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The US Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for aripiprazole 2-month, ready-to-use, long-acting injectable, a medication administered for the treatment of schizophrenia in adults and for maintenance monotherapy treatment of bipolar I disorder in adults. It is intended for dosing every 2 months via intramuscular injection in the gluteal muscle.

If approved, it would be the first 2-month LAI antipsychotic indicated for both the treatment of schizophrenia and the maintenance treatment of bipolar I disorder in the United States.

“This is an important milestone in our efforts to offer adult patients with schizophrenia or bipolar I disorder a new option designed to support treatment goals and offer greater flexibility. The trial results reinforce the long-standing efficacy and safety profile of the once-monthly aripiprazole long-acting injectable,” said Johan Luthman, executive vice president, Lundbeck Research & Development.

The 2-month long-acting injectable of aripiprazole in 960 mg and 720 mg prefilled syringes will deliver sustained plasma concentrations similar to that demonstrated in studies with aripiprazole once-monthly long-acting injectable.

“Stability is critical for patients with schizophrenia and bipolar I – which means delaying time to relapse or recurrence and supporting their role as functioning members of their community,” said Robert McQuade, PhD, executive vice president and chief strategy officer of Otsuka Pharmaceutical Development & Commercialization. “As we continue our efforts to bring aripiprazole 2-month to market, we remain committed to our patients and confident that the favorable safety and tolerability profile will be clearly visible.”

The FDA target date for review completion is April 27, 2023.

Visit psychiatrictimes.com regularly for more updates and breaking news.

1. Otsuka and Lundbeck Announce U.S. FDA acceptance of new drug application for aripiprazole 2-month, ready-to-use, long-acting injectable to treat schizophrenia and bipolar I disorder in adults. News release. Business Wire. September 13, 2022. 

https://www.businesswire.com/news/home/20220913005499/en/Otsuka-and-Lundbeck-Announce-U.S.-FDA-Acceptance-of-New-Drug-Application-for-Aripiprazole-2-month-Ready-to-Use-Long-acting-Injectable-to-Treat-Schizophrenia-and-Bipolar-I-Disorder-in-Adults

The FDA has accepted the NDA for aripiprazole 2-month, ready-to-use, long-acting injectable.

NDA for Long-Acting Injectable for Schizophrenia and Bipolar I Accepted

The key takeaways from the roundtable discussion we had that stood out to me after hearing from colleagues is that there is still a fair amount of use of the older medicines out there like lithium. Part of the problem is, however, when we take a look at agents with a low therapeutic index. There is the possibility of no benefit depending on too low a level, or the possibility of serious life-threatening issues with too high a dose; thus the need for monitoring. There is also a need to consider issues based on thyroid function and renal function aside from the litany of thins, including dermatological and central nervous system issues associated with this basic elemental solve.

The use of anticonvulsants also came up. In individuals that may be “self-medicating” with alcohol, some agents like depakote might be more useful in individuals with underlying hostility or explosiveness aimed at potentially harming others. Agents like carbamazepine or divalproex might be useful agents. There was discussion about lamotrigine, but that is a medicine that is also FDA approved for bipolar depressive maintenance. There are several studies where it did not show solid efficacy; additionally, you have to titrate up very gradually to avert the likelihood of Stevens-Johnson syndrome. The possibility of these additional factors might become problematic for individuals, keeping it mind that it certainly could be something useful.

The utilization of atypical antipsychotics has now garnered a bit more attention; certainly, the advent of Seroquel XR (quetiapine) helped lead a charge of taking a look at the malleability associated with atypical antipsychotics prior to that olanzapine combined with fluoxetine would certainly be a consideration. Trying to keep things as simple as possible can be a challenge when mixing in additional medicine. That is where single agents may be worthwhile. With Seroquel XR, unfortunately, 1 out of 2 people feel very sleepy, 1 out of 3 have severe dry mouth. Sometimes, finding the right dose can be difficult. That is where the dosing becomes a little bit trickier. It is a medicine given with food and can give a severe hungover feeling in individuals later on; that is where clinicians may feel reticent.

