John Beyer, MD. Professor of psychiatry, Duke University Medical Center. Durham, NC. Dr. Beyer has consulted for Express Scripts. Relevant financial relationships listed for the author have been mitigated.
CGPR: Bipolar depression is one of the most difficult conditions to treat in psychiatry. Older adults seem to have more treatment-refractory symptoms, especially if they have comorbid cognitive impairment. What medications are approved to treat bipolar depression, and how do you choose among them?
Dr. Beyer: If we were having this discussion about 20 years ago, the options to treat bipolar depression would be very limited: electroconvulsive therapy (ECT), an antidepressant plus lithium, or lithium by itself. But now, we have five medications with FDA approval for bipolar depression: the combination of olanzapine and fluoxetine, quetiapine, lurasidone, cariprazine, and lumateperone. We also have a lot of experience in using other medications for this indication. One challenge in treating older adults with bipolar disorder (BD) is that they have often tried many treatment options. They may have medication regimens or medical comorbidities that prohibit the use of certain medications. The number one question I ask my patients is whether they have responded to a certain medication in the past. If they have, then I will prioritize that option. Often, a patient in a depressive episode may note that their current treatment has been very helpful overall, though it is not currently covering their mood instability. In these cases, I may focus on augmentation strategies to treat the current symptoms.
CGPR: In a treatment-naïve older adult, which medications do you try first to treat bipolar depression?
Dr. Beyer: Evidence-based treatment for bipolar depression in older adults is limited. The largest samples are derived from sub-analyses of the registration trials. Thus, the best data for initial treatment monotherapy in older adults support the use of quetiapine and lurasidone. In the case of lurasidone, we have 142 patients over the age of 55, and we have about 72 patients in the clinical trials with quetiapine above the age of 55 (Sajatovic M et al, J Clin Psychiatry 2016;77(10):e1324–e1331). The good news is that the older adult group appears to have responded about as well as the younger adult group (Sajatovic M et al, J Bipolar Disord 2008;10(6):662–671).
CGPR: How do you titrate quetiapine in older adults?
Dr. Beyer: Initially, I start at a dose of 100 mg, and then I increase every few days by 50–100 mg. In the clinical trials, the quetiapine target dose was 300 mg and 600 mg (average dose was 550 mg). These doses may have significant sedative effects in our older group. In our clinic, we often find that older adults respond to lower doses, so I aim toward 300 mg.
CGPR: When patients don’t respond to your first-line treatment, do you switch or augment?
Dr. Beyer: After a first monotherapy failure, I would prefer to switch. However, after two monotherapy trials fail, I focus on augmentation strategies. Most patients have already been diagnosed and treated for their BD; when they present in an episode, we are beyond the first-line treatment options. In these cases, I am often at the augmentation step. The primary augmentation strategies begin with consideration of lithium or valproate, since there is a lot of clinical and research experience with these medications. Using a combination of a mood stabilizer with a second-generation antipsychotic makes sense. Older adults are probably more sensitive to side effects, and a more conservative management technique—if they are not in acute distress—is probably the best treatment.
CGPR: Can you go through the other three FDA-approved treatments for bipolar depression and why they are lower on your algorithm?
Dr. Beyer: We have limited data for the combination of olanzapine and fluoxetine, in part because the combination arm in the initial study was fairly small. But the data suggest that those over the age of 55 also responded well to this combination. It is an underused option for the treatment of older adults with bipolar depression. As for the use of cariprazine and lumateperone, we are waiting for the sub-analyses on older adults from the registration trials.
CGPR: Are there any advantages to the newer medications for bipolar depression? Efficacy-wise, it doesn’t sound like they beat out the others.
Dr. Beyer: Ziprasidone’s and aripiprazole’s FDA trials did not show a differentiation from placebo. The hope was that these medications would show that the newer class of second-generation medications may be effective for bipolar depression but with fewer metabolic side effects than earlier second-generation medications like quetiapine or olanzapine. Lurasidone, cariprazine, and lumateperone seem to have improved tolerability. Hopefully, we will also be able to confirm their effectiveness.
CGPR: When do you use lithium or lamotrigine as monotherapy for bipolar depression in older adults?
