and even medications that have shown efficacy in adults may "differ in their effectiveness across developmental stages."15 Lithium may be more effective when started early in the disease course,19 but the long- and short-term tolerability of lithium and other agents and their role in preventing BPD "need to be carefully weighed against the individual risk of developing [BPD]," given the potential adverse effects of these agents.1
Talking to Patients and Families
"We need to understand potential features that go beyond 'adolescent moods' in a young person and inform the patient and family in a nonstigmatizing way," Dr Vieta said.
He advised clinicians to avoid saying, " 'This is bipolar disorder,' or, 'It's going to become bipolar disorder,'" but rather to inform the family that these symptoms do not necessarily point to a definitive diagnosis but, rather, the possibility that it might develop in the future. "Symptoms should be noted in a nonmedicalizing way as risk factors, similar to hypertension in cardiovascular disease."
In people with these "nonspecific symptoms, merely providing information and monitoring can be sufficient and can prevent many complications," he added.
However, in patients with true prodromal symptoms, such as hypomania or psychosis, the potential to evolve into BPD is much greater. "Early intervention means more than just informing and monitoring, and these patients need to be treated," he said.
"Early intervention" can mean secondary rather than primary prevention, as the patient already has an episode under way. But in the event of a first episode, intervention can prevent further episodes.
"I think some clinicians have too much of a cross-sectional view of a patient, and while that is important, it is also important to look further ahead," he commented. "It is important not only to treat what you see today but [also] anticipate what might happen tomorrow and take action before it happens," he concluded.
- Vieta E, Salagre E, Grande I, et al. Early intervention in bipolar disorder [published online January 24, 2018]. Am J Psychiatry. doi: 10.1176/appi.ajp.2017.17090972
- Martin A, Young C, Leckman JF, Mukonoweshuro C, Rosenheck R, Leslie D. Age effects on antidepressant-induced manic conversion. Arch Pediatr Adolesc Med. 2004;158:773-780.
- Barbuti M, Pacchiarotti I, Vieta E, et al. Antidepressant-induced hypomania/mania in patients with major depression: evidence from the BRIDGE-II-MIX study. J Affect Disord. 2017;219:187-192.
- Hafeman DM, Merranko J, Axelson D, et al. Toward the definition of a bipolar prodrome: dimensional predictors of bipolar spectrum disorders in at-risk youth. Am J Psychiatry. 2016;173:695-704.
- Preisig M, Strippoli MF, Castelao E, et al. The specificity of the familial aggregation of early-onset bipolar disorder: a controlled 10-year follow-up study of offspring of parents with mood disorders.J Affect Disord. 2016;190:26-33.
- Duffy A, Horrocks J, Doucette S, Keown-Stoneman C, McCloskey S, Grof P. The developmental trajectory of bipolar disorder. Br J Psychiatry. 2014;204(2):122-128.
- Axelson D, Goldstein B, Goldstein T, et al. Diagnostic precursors to bipolar disorder in offspring of parents with bipolar disorder: a longitudinal study. Am J Psychiatry. 2015;172(7):638-646.
- Papachristou E, Oldehinkel AJ, Ormel J, et al. The predictive value of childhood subthreshold manic symptoms for adolescent and adult psychiatric outcomes. J Affect Disord. 2017;212:86-92.
- Leopold K, Ritter P, Correll CU, et al. Risk constellations prior to the development of bipolar disorders: rationale of a new risk assessment tool. J Affect Disord. 2012;136(3):1000-1010.
- Correll CU, Olvet DM, Auther AM, et al. The Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls.Bipolar Disord. 2014;16(5):505-522.
- Hidalgo-Mazzei D, Murru A, Reinares M, Vieta E, Colom F. Big Data in mental health: a challenging fragmented future. World Psychiatry. 2016;15(2):186-187.
- Adams Z, McClure EA, Gray KM, Danielson CK, Treiber FA, Ruggiero KJ. Mobile devices for the remote acquisition of physiological and behavioral biomarkers in psychiatric clinical research. J Psychiatr Res. 2017;85:1-14.
- Luo W, Phung D, Tran T, et al. Guidelines for developing and reporting machine learning predictive models in biomedical research: a multidisciplinary view. J Med Internet Res. 2016;18(12):e323.
- Vieta E. The bipolar maze: a roadmap through translational psychopathology. Acta Psychiatr Scand. 2014;129(5):323-327.
- Malhi GS, Morris G, Hamilton A, Outhred T, Mannie Z. Is "early intervention" in bipolar disorder what it claims to be?Bipolar Disord. 2017;19(8):627-636.
- Miklowitz DJ, Schneck CD, Singh MK, et al. Early intervention for symptomatic youth at risk for bipolar disorder: a randomized trial of family-focused therapy. J Am Acad Child Adolesc Psychiatry. 2013;52(2):121-131.
- Hidalgo-Mazzei D, Mateu A, Reinares M, Matic A, Vieta E, Colom F. Internet-based psychological interventions for bipolar disorder: review of the present and insights into the future. J Affect Disord. 2015;188:1-13.
- Lauder S, Chester A, Castle D, et al. A randomized head to head trial of MoodSwings.net.au: an Internet based self-help program for bipolar disorder. J Affect Disord. 2015;171:13-21.
- Kessing LV, Vradi E, Andersen PK. Starting lithium prophylaxis early v. late in bipolar disorder. Br J Psychiatry. 2014;205(3):214-220.