Latuda (lurasidone) has a decent track record. Unlike Seroquel XR, it should be given with food for it to work well. Otherwise, you only get half the benefit. And then the question is: what does will you need. And sometimes people may experience nausea and sedation associated with the use of the medicine, thereby limiting sometimes the possible full use of the agent. Vraylar (cariprazine) is a newer medicine that does not have the same track record a Latuda based on how long it has been available, but it certainly is one of the few medicines that has a broader spectrum of utilization, not just in the depressive episode but also the manic mixed episode state. That, to a degree, also brings a sense of comfort for clinicians, because Latuda is only approved for bipolar depression. Sometimes clinicians may feel gun-shy: might this medicine activate individuals and flip them over into a manic episode, and, if so, do we really have a sufficient amount of data associated with its use? Vraylar can be given once-daily it is not sedating, not activating, and it has a very long half-life, which means that sometimes people forget to take their medicine, that is ok. The flip side to that, though, side effects might linger for a week. It is a drug that has been well studied in doses even up to 3 times its highest dose. It is currently FDA recommended as not really compromise when it comes to cardiac status and has a placebo like effect on metabolics. It looks quite attractive for individuals where you don’t want gaining weight or having specific issues that might compromise metabolics. The other nice use of that particular medicine is that when patients show up with predominantly depressive symptoms, they will start out at the lowest dose and for the most part stay there. We certainly note that 1.5 mg but up to 3 mg will work there. If patients are having more mixed symptoms that is where the 3 mg dose might be better. If they are having more manic symptoms, that is where 4.5 mg or 6 mg might be a better fit.

Latest entrant in this game is Caplyta (lumateperone). It has a fixed dose of 42 mg and is only indicated for bipolar depression, but it is indicated for bipolar type 1 and type 2, which is interesting because only Seroquel XR and Caplyta have been studied in bipolar 2 patients and you see benefit there. You also note a very clean metabolic profile associated with the medicine. Part of the discussion with the colleagues was taking a look at all of the different options we have, keeping in mind that lithium is the only medication we have that averts suicidality in bipolar disorder. Sometimes patients don’t just respond to one medicine. That is where additional data with other agents are useful.

The important thing is that when we take into consideration bipolar depression, this is a topic that on the surface looks simple but, in reality, can be complex but at the same time training individuals even in the primary care setting to take into consideration these options can help someone so that they are not necessarily lingering in a state in which they are experiencing different difficulties because of financial or interpersonal problem or even the likelihood of suicidality.

Wrapping it all up, there is a current sentiment that we have evolved to the point at which that although some individuals may be treatment refractory and require things including ECT or otherwise. Other modalities like repetitive transcranial magnetic stimulation, intranasal esketamine are not FDA approved in bipolar disorder. It resolves some discussion that ECT-intravenous ketamine might sometimes be useful for some individuals. But the important point is that we have additional tools in our psych-armamentarium and that readily help many individuals in the past that have been mired in suffering and might have experienced additional problems.

Causes like this represent to us the fact that moderate depressive symptoms are not always what they seem. We need to instruct our colleagues and counterparts about the differential associated with depressive symptomatology to take into consideration prior history, family history, and the comorbidity that the induvial experiences, also keeping in mind the aspirational note of what were trying to accomplish: above all, do no harm, and when presenting someone with options, make sure out option list is comprehensive and readily understood.

I appreciate the opportunity of taking part in this didactic experience and the fact that we continue to move down a path in which additional tools are set before us as clinicians. Thank you.

Gus Alva, MD, DFAPA, discusses key takeaways for the management of bipolar disorder.

Clinical Insights Regarding the Management of Bipolar Disorder

I think that this particular clinical history encapsulates some very fascinating points. Among these points might be what our first impression of this case might be, and what types of challenges a patient like this presents when they come into treatment. This is a young female patient of child-bearing age, who, upon speaking about her current symptomatology, one would immediately latch onto the concept that depressive symptoms are in play, as she has had several episodes that look like this. Upon further investigation, it turns out that there might be some mood oscillation in the background, which is a very important point, particularly in the primary care setting but also in the specialist setting. Our patients are not going to be the best historians; that means that sometimes we miss subtle points of import, such as periods of either mood oscillation, excessive activity, decreased need for sleep, irritability, and impulsivity. In the case of our patient, we certainly note that aside from depressive episodes she has had, she has certainly had some mood oscillatory issues that we need to keep in mind.