Dr. Beyer: Lithium is the gold standard for the treatment of BD. Unfortunately, while we have a large amount of data about its use in manic episodes, we have a much smaller database about its use in bipolar depression. Many of the clinical trials for newer medications used lithium as an augmentation agent, thus allowing us good confidence for what our practice has long been. Thus, in many expert guidelines, lithium augmentation for bipolar depression are often more highly recommended than lithium monotherapy treatment. Similarly, valproate and lamotrigine, often considered more conventional “mood stabilizers,” are also considered second-line monotherapy options for bipolar depression. In the lamotrigine registration trials, both lithium and lamotrigine showed good efficacy in preventing recurrence of illness. Lamotrigine appeared better at preventing depression relapses, while lithium appeared better at preventing mania relapses.
CGPR: Older adults often have medical comorbidities. Which ones do you pay attention to when thinking about mood stabilizers?
Dr. Beyer: Most older adults have four or five significant medical comorbidities. Further, older adults commonly take five to 10 medications for a variety of illnesses or health maintenance, thus complicating medication regimens. Adding medications to this vulnerable population is something we should take very seriously, which is why monotherapy is preferable. For patients taking lithium, we want to be thoughtful about kidney disease and thyroid disease, as rates are higher in older adults and may limit lithium’s use. Older adults taking lithium are also at higher risk of dehydration and lithium toxicity. We should also be thoughtful about metabolic problems that antipsychotic medications can cause. If I have patients who are obese, or who have cardiovascular disease or type II diabetes, I’m more concerned about the use of early second-generation antipsychotics such as quetiapine or olanzapine.
CGPR: Do you monitor at the same frequency when prescribing a mood stabilizer in older adults?
Dr. Beyer: That decision is determined less by age and more by health or medical frailty. If I have a fairly healthy older adult, I do not make significant changes in the recommended monitoring practices. However, if an older adult has a history of cardiovascular disease, I will check an ECG if I’m considering lithium. Further, if an older adult on lithium shows early kidney disease, I will monitor kidney function more often. Otherwise, I just make sure that we follow the recommendations of either the American Diabetic Association or the American Psychiatric Association, taking into account the patient’s underlying health concerns.
CGPR: I’ve had patients who were stable on lithium for decades, but then had to come off lithium and relapsed. I sometimes wonder whether they could have remained on lithium with closer collaboration with a specialist. Could you tell us about the contraindications to prescribing lithium and how to minimize some of them?
Dr. Beyer: Lithium can affect the kidneys, so we need to pay attention to patients with kidney disease, volume and electrolyte imbalances, or orthostatic hypotension. If a patient has mild kidney disease, they do not necessarily have to stop lithium. Rather, we monitor their creatinine levels and/or glomerular filtration rate more closely. Significant kidney disease is a relative contraindication for using lithium. Also, thyroid goiters or hypothyroidism are often associated with lithium use. Thyroid function must be monitored within the first six months of starting lithium, and at least every 6–12 months afterward. If there is underlying thyroid disease, you may need to work with the patient’s endocrinologist. Other relative contraindications include psoriasis, a condition that lithium can exacerbate.
CGPR: At what creatinine level do you start to worry?
Dr. Beyer: Long-term lithium use is often associated with chronic kidney disease. For the most part this is mild, but it can progress to end-stage kidney disease. More careful attention and monitoring should be given when a patient’s creatinine reaches 1.3–1.5 mg/dL. In our research protocols with lithium, we will withdraw participation if a patient’s creatinine level reaches 2.0 mg/dL. We should not forget to monitor for polyuria and nephrogenic diabetes insipidus, two other kidney effects caused by lithium.
CGPR: Do you use antidepressants together with mood stabilizers or antipsychotics in refractory bipolar depression?
