Issue 104, Dec 2020
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Bipolar disorder in older adults: Taskforce report to advance patient care

Sajatovic M et al. Bipolar Disord.2015. Nov 17(7):689-704. doi:10.1111/bdi.12331. Epub 2015 Sep19.

PMID:26384588

Background

There will be an increase in older adults with bipolar disorder in the future as the population ages. This will be in absolute numbers as well as the proportion of the general population. This is the first report of the International Society for Bipolar Disorder (ISBD) Task Force on Older-Age Bipolar Disorder (OABD).

Methods

This task force report focuses on the nuances of management of OABD including epidemiology and clinical features, neuropathology and biomarkers, physical health, and cognition. This report also focuses on management.

Results

This report describes an expert consensus summary on OABD that is intended to advance the care of patients and BD research across the lifespan. Although there is still a dearth of research and health efforts focused on older adults with BD, emerging data have brought some answers, innovative questions, and novel perspectives related to the notion of late-onset, medical comorbidity, and the vexing issue of cognitive impairment and decline.

Conclusions

Improving our understanding of the biological, clinical, and social underpinnings relevant to OABD is an indispensable step in building a complete map of BD across the lifespan.

Clinical Commentary

Expert consensus and task force reports have recently gained importance. In psychiatry, there has been a push to standardize treatments so that they are evidence based and not eminence based. These guidelines are often followed by payors and are referenced in the court of law. Hence the importance of this task force report

Epidemiology and clinical features: Bipolar disorder has a bimodal distribution of onset, with   late-life onset BD associated with vascular changes or other brain pathologies.

OABD: The taskforce recommends OABD to be defined as ages 50 years and older, in an effort to evaluate possible correlations involving comorbidities and reduced lifespan.  Some studies have used age 60 as a benchmark in the past.

The report indicates the types I and II BD affect 0.5-1.0 % of the population of older adults. This excludes the bipolar spectrum. OABD accounts for 6% of geriatric psychiatry outpatient visits and 8-10 % of geriatric inpatient admissions. Women account for 70% of OABD.

The current thinking suggests that late-onset bipolar disorder (LOBD) cut off should be age 40 or higher. LOBD is progressive and has an increasing risk of recurrence.

Neuropathology and biomarkers:

Structural neuroimaging studies in OABD patients show regional gray matter volume reduction, white matter hyperintensities, and biochemical alterations. Currently, fMRI, DTI, and MRS do not support a neuroprogression model in BD. In the future neuroimaging studies may better our understanding of mood, functioning, and cognition in OABD.

Physical health

OABD is associated with extensive medical comorbidity. Death occurs an average of 10 years earlier than in the general population. Cerebrovascular disease occurs in the majority of patients regardless of the age of onset. A close collaborative relationship should exist between primary care, specialists, and mental health clinicians to screen and address medical comorbidities such as cardiovascular and cerebrovascular diseases, metabolic syndrome, and smoking/vaping issues. Long-term studies are needed to address many of these issues.

Cognition:

30% of patients with OABD have cognitive dysfunction. Those with higher IQ, education, or occupational attainment have a lower risk of developing dementia. Limited data suggests that BD might reduce cognitive reserve and accelerate the aging process. Individuals with LOBD have more extensive neurocognitive impairments, which supports a possible different etiological mechanism. As clinicians, we need to consider cognitive dysfunction in the overall treatment of OABD and avoid medications that may worsen cognitive function (e.g. anticholinergic agents).

Pharmacologic management:

The data are limited. There is a lack of controlled prospective studies in OABD. There is data to support the use of lithium, lamotrigine and atypical antipsychotics especially quetiapine and lurasidone. It is important to assess thyroid and kidney function in older adults. There are no controlled studies on psychosocial treatments in OABD, however data from those with mental illness are supportive of this modality.

Summary

In my opinion, it would be helpful to read the original paper. I also suggest that in clinical practice we carefully look for cognitive issues in those with OABD as well as late-onset bipolar disorder. The differential diagnosis is important. A patient with LOBD can be mistaken as an individual with dementia-related psychosis. I have encountered this on the consultation service. In these individuals, accurate diagnosis and appropriate treatment can make a significant difference in the outcomes. Clinicians should screen these individuals for medical comorbid conditions and treat them collaboratively.