Some of the red flags to keep in mind include different factors, such as lingering vegetative symptoms. She has been fine with treatment that might actually work for most individuals. She has been exposed to an SSRI agent that has been ramped up sufficiently. We note, however, that as dose was being ramped up, a bit of activation occurred. Sometimes, the thought in mind should be: Are we potentially evoking medication that doesn’t work for our patient as opposed to actually reconsidering the possibility that in our differential of major depressive order that bipolar disorder may not have been captured previously. We know that family history is strongly burdened by the possibility of mood oscillatory states, and this would be indicative of problem. We know that her age and medical comorbidities are of great import. We obviously want to make sure that someone who is already weighing a little extra is not exposed to agents that might pack on more weight, and, as a consequence of that compromise, the possibility of continued use of medications that otherwise would be highly advantageous. We know that when someone walks into clinical setting and say they have been depressed the past 2 weeks, are experiencing vegetative symptoms that are impacting their day-to-day life and interactions with others, we don’t always jump to the conclusion of unipolar depression. DSM-5 stipulates that differential diagnosis of bipolar disorder of depressive episode be kept in mind. Our case her illustrates those very points.

You’ll note that initially she was managed with psychotherapy but then, subsequently, the thought was, are we barking up the wrong tree? Should we seek out some specialty care that was done in appropriate manner. In the past, we would have thought that different types of mood stabilizing medications, which typically would be a but more useful in individual who are experiencing a bit more manic or mixed symptomatology. Sometimes we don’t capture the essence of countering specific problems with an agent that might actually have a profile that is attractive for an individual like our patient.

In the primary care setting, when someone sees a PHQ9 of 18 that designates severe depression. But we now see couched behind that the mood disorder questionnaire as a way of propelling additional dialogue about the possibility of bipolar disorder based on current depressive symptoms the patient is experiences. Obviously, an SSRI would not be the indicated agent to utilize in this patient at this particular juncture, because she has been experiencing more depressive symptoms that are tied in with bipolar disorder. In this case, a mood stabilizer that could have a nice impact on lifting depressive symptoms would probably be of greater benefit, keeping in mind the weight related issues and the fact that she is already diabetic and we don’t want to aggravative underlying metabolic issues. There are also other agents that might actually help out in stabilizing mood, particularly when someone is experiencing a depressive episode. We know that within the family of the antipsychotics would be agents that would address symptomatology that this patient is experiencing. But we want to keep in mind the overall ambulatory state of the individual. if someone is having problems with sleep, they will seek out an agent that helps with sleep but then subsequently might complain that they feel “out of it”; that is where agents that have a profile that is not necessarily evoking too much sedation might be useful. Sometimes, taking a medication with or without food could create an impediment for someone to actually comply with their utilization with the medicine and the dosing associated with the medicine would be of great import. Taking into context the overall profile of these medications based on the data available is also of great aid.

This case illustrated that if it walks, quacks, moves around like a duck, it might well be a chicken. In this case, it is well worth while reconsidering what our diagnosis is and consider the possibility of a mood disorder like bipolar disorder. We noted that at the very least she had had flares with her mood, where she did not need to sleep as much and felt more active and productive. Peering into those periods would be a great benefit for us in solidifying a diagnosis. Ultimately, when we try to get someone on the right trajectory. It is about getting the right questions in front of the person, to be able to unmask underlying issues that may have been in play. Although the lifetime problems for major depressive disorder are far greater than for bipolar disorder with depressive episodes, those of us who manage specialty settings often see individuals who bounce back between different clinicians and are now surprised that some people take 5 to 10 years before right diagnosis is made. This case readily illustrates multiple points that we need to keep in mind and helps solidify the approach that should be held with patients. There is no preset way of diagnosing individuals; our diagnosis can sometimes be fluid. That is why it is so important to look at family history and previous symptomatology, and maybe the possibility of individuals who have been misdiagnosed, having had psychiatric comorbidities that would be indicative of the likelihood of a condition like bipolar disorder.