Dr. Beyer: The reality in clinical practice is that antidepressants are the most frequently prescribed class of medications for patients with bipolar depression. However, the data suggest that we should be more discriminating about our use of antidepressants with either mood stabilizers or antipsychotics. The combination of olanzapine and fluoxetine has been shown to be beneficial, but this is the only antidepressant that has received FDA approval—and only as a combination therapy. There are very limited data about the efficacy of most antidepressants in bipolar depression, and the data we have are mixed. We also want to avoid doing harm. We may do harm if we’re treating a patient with mixed features or with rapid-cycling BD with an antidepressant. We may also be doing harm if we treat a patient with an antidepressant without a mood stabilizer. The use of antidepressants is complicated. I believe they have a role in bipolar depression, but they are not a first-line, second-line, or even third-line treatment option.
CGPR: Does the use of antidepressants increase the rates of switching to mania or rapid cycling as patients age?
Dr. Beyer: The rate of switching to mania or hypomania is definitely increased in patients taking antidepressants. The rate is probably also increased in patients who have taken antidepressants in the past. Patients who have had greater exposure to antidepressants, especially without a mood stabilizer, have a greater sensitivity to rapid cycling and switching later in life.
CGPR: If you inherited a stable patient on lithium and an SSRI, would you taper off the SSRI?
Dr. Beyer: This decision is made on a case-by-case basis, taking into consideration a patient’s symptom history, past treatment responses, and current presentation. I probably would not change the antidepressant until I understand what that medication is doing in their maintenance treatment. In general, we find that if we taper a patient with BD off an antidepressant too quickly, we have a higher likelihood of causing depressive episodes to return. Still, we want to avoid unneeded medications long term. We would like to observe stability over at least 9–12 months before considering medication changes. Some older adults do better when they have an antidepressant medication, and others will do worse with more cycling.
CGPR: You mentioned “switching” versus “augmenting,” and I want to throw in a third option of ECT. At what point do you think about ECT rather than another medication trial or augmentation?
Dr. Beyer: ECT remains one of the most effective and powerful treatments for both unipolar and bipolar depression. If the patient is so severely depressed that they are not functioning, and if they have not been able to tolerate medications or participate in their treatment, ECT may be the primary option. In general, ECT tends to be a third-line treatment (often after four or five trials). A lot depends on how quickly an intervention needs to be done. Depression is a terrible illness, and it weighs not only on the patient but also on the family.
CGPR: What about transcranial magnetic stimulation (TMS) for treating bipolar depression in older adults?
Dr. Beyer: There is not as much information about TMS in older adults with bipolar depression. It is often a time-intensive treatment, and patients have to be able to receive it on a regular basis. It appears to be effective if patients have failed one antidepressant trial in unipolar depression. In my algorithm, I tend to put it below ECT. But the data suggest that it might be a reasonable approach for patients earlier on, depending on accessibility and the patient’s desire, as well as medical comorbidities. It is a safer option than ECT, and the only absolute contraindication to TMS is the presence of metal implants in close proximity to the TMS coil.
CGPR: What additional treatments do you discuss with older patients with bipolar depression?
Dr. Beyer: With all my older depressed patients, I discuss the role of exercise in their treatment. If a patient can walk one mile a day, that is a good first treatment step and prognostic sign for recovery. Additionally, I recommend a Mediterranean diet for patients struggling with continued mood instability. I also discuss the importance of meaningful activities and a stable daily sleep/wake schedule, as well as limiting alcohol and substance use.
CGPR: We spoke a lot about bipolar depression. How do you treat mania in older adults?
Dr. Beyer: We have good data in mania, especially for our older adult bipolar group. Lithium is a fantastic medication and probably the most effective treatment of mania. Both lithium and valproate are very effective treatments for bipolar mania in older adults (Young RC et al, Am J Psychiatry 2017;174(11):1086–1093). Lithium is probably a little more effective than valproate, but it is less well tolerated. There are also now 14 medications that have FDA approval for the treatment of mania, mostly atypical antipsychotics. While there have not been studies powered to identify the “best” medication, we have good evidence that all are effective compared to placebo and many are comparable to lithium.
CGPR: Is there anything in the research pipeline we should know about?
Dr. Beyer: We’re anticipating that brexpiprazole may submit clinical trial data for consideration of FDA approval in bipolar depression within the next year. There are also ongoing studies with ketamine and its use in bipolar depression.
CGPR: Thank you for your time, Dr. Beyer.
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