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Progress in diagnosis and treatment of bipolar disorder in children and adolescents: International perspective

 Findling RF. Evid Based Ment Health. 2018 Nov 21 (4): 177-181. doi: 10.1136/eb-2018-102912. [Epub 2018 Oct 16]

PMID:30327338

Background

Bipolar disorder (BPD) is a lifelong condition characterized by extreme changes in mood that may begin in childhood and result in substantial impairment. Over the past decades, BPD has been the focus of increased attention mainly due to controversies surrounding its prevalence, diagnosis, and treatment in children and adolescents. This report addresses these controversies.

Methods

The extant evidence base was reviewed, providing clinicians with a summary of the literature on diagnosis, phenomenology, and treatment of pediatric BPD. The debate regarding diagnosing children with BPD based on severe irritability and aggression is mostly resolved.

Results

The current data support utilizing the diagnostic criteria based on episodic changes of mood polarity. Therefore, the longitudinal course of illness should be explored in detail when diagnosing BPD. Given the high rates of the genetic predisposition for BPD, assessment of youth should focus on obtaining an accurate family history of this condition. Additionally, there has been a substantial increase in randomized placebo-controlled clinical trials evaluating pharmacological agents for mood stabilization in children and adolescents, which are summarized in this review.

Conclusions

Despite significant progress being made in the field of pediatric BPD, more research is needed in the areas of phenomenology, pathophysiology, course, and treatment of this condition in youth.

Clinical Commentary

Bipolar disorder (BPD) is a difficult illness to diagnose in adults and even harder in children and adolescents. The teenage years are tumultuous, and there are mood and anxiety issues associated with this age group which can be misleading. There are multiple controversies, but recent studies have helped provide tips for clinicians for diagnosis as well as treatment.

Diagnosis:

The DSM-5 criteria require the presence of a manic episode, while the International Statistical Classification of Diseases 10th edition (ICD-10) needs a manic as well as a depressive episode for diagnosis. The DSM-5 recognizes the bipolar spectrum such as bipolar -II and BP-NOS, while ICD-10 does not.

Recent evidence suggests that youth presenting with chronic irritability are unlikely to have BPD. There is a consensus that DSM criteria implementation can help achieve a diagnosis of BPD accurately. The type of BPD also predicts impairment. Those with BP-1 have a greater functional impairment, more likely to attempt suicide, psychiatric hospitalizations, and also have a greater likelihood of having psychotic symptoms. The other subtypes of BPD are less stable across the lifespan. Please note that longitudinal data has revealed that 25% of BP-II convert to BP-I, and 38% of those with BP-NOS/cyclothymia converted to BP-I/BP-II over four years.

Poor outcomes are associated with early age of onset, low socioeconomic status, and a family history of mood disorders. BPD is highly heritable and hence we should get a careful family history.

Prevalence

The prevalence of BPD is 1 in 200 across the globe, but the rate of subthreshold symptoms is much higher at 4.3%. The rates in the US and other European countries are the same. This was based on a large metanalysis of 12 epidemiological studies and another study comparing Dutch and US patients with BPD. Studies have reported lower rates in Africa and Asia than in other parts of the world.

Phenomenology

The rates of manic symptoms were similar across studies: the most common was increased energy (79%), followed by irritability (77%), and mood lability 76%. Studies revealed 82% recovered from their index mood episode after 2.5 years. There was a high recurrence (63%) 1.5 years after recovery. Age of onset of illness is an important marker indicating earlier onset is associated with greater functional impairment (employment, living independently, marriage and children, and education). There is an earlier age of onset in the US than in Europe, reasons being unclear. The most common comorbid diagnosis is ADHD in children, while substance use disorder is most common in adolescents.

Assessment

Diagnostic interviews should assess core symptoms specific to BPD such as elevated mood, grandiosity, decreased need for sleep, and racing thoughts. Besides, one should review the longitudinal course and spontaneous episodicity. It is important to pay attention to the maternal and paternal family history of psychiatric illness. In the case of ADHD, it is important to ascertain whether hyperactivity and distractibility have occurred in the context of the mood episode.