Dr. Gus Alva shares his initial impressions on this case and treatment approaches to bipolar 1 disorder.

Clinical Impressions From the Patient Case

 Psychiatric Times presents this roundtable on the management of bipolar disorder, a phenomenal dialogue allowing clinicals a perspective regarding current trends and where we may be headed in the future.

This is an interesting case, as we take a look at this 23-year-old female who first comes in to see her psychiatrist with moderate depressive symptoms. At the time of the interview, her chief complaint included feeling like she’s lacking energy, she’s feeling depressed. She’s also reporting difficulty in paying attention, organizing her day, and accomplishing her tasks at work. Notably these symptoms started abruptly. Three weeks early, prior to that, she had been functioning better than usual, requiring very little sleep and getting more accomplished. Of significance, she reported two brief episodes of depression over the past 2 years. Each lasting about 2 months. And although the patient reported these depressive episodes as coming out of the blue, she learned after consulting with her therapist that they were related to significant psychosocial stress, stemming from the loss of her job and the deaths of 2 uncles, both of which were related to the COVID-19 pandemic. The patient reported that she still finds enjoyment talking to friends and socializing and she has hope of finding a new job and she’s constantly looking.

It’s noteworthy to bear in mind that in her first depressive episode she was treated with methylphenidate 25mg titrated up to 50 m and she stated feeling improved on this does with psychotherapy. Her second depressive episode, her does was bumped up to 100 mg which we saw improvement in depression, but she noted she felt a little activated and had trouble sleeping. With her third depressive episode, the therapist and PCP referred the patient over to a psychiatrist. Of great note should be her past psychological history: she was diagnosed with ADHD in middle school, during which time she responded well to methylphenidate. She continued to do well until her college years at which time she began experiencing difficulty falling asleep as well as irritability. At that time, she discontinued methylphenidate and was psychiatric drug free. She found that practicing mindfulness and yoga on a daily basis helped her residual ADHD symptoms. Of note, she had no history of suicidal thoughts or behavior, self-injurious behaviors, psychiatric hospitalization, or problems with substance abuse. Of note, regarding medical comorbidities, she was diagnosed a year earlier with type 2 diabetes, which was managed with metformin 1000 mg twice daily and her hemoglobin A1C was not poorly controlled. She was also diagnosed with high blood pressure 2 years earlier, that is managed by lisinopril 20 mg once daily. We noted that her BMI is 31, which is indicative of obesity. All other lab values were within normal limit. Significantly, her TSH was in the normal range and her urine toxicology screening was negative. Upon further querying of her family history, her maternal grandmother was diagnosed with a nervous breakdown and spent 2 months in a psychiatric hospital in her 30s. Her mother required little sleep, had a history of impulsive spending, and had a history of starting projects that she didn’t finish. The patient’s paternal uncles had a history of depression as well as alcohol abuse. Upon doing assessments, her PHQ9 is indicative of 18 points and her mood questionnaire she scored an 8.

Gus Alva, MD, DFAPA, presents the case of a 23-year-old female diagnosed with bipolar 1 disorder.

Case Presentation: A 23-Year-Old With Bipolar Disorder

Bethanie Simmons-Becil, DNP, MSN, APRN, PMHNP-BC, APHN-BC:

The roundtable discussion was fantastic. There was a variety of different types of providers. We had both psychiatrists, medical doctors, and psychiatric nurse practitioners present, and it was great to see and to hear the different points of view and the styles of treatment from my peers in the community. I really enjoyed being able to provide additional research, especially newer, more relevant research on presenting symptoms and best practices for diagnosing and identifying bipolar in the community. I enjoyed that there was open discussion about medications to use and everybody was very comfortable in sharing their preferred medication and why it was preferred. It was interesting to watch several of the providers kind of raise their eyebrows. That's something new. I might need to try that. It impressed me and it gave me hope for the psychiatric community, specifically for those of us who prescribe in the psychiatric community, just because the more we work together, the better we do for our patients. The more open communication we have as providers, the less stigma there will be associated with bipolar disorder and the more willing patients might potentially be to seek help. Further, for those of us who meet each other in the community and work together, we can also realize that we are not alone in this battle, either, and that we have valuable peers, educated professionals that can support us and work with us to help ensure best outcomes for all of our patients.

As an advanced practice educator, one of the biggest gaps I see in care of patients with bipolar disorder predominantly is consistency of management. There are different styles. Every provider has their own style and treatment and how they work with their patients and there are different types of education. Medical doctors receive very disease-focused education as that's part of the medical model. Whereas nurses receive very holistic patient education regarding symptomology to where it's not necessarily just a diagnosis, but it's all the environmental impact. What I think needs to happen for us in psychiatry is we need to combine those 2 thoughts together. We need to identify that bipolar disorder is truly a medical diagnosis and that it has enough research to support common symptomology and common presentation, which helps with ease of diagnosis. The biggest gap that I find both on the psychiatry side, as well as the nurse practitioner side, is that we tend to prescribe based upon diagnosis. As a prudent prescriber and as someone who loves the work of Dr Stephen Stahl, MD, PhD, and understanding neuroanatomy, we really need to focus our efforts on identifying the presenting symptoms of the individual because not every patient presents the same. If we focus on the presenting symptoms of the individual and we connect that to our knowledge of the brain and to the neuroanatomy and to what neurotransmitter may be in flux for that particular patient, we will prescribe more efficiently.

When a patient is presenting manic or hypomanic, we know that that's rooted in the excess of [dopamine receptor] D2 and D3. You would want to pick a medication that is going to be more focused on D2 and D3 to modulate that and help bring that patient to a more consistent level. Conversely, if you have a patient that is presenting with predominant depressive symptoms, again, we connect that to partially D2 but also serotonin. We pick a medication that modulates both that D2 and that serotonergic aspect so we don't get caught in that trap of, “OK, well, I've diagnosed you with bipolar depression so these are the only 4 medications that are approved for depression,” and those are going to be what I use because it's not a cookie-cutter model. We work in psychiatry at a detriment because there's no lab, there's no scan. There's nothing tangible that I can assess to give a finite diagnosis. It's all based on my perception and patient report. There can be so much variability in that treatment, but if we truly focus on the symptom presentation of that patient, and we tie that to our knowledge of the brain and how those symptoms are evidencing themselves and how they're connected to those changes in the brain–our medication selection is based upon that knowledge. Then, we will be more prudent providers and we will choose medications that are more appropriate for that particular individual, rather than that individual's diagnosis.

I thoroughly enjoyed the event. I was impressed with the professionals that were brought together for the case study, and I thoroughly enjoyed having multiple different perspectives and opinions in the same room because it allowed us to have open, comfortable conversation with our peers about best practice for bipolar patients. I think that moving forward, events like this can significantly improve the consistency in treatment for bipolar disorder, as well as a sense of collegiality among those who work in psychiatry. I think that with these particular types of events, the more they happen, the more attended, the more folks that are willing to take a moment and listen, I think that it will significantly improve not only our experience as psychiatric providers but our clients’ experience that come to us in need. Thank you so much for your time today. I sincerely appreciate the incredible opportunity that I had in moderating this event and being part of future education.

A psychiatric nurse practitioner shares gaps in care in bipolar 1 disorder treatment.

Unmet Needs in Bipolar Disorder Management

Atypical antipsychotics for patients with bipolar disorder are generally indicated, especially those that are FDA [Food and Drug Administration] indicated for treating bipolar mania, depression, or mixed features. When we're talking about someone who is over the age of 65, we know that atypical antipsychotics have a significant amount of black box warnings that can contribute to more cardiovascular issues and falls for this particular population. However, in this particular patient's case, she was effectively maintained on lithium for quite a long time. Right now, we're not so worried about her manic or hypomanic episodes. We're more focused on her depressive episodes. The potential to add on an atypical antipsychotic could be very effective and potentially replace the lithium especially if we use a more advanced medication–a newer medication to treat those particular symptoms so basically that we would be able to replace lithium with an atypical antipsychotic that's able to manage both the mania–hypomania features as well as the depressive features and have less potential for interaction among the medication she's already taking.

At this point in time, there are only 3 or 4 medications on the market that are specifically indicated for bipolar 1 depression. Of those, they are atypical antipsychotics and they also carry that black box warning, especially for those over the age of 65. For this particular patient, in this case, you would want to make sure to choose a medication that will play nicely in the sandbox, so to speak, with the other medications that she has onboard and not potentially increase her risk of adverse drug reactions such as falls or increased UTIs [urinary tract infections] or confusion. When we're talking about medications in that aspect, we also want to think about the symptoms and how they present for this patient. With a history of mania or hypomania or thinking of things when we're talking about neurotransmitters like dopamine receptor D2 and D3 and then serotonin 5-HT2A and 1A and 2C, when we're thinking about those particular neurotransmitters, we want to make sure that we select a medication that is going to work at the root of the patient's presentation. For someone who's presenting with more depressed features, we want to consider a medication that's going to work both on serotonin as well as dopamine so newer medications as Dr. Stephen Stahl, MD, PhD, refers to as “Two Pips and a Rip”. We're talking about aripiprazole, brexpiprazole, and cariprazine. Those medications have less interactive medication profiles where they don't necessarily interact with other meds the patient may be taking. Those might be a better option for this particular patient, considering the metformin, Invokana [canagliflozin], olmesartan, the rosuvastatin and the PRN nitrofurantoin that she's taking.

For patients with bipolar disorder whether it's bipolar 1, 2, or any of the myriad of presentations, we really do have to consider the potential for adverse drug reactions from the medications that we prescribe. Traditional atypical antipsychotics, particularly second-generation, do have a high risk of metabolic side effect. Many of these medications increase insulin resistance, cause increased appetite, which results in weight gain. It can have the potential to affect their circulatory system and their blood pressure and things like that. When you're looking at a patient like this one in the example that already has an established history of diabetes, hypertension, and high cholesterol, you're already kind of pushing out many of the atypical antipsychotics that could potentially be effective for this patient simply because they have the risk to increase these particular issues for this patient. This patient has been well maintained for her diabetes, her hypertension, and her cholesterol issues with the medications that she's been taking for well over 10 years in most cases. You want to make sure that you're selecting a medication that is not going to exacerbate those particular symptoms and make them worse. Again, when you're looking at atypical antipsychotics, especially considering monotherapy, you're going to choose something that has a much cleaner metabolic profile so that you're not potentially causing more complications for the patient.

A psychiatric mental health nurse practitioner shares her approach to treating bipolar 1 disorder and considers the role of comorbidities in shaping treatment selection for patients.

Pharmacological Treatment Considerations for Bipolar Disorder

Bethanie Simmons-Becil, DNP, MSN, APRN, PMHNP-BC, APHN-BC: 

In any mental health diagnosis or any mental health treatment, patient communication and education is incredibly important. Oftentimes, these patients have been to their primary care providers on at least 2 or 3 occasions before they make it to those of us that specialize in psychiatry. We really need to make sure we understand the implications and the ramifications of their disease. A lot of patients are not happy with the diagnosis of bipolar disorder. There's a lot of social stigma involved with bipolar disorder mostly because of social media. We only get to see those folks that have the worst of the worst. It is always a struggle when you tell a patient, especially for the first time, that, “I think that you might have bipolar disorder.” Sometimes, it's important to educate them that bipolar disorder is a functional disease. You don't have to go on disability, you don't have to be out of work. You don't have to give up your life. These are conditions that can be managed and managed well with medication and have little impact over time, especially if you maintain treatment and regular therapy, which is always incredibly helpful. I really encourage my students and my peers to really provide the patient with a true understanding of what bipolar disorder is, which is that it's simply just a modulation, a shifting of moods.

My job in the situation is to one, help them identify when they're having prodromal symptoms when things are starting to crop up and catch them before they come back, become worse, or also help them understand that this is a diagnosis that's wholly their own. They don't have to share this information with anybody else. They don't have to be embarrassed by their situation, and it's helpful for them to have more education and to take it upon themselves, to educate themselves about their disorder. I really enjoy giving handouts and websites for NIMH, the National Institute of Mental Health, or NAMI the National Alliance for Mental Illness. I make sure that they have access to handouts here in my office to kind of educate them on the presenting symptoms and how to kind of catch things before they come about. Also, try to make sure, especially for those that don't have a good support system in their community, to give them references to community support groups, not just NAMI, but also, open group therapy and things that might be more beneficial, especially if they're starting to struggle with social isolation or feeling lonely because of their diagnosis. A lot of it for me is when I'm speaking with someone who has bipolar disorder and may not fully understand their diagnosis, I really try to meet them where they are and give them as much material and education as they're willing to receive just so they know that they can continue to live a normal, functional life.

Bethanie Simmons-Becil, DNP, MSN, APRN, PMHNP-BC, APHN-BC, highlights the importance of patient communication and education when treating bipolar 1 disorder.

Role of Patient Education for Bipolar 1 Disorder Treatment

 Our case presentation today focuses on a 75-year-old female patient who has had a long history of bipolar 1 disorder for about 40 years recently referred for consultation by a fellow psychiatrist at the nursing home due to persistent depressive symptoms. For the last 40 years, she's been effectively maintained on lithium with the dose only recently increased to help with her reported depression. She suffered from a significant tremor as well as some polyuria polydipsia, which then again aggravated her propensity for UTIs [urinary tract infections]. Historically, her lithium levels were stable in the low normal range around 0.6 mEq/L but recently increased about a month ago with the dose increase and an attempt to treat her depressive episodes. Her current lithium level is about 1 mEq/L. Her lithium dosage was decreased to achieve the prior stable level of 0.6 before she came to us. Lithium was then augmented with a little Lamictal or lamotrigine, which was then slowly titrated to 300 mg per day, but unfortunately, she failed to improve. Most recently, she underwent a trial of lurasidone 20 mg every evening with supper, but after about 7 days, she could not tolerate the nausea so then it was discontinued. She has historic diagnosis of diabetes Type 2 for about 30 years. She's being currently treated with Metformin 1000 mg a day and Invokana 300 mg a day. Hypertension for about the last 10 years effectively managed with olmesartan 40 mg a day. High cholesterol for about 40 years, effectively managed with rosuvastatin 40 mg a day and then also a history of frequent and recurrent urinary tract infections, about 5 years ongoing and effectively treated with nitrofurantoin 100 mg or other antibiotics when indicated.

Sadly, this presentation is quite common. As people age, our bodies process medications, and medications that have worked for long periods of time sometimes lose their efficacy as we age. Mostly due to those pharmacodynamic changes where our bodies age, our kidneys and our liver don't just quite function the way they did when we were younger and process things out. There's always a concern when you're using multiple medications on someone in this age range, just for interactions. Most notably in a review of the medications, Invokana itself actually can increase the incidence of polyuria and polydipsia and does have a potential side effect of an increase in urinary tract infections. As a provider, I do have some concerns about that particular medication being on board. Regarding her presentation, the onset of depressive symptoms, especially for a patient who might be within an assisted living facility, this is kind of common. Patients who live in assisted living facilities tend to get distanced from their families and don't have quite as much daily interaction and so an increase in depressive symptoms is quite common. Unfortunately, she's been maintained very well on lithium for quite a long time. It looks like even with the dose adjustment she was doing OK, but the addition of the lamotrigine really didn't help her depression so now we have concerns of what can we add on or what can we take away to help improve her overall outlook? Again, one of those concerns is that she's already got several medications onboard and the risk for polypharmacy among the elderly is always very high, including the potentiated risks of the medications interacting with each other.

Bethanie Simmons-Becil, DNP, MSN, APRN, PMHNP-BC, APHN-BC, presents the case of a 75-year-old female with bipolar 1 disorder and discusses challenges in bipolar disorder treatment.

Patient Case: 75-Year-Old Female With Bipolar 1 Disorder

frequently receive polypharmacy, with up to 20% of patients getting 4 or more bipolar medications.

 Problematic drug-drug interactions occur often, impacting effectiveness or safety. They can be pharmacokinetic or pharmacodynamic. Yet these interactions receive little attention in the various practice guidelines and algorithms for the psychopharmacologic management of bipolar disorder. Some of these will be summarized here and in a subsequent article.

—especially olanzapine, quetiapine, and clozapine—can cause even more weight gain when added to valproate.

Lithium is well known to interfere with the synthesis and release of 

 hormones and, in the brain’s effort to compensate for this, thyroid-stimulating hormone will increase. Periodic monitoring is required. What is not so well known is that carbamazepine (CBZ) decreases T4, possibly by induction of the UGT metabolizing enzyme, which exacerbates or hastens the onset of hypothyroidism.

 Thus, the combination of lithium and CBZ may present additive risks. Quetiapine also has some evidence of causing thyroid dysfunction.1

Lithium and anticonvulsants—especially valproate and CBZ—produce a metabolic-type or action tremor (ie, it is worse when doing an action like extending the arms—similar to benign familial essential tremors and tremors associated with hyperthyroidism, electrolyte abnormalities, and alcohol intoxication and withdrawal). When these medicines are used in combination, the severity or likelihood of tremor increases.

Antipsychotics—especially the older neuroleptics and risperidone/paliperidone—produce 

 (resting tremors—slower than metabolic tremors, rhythmic, typically 4 to 6 beats per second).

 Lithium seems to increase antipsychotic-induced Parkinsonian tremors by a not-well-understood mechanism.

Antipsychotics that raise prolactin (eg, risperidone, paliperidone, and most first-generation antipsychotics) increase osteoporosis risk through a pharmacodynamic effect. For this reason and others, guidelines now recommend routine monitoring of 

 Selective serotonin reuptake inhibitors (SSRIs), which are usually not recommended in bipolar patients but often used, also increase osteopenia by a different mechanism involving serotonin. With use of both agents, one can expect an additive harmful effect on bone metabolism.

CBZ also causes osteoporosis through its effect to induce the metabolism of vitamin D. Thus, the combination of CBZ with the prolactin-inducing antipsychotics or with SSRIs, or all three in combination, may produce additive bone harms over the long term.

 But here’s some good news: Lithium may protect from osteoporosis. The use of lithium in combination with antipsychotics and/or SSRIs could reduce the risk associated with the other agents. Better still: Use lithium alone for your patients with bipolar disorder if you can.

Watch out for drug-drug interactions with combinations involving ziprasidone, haloperidol, citalopram, escitalopram, quetiapine, risperidone, and lithium.

is associate professor of psychiatry at Harvard Medical School and codirector, US Department of Veterans Affairs, National Bipolar Disorder Telehealth Program, in Brockton, Massachusetts. The author reports no conflicts of interest concerning the subject matter of this article.

Possible pharmacodynamic and pharmacokinetic drug-drug interactions that are likely to be clinically relevant and/or frequent in bipolar disorder.

2. Osser DN. Neuroleptic induced pseudoparkinsonism. In: Joseph AB, Young RR, eds. 

Movement Disorders in Neurology and Neuropsychiatry, 2nd Edition

Prolactin monitoring in first-episode psychotic patients.

4. Hindley G, Gall N. QT interval prolongation. In: Taylor DM, Gaughran F, Pillinger T, eds. 

The Maudsley Practice Guidelines for Physical Health Conditions in Psychiatry

Up to 20% of patients with bipolar disorder have 4 or more medications, so it is important to be aware of these common drug-drug interactions.

Drug-Drug Interactions in Patients with Bipolar Disorder

 I really enjoyed the roundtable discussion. I really enjoyed how thorough everybody was. There were a lot of questions about “Well, how did you make the diagnosis of bipolar I? Give me more details about the mania. Flesh out the case for me.” I would not want to give someone a diagnosis of bipolar I, which is a lifelong disorder, without knowing exactly what they've been through, and I thought that was nice. People talked about dilution of care and how quick encounters where patients are not given the time that they need is not a good thing, and I agree. People also talked about how important it is to educate patients and work with them and establish that nice rapport that makes you know your doctor is on your side. Your doctor is really trying to get you to be functional and happy. I also thought it was interesting that you have people who are willing to start with atypical second-generation antipsychotics and people who are willing to start with lithium, and I'd say the room was evenly split. That probably indicates that the trends in treatment of bipolar disorder are changing throughout our country.

Dr Moukaddam discusses key takeaways for the management of bipolar disorder.

Bipolar I Disorder