Treatment

The medication treatment in youth is guided by the phase of the illness. Lithium and the atypical antipsychotics are safe and effective for the short-term management of acute manic and mixed-phase. Some of these include risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, and asenapine. The depressive phase is harder to treat. The combination of olanzapine and fluoxetine is effective in bipolar depression. Lurasidone is also effective for bipolar depression. Quetiapine though efficacious in adults, did not separate from placebo in depressed children and adolescents. Lamotrigine is effective in maintaining euthymic mood in adolescents 13-17 years of age compared with younger children. Meta-analyses have revealed greater efficacy of second-generation antipsychotics compared with anticonvulsants and lithium.

Combinations treatments, such as lithium or divalproex with an atypical antipsychotic, are effective for treating manic symptoms especially if there is a partial response to one agent. Psychosocial interventions must always be included.

Neurobiology

Findings on imaging modalities are similar to adults except the amygdala volumes are smaller in youth compared with controls. The modalities include MRI, Diffusion tensor imaging (DTI), and functional MRI (fMRI).  The findings reveal hyperactivation of the amygdala, prefrontal, and visual system and hyperactivation of the anterior cingulate cortex.

Summary

There has been great progress in the field of childhood psychiatric disorders. There appears to be an international consensus regarding the validity of the DSM criteria for diagnosing BPD in children and adolescents. The prevalence of BP-1 and BP-II is similar in Europe and the US while lower in Asia and Africa. It is important to pay attention to the core symptoms of BPD and longitudinal history and episodicity of mood symptoms in making the diagnosis. It is important to pay attention to family history. Atypical antipsychotics are effective in treatment as monotherapy or in combination with lithium or divalproex in controlling manic/mixed states. Lurasidone (FDA approved 13-17years), olanzapine and fluoxetine combination, and possibly cariprazine (not approved in adolescents but in adults) are helpful in bipolar depression. It is important to monitor for side-effects including metabolic effects and tardive dyskinesia. Always include psychosocial interventions.

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Maintenance treatment of bipolar disorder in adolescents: Review and Meta-analyses

Yee CS et al. Int J Neuropsychopharmacol. 2019 Aug 1; 22 (8):531-540. Doi: 10.1093/ijnp/pyz034.

PMID:31211354

Background

Guidelines for maintenance treatment of juvenile bipolar disorder rely heavily on evidence from adult studies and relatively brief trials in juveniles. This leads to uncertainty about long-term optimal management. This study aimed to systematically review long-term treatment trials for juvenile bipolar disorder.

Methods

This study analyzed data recovered by a systematic literature search using the PRISMA guidelines statement, through 2018, from peer-reviewed reports on pharmacological treatments for juvenile bipolar disorder lasting ≥24 weeks. The inclusion criteria included peer-reviewed published reports of prospective studies (RCTs, uncontrolled trials, and naturalistic studies). The medications included Lithium, anticonvulsants, second-generation antipsychotics, or their combinations prescribed for a minimum of six months. The exclusion criteria were retrospective studies, case reports, chart reviews, and studies lasting less than six months.

Results

Of 13 reports 18.8% were randomized and controlled with 1773 subjects (94.4% BD-I; ages 6.9-15.1 years), lasting 11.7 (6-22) months. Pooled clinical response rates were 66.8% with drugs vs 60.6% in the 3 placebo-control arms (not statistically significant). Apparent efficacy ranked: combined agents >anticonvulsants ≥lithium ≥antipsychotics. Factors favoring response ranked: more attention-deficit/hyperactivity disorder, polytherapy, randomized controlled trial design, nonrecurrence vs response. Adverse events (incidence, 5.50%-28.5%) notably included cognitive dulling, weight gain, and gastrointestinal symptoms; early dropout rates averaged 49.8%.

Conclusions

Pharmacological treatments, including anticonvulsants, lithium, and second-generation antipsychotics, may reduce long-term morbidity in juvenile bipolar disorder. However, study number, quality, and effect magnitude were limited. From the scientific perspective, the results are inconclusive suggesting the need for further well-designed research in this important field.

Clinical Commentary

Bipolar disorder in adolescents is a life long illness and hard to diagnose accurately. Adolescents with BD spend more time symptomatically ill compared to adults. This meta-analysis (first systematic review of its type) was conducted with limited data being available in terms of randomized controlled clinical trials. 9/13 trials had pharmaceutical funding and a positive response raising the possibility of reporting bias.

The trials for each agent were too few to make meaningful comparisons of individual treatments.

Response rates (66.8%) were not statistically significantly greater than the response in the placebo arm of three trials which included (60.6%). The pooled response rates were best for combination treatments such as lamotrigine, lithium, or valproate with a second-generation antipsychotic (SGA). However international guidelines suggest using monotherapy before going to combination therapy. The order of efficacy in this meta-analysis is as follows: combination therapy, anticonvulsants, lithium, and then antipsychotic agents.

Adverse events are reported below in order of frequency.

Cognitive dulling most common 28.5. % of patients

Weight-gain 28%

Nausea and vomiting 25%

Summary

In my opinion, this study is only a guide and we should start with well-established treatments especially those with FDA indications, and then move to strategies that have supportive data but do not have an FDA indication. At this point using standardized adult treatments might be helpful. In females, one needs to be careful using anticonvulsants such as divalproex due to the risk of polycystic ovarian syndrome as well as the possibility of an unplanned pregnancy on divalproex. It is important to note the 50% discontinuation rate due to adverse effects, suggesting the start low and go-slow strategy for medication titration.

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Lamotrigine: Preventive effects in bipolar II versus bipolar I disorder

Terao T. et al.  J Clin Psychiatry Sept/Oct 2017; 78(8): e1000-e1005. doi:10.4088/JCP.16m11404 [Epub ahead of print]

PMID 28817765

Background

The preventive effects of mood stabilizers on recurrence/relapse in bipolar disorders have been investigated mostly in bipolar I disorder (BPI) patients, with limited reports on bipolar II disorder (BPII) patients. This study was conducted to investigate the preventive effect of lamotrigine on recurrence /relapse in both disease states.

Methods

Data from Japanese patients with a diagnosis of BPI or BPII according to DSM-IV-TR were analyzed in an open-label, noninterventional, naturalistic, prospective post-marketing surveillance study of lamotrigine (N=966). This study was carried out from October 2011 to November 2014, and each patient was observed for 1 year. The time to recurrence/relapse of mood episodes after the commencement of lamotrigine treatment was evaluated as a primary endpoint.

Results

Lamotrigine was associated with a statistically significantly longer time to recurrence/relapse of mood episodes in BPII than in BPI. Lamotrigine also prolonged time to recurrence/relapse of mania-related episodes, including hypomanic episodes, more in BPII than in BPI.

Conclusions

Although the preventive effect of lamotrigine on recurrence/relapse of mood episodes in BPI has been established in a variety of clinical studies, the present study suggests that lamotrigine may be more suitable for maintenance treatment in BPII than in BPI.

Clinical Commentary

The findings that lamotrigine is associated with a longer time to relapse/recurrence in BP-II than BP-1 is interesting. It should be noted that this is a naturalistic study and has no control group. This study included relapse and recurrence as one category for analysis. It should be noted that relapse is the return of symptoms such as mania, hypomania, and depression within the index episode after a period of wellness. Recurrence is an entirely new episode. This study was backed by large sample size (N=966) and a two-year follow-up. It included various combinations of lamotrigine with lithium, valproate, carbamazepine, and antidepressants. There has always been a debate regarding the use of lamotrigine in BP-II patients.

Significantly more BP-I than BP-II patients were also on lithium (47.6% vs 26.3%), valproate (25.1% vs 16.5%), and atypical antipsychotics (51.3 vs 31.6%). The patients on antidepressants were greater in the BP-II group (28% vs 48.9%). The mean lamotrigine dose did not differ significantly between the two groups (B-PI 106 mg/day vs BP-II 136.2 mg/day).

The finding that lamotrigine has significantly better relapse/recurrence prevention for hypomania in BP-II is interesting in addition to the prevention of depressive episodes.

Lamotrigine is FDA approved for the maintenance treatment of bipolar I disorder in adults to delay the occurrence of any mood episode.

Summary

In my opinion, Lamotrigine is an underused drug. Its metabolic side-effect risk is not an issue. Slow titration is needed to prevent the serious drug rash which occurs in 0.08% of patients. Rarely, the rash can progress to Steven Johnson Syndrome. Lamotrigine should be used for maintenance treatment in BP-I and can also be tried in BP-II in combination with mood stabilizers/atypical antipsychotics.

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Recurrence rates in stable bipolar patients after drug discontinuation v. drug maintenance: Review and meta-analysis

Kishi T et al. Psychol Med. 2020 Oct 13; 1-9. doi: 10.1017/S0033291720003505.  [Online ahead of print]

PMID 33046156.

Background

Bipolar disorder (BPD) is a life-long illness needing long-term treatment to prevent a recurrence. This disease state has multiple medical and psychiatric comorbidities. Treatment is discontinued when patients are stable for multiple reasons, such as intolerable medication-related side-effects and frustration of patients for the need to take long-term medication.

This meta-analysis of double-blind, randomized placebo-controlled trials compared recurrence rates in bipolar disorder (BD) patients between antipsychotic/mood stabilizer discontinuation and maintenance groups.

Methods

This Japanese study included a systematic literature search of Embase, PubMed, and CENTRAL databases without language restriction from inception until 22 May 2020. Independent investigators assessed studies and extracted data. The risk ratios (RRs) and numbers needed to benefit or harm (NNTB/NNTH) were calculated. The primary outcome was the recurrence rate of any mood episode at 6 months. Secondary outcomes were recurrence rates of depressive episodes and manic/hypomanic/mixed episodes and all-cause discontinuation at 6 months. This study also investigated these outcomes at 1, 3, 9, 12, 18, and 24 months.

Results

22 studies (n = 5462) were identified with patients receiving aripiprazole, asenapine, divalproex, long-acting injectable (LAI)-aripiprazole, LAI-risperidone, lamotrigine, lithium, olanzapine, paliperidone, or quetiapine. The mean study duration was 64.50 ± 69.35 weeks. The maintenance group demonstrated lower recurrence rates of any mood episode, depressive episodes, and manic/hypomanic/mixed episodes as well as reduced all-cause discontinuation at every observational point. The RRs of recurrence rate at 6 months was 0.61 (39% less) for any mood episode, 0.72 (28% less) for depressive episodes, and 0.45 (55% less) for manic/hypomanic/mixed episodes. The RR for all-cause discontinuation at 6 months was 0.71 (29% less).

Conclusions

Maintaining drug treatment during clinically stable BD prevented recurrence for up to 24 months. Discontinuation of medications for ⩾1 month significantly increased recurrence risk. However, 47.3% of patients who discontinued drugs for 6 months did not experience recurrence.

Clinical Commentary

This study tackles a common and important clinical question. In the clinical world we are often asked "I am well for a year do I still need the medication". These results provide the information to provide an informed answer specifically for any mood, depressive, or manic episode. This study had a large sample in the meta-analysis involving 22 studies.

It is important to note the recurrence estimates were most impressive for manic episodes, followed by any mood episode, followed by a depressive episode. This is compared with those who have discontinued their medications.

It is important to note that 47% of the individuals did not have any recurrence despite discontinuing medications.  

There were no significant differences in outcomes between LAI-SGA v oral medication. The subgroup analyses revealed that LAI-SGA and OSGA were superior to placebo for preventing the recurrence of any mood episode and manic/hypomanic/mixed episodes. The event rate for the recurrence of the depressive episode was lower in the LAI-SGA discontinuation subgroup than the OSGA discontinuation subgroup. This may be because the systemic drug concentration declines gradually in the LAI-SGA group.

This study notes that maintaining on SGAs or mood stabilizers is effective in preventing recurrence over a 24month time-frame. The key finding is discontinuation for greater than 1 month increases the recurrence risk

Summary

Currently, we cannot predict the patients who will have a recurrence off medications from those who don't.  I suggest that the data support long-term therapy (24 months as per this study). In my clinical opinion, LAIs should be used if antipsychotics are prescribed. Monthly visits with patients who have medication adherence issues can help prevent recurrence.  

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Sanjay Gupta, MD
Clinical Professor of Psychiatry, SUNY Buffalo

GME Research Review is a monthly newsletter edited by Sanjay Gupta, MD, Clinical Professor of Psychiatry, SUNY Buffalo. Dr. Gupta selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. 

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Gupta the citation at [email